portfolio 2016 - nlcg.ru · portfolio 2016. Services NGS General Panels NGS Specific Panels...

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folio

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Services

NGS General Panels

NGS Specific Panels

Hypertrophic Cardiomyopathy Basic Panel Extended PanelDilated CardiomyopathyArrhythmogenic CardiomyopathyNon-Compaction CardiomyopathyRestrictive CardiomyopathyRASopathies (Noonan, LEOPARD, Costello)

17 genes104 genes

96 genes21 genes37 genes20 genes18 genes

Aortic DiseasesCongenital Heart Diseases SNP arraysSkeletal MyopathyHereditary Hemorrhagic TelangiectasiaPulmonary HypertensionFabry DiseaseFamilial Amyloidosis

35 genes114 genes

57 genes9 genes

16 genes1 gene1 gene

Long QT Syndrome Basic Panel Extended PanelShort QT SyndromeCatecholaminergic Polymorphic Ventricular TachycardiaBrugada Syndrome_J Wave SyndromeCardiac Conduction DiseaseAtrial Fibrillation

8 genes28 genes

7 genes9 genes

25 genes34 genes43 genes

380 genes173 genes218 genes

77 genes

Cardiovascular Diseases General PanelCardiomyopathies General PanelArrhythmias General PanelVentricular Arrhythmia & Sudden Death panel without Structural Heart Disease General Panel

Clinical exome

NGS sequencing DNA-seq RNA-seqSanger sequencing Genes associated with familial cardiopathies

Custom services

The most complete study of the most clinically relevant genome fraction Clinical Exome ISequencing + FASTQ Clinical Exome IISequencing + FASTQ + variant annotation Clinical Exome IIISequencing + FASTQ + variant annotation and interpretation

Mitochondrial disease

Whole mitochondrial genome and nuclear gene sequencing

Molecular cytogenetic testing based on whole- genome microarrays: It provides a high-resolution approach It allows for the analysis of CNV (number of DNA copies), LOH (loss of heterozygosity), or IBD variants (identical-by-descent segments)

SequencingMicroarrays

Painéis Health in Code Health in Code (HIC) is a biotechnology company with an international scope which is built up from years of clinical experience and worldwide scientific collaborations. The company specializes in genetic diagnosis of inherited cardiovascular diseases and in the interpretation of mutations, allowing clinicians to perform individualized medicine with the support that genetic research provides. We believe in continuous innovation, development, and constant improvement of our portfolio and clinical reports.

We work with cutting-edge technology

Our laboratory is equipped with NGS systems, a cutting-edge technology for genetic sequencing. The company has made a significant effort in automating key laboratory processes (in regard to equipment and software) in order to ensure their traceability and minimize human errors.

We offer complete panels

HIC panels include all the genes described in clinical practice guidelines, plus those that have been associated with disease in the literature; they also include “candidate” genes—whose function might be related to the development of a disease. We offer panels based on our own and our partners’ clinical experience and designed to suit the demands of our clients.

The clinical report – our true value

We have developed a unique database that collects all clinical information on studied cardiovascular diseases (about 100,000 individuals) as well as information coming from our partner research groups. This database is fundamental for creating detailed reports that contain all available clinical data on the detected mutations. The quality and implications of this information are evaluated by in-house experts (cardiologists, clinical geneticists, bioinformaticians, and molecular biologists) who provide essential information concerning practical applications as well as recommendations for the clinical management of the patient. Health in Code provides the physician with the necessary tools and information to make the best decisions based on the available knowledge on each mutation detected in the patient. It does not substi-tute evaluation by a physician under any circumstances.

Team

We are a multidisciplinary team that includes, among others, cardiologists, biologists, geneticists, documentalists, nurses, epidemiologists, and bioinformaticians. Collaborating with various research groups and consulting a network of international experts—our scientific advisors—is essential for the development of our product. This allows us to offer services of the highest quality based on the most accurate and current knowledge.

Where can you find us?

Contact us at [email protected] Communication with our clients is important. Our experienced cardiologists—specialists in inherited cardiovascular diseases—are available at any time to help you solve any possible inquiries about the interpretation and implications of the provided test results.

Health in Code Team,

[email protected]: +34 881 60 00 03 F: +34 981 16 70 93

ISO 9001 - ISO 14001 - Acreditado por la Xunta de Galicia (Reg. C-15-002226) Registrado en GeneTests de NCBI

www.healthincode.com

Health in Code:

General Panels

Cardiovascular Diseases General Panel

Diseases involved: Cardiomyopathies, channelopathies and cardiac arrhythmias, congenital heart diseases, aortic vascular diseases, skeletal myopathy, dyslipidemias and early atherosclerosis, and pulmonary hypertension.

Indication for genetic testing:

• This panel includes all genes associated or potentially associated with the development of inherited cardiovascular diseases as well as genes associated with increased global/general cardiovascular risk.

• It covers a group of heterogeneous diseases, and genetic testing allows for the differential diagnosis between them. It is also useful when a multigenic etiology is suspected.

• It should be considered when an exhaustive study of all genes related to cardiovascular pathologies is intended, especially in cases of sudden death where clinical or pathological information is incomplete or the diagnosis is unclear.

• As for research, it is an attractive alternative to the exomes because it includes both genes with proven pathogenicity and candidate genes. The study ensures maximum yield with adequate coverages (which allows for assessing structural variants, such as large deletions and duplications).

• It includes all genes associated with cardiomyopathies and their differential diagnoses, cardiac arrhythmias, early atherosclerosis (dyslipidemias), and aortic diseases. It includes priority genes with a clear association with these diseases, secondary genes where the evidence is lower, and candidate genes (interesting for research projects).

Health in Code General Panel

380 genesCardiovascular Diseases General Panel

380 Genes

www.healthincode.com [email protected]

Priority genes: Genes where there is sufficient evidence (clinical and functional) to consider them as associated with the disease; they are included in clinical practice guidelines. Secondary genes: Genes related to the disease but with a lower level of evidence or constituting sporadic cases. *Candidate genes: Without sufficient evidence in humans but potentially associated with the disease.

03/2016

ACTC1ACVRL1APOBBAG3BMPR2BRAFCACNA1CCASQ2DESDMDDSC2DSG2DSPELNEMDENGFBN1FLNCGATA4GLAJAG1JUPKCNE1KCNE2KCNH2KCNJ2KCNJ8KCNQ1KRASLAMP2LMNAMYBPC3

MYH7MYL2MYL3NF1NKX2-5PKP2PLNPRKAG2PTPN11RAF1RBM20RYR2SCN1BSCN5ASOS1SOS2TAZTGFBR2TMEM43TNNC1TNNI3TNNT2TPM1TTNTTRA2ML1AARS2ABCA1ABCB1ABCC9ABCG1ABCG5

ABCG8ACAD9ACADVLACTA1ACTA2ACTN2ACVR1ACVR2BADAMTS2ADAMTSL4AGKAGLAGPAT2AKAP9AKT2ALMS1AMPD1ANGPTL3ANK2ANKRD1ANO5APOA1APOA5APOC2APOC3APOEASPHATP5EATP7AATPAF2B3GAT3B4GALT7

BLKBMP10BMPR1ABMPR1BBSCL2CACNA1DCACNA2D1CACNB2CALM1CALM2CALM3CALR3CAPN3CAV1CAV3CBLCBSCELCETPCFC1CH25HCHD7CHRM2CHST14CIDECCITED2COA5COA6COL1A1COL1A2COL3A1COL5A1

COL5A2COL7A1COQ2COX15COX6B1CPT2CREBBPCRELD1CRYABCSRP3CTNNA3CYP2D6CYP3A4CYP3A5DLDDNAJC19DOLKDTNAEFEMP2EHMT1EIF2AK3EIF2AK4ELAC2EP300EVCEYA4FAHFBN2FHL1FHL2FHOD3FKBP14

FKRPFKTNFLNAFOXC1FOXD4FOXF1FOXH1FOXP1FOXP3FOXRED1FXNGAAGATA5GATA6GATAD1GCKGDF1GDF2GFM1GJA1GJA5GLB1GLIS3GNPTABGPD1GPD1LGPIHBP1GUSBHAND2HCN4HFEHNF1A

HNF1BHNF4AHRASIER3IP1INSINSIG2INSRIRX4ISL1JPH2KANSL1KCND2KCND3KCNE5KCNE3KCNJ11KCNJ5KCNK17KLF11KMT2DLAMA2LAMA4LCATLDB3LDLRAP1LEFTY2LEPLIASLIPALIPCLMF1LPA

LPLLRP6LZTR1MAP2K1MAP2K2MCTP2MED12MED13LMEF2AMFAP5MIB1MLYCDMRPL3MRPL44MRPS22MTO1MTTPMURCMYH11MYH6MYLIPMYLKMYOM1MYOTMYOZ2MYPNNEBLNEUROD1NEUROG3NEXNNKX2-6NNT

NODALNOTCH2NOTCH3NPC1L1NPHP4NRASOBSCNPAX4PCDH15PCSK9PDGFRAPDHA1PDX1PHKA1PITX2PLIN1PLOD1PLTPPMM2PNPLA2PPARAPPARGPRDM16PRKG1PSEN1PSEN2PTF1APYGMRANGRFRASA1RASA2RFX6

RIT1RRASRYR1SALL4SAR1BSCARB1SCN10ASCN2BSCN3BSCN4BSCO2SDHASGCDSHOC2SKISLC22A5SLC22A8SLC25A3SLC25A4SLC25A40SLC2A10SLC2A2SLC39A13SLCO1B1SLMAPSMAD1SMAD3SMAD4SMAD6SMAD9SNTA1SPEG

SPRED1SURF1SYNE1SYNE2TAB2TBC1D4TBX1TBX20TBX5TCAPTDGF1TFAP2BTGFB2TGFB3TGFBR1TMEM70TMPOTNNI3KTOPBP1TOR1AIP1TRDNTRIB1TRIM63TRPM4TSFMTXNRD2UPF3B VCLWFS1XKZDHHC9ZFPM2

ZIC3ZMPSTE24LDLRANK3*CTNNB1*DNM1L*FGF12*GREM2*IDH2*ILK*IRX3*KCNA5*KCNK3*KLF10*MYLK2*NOS1AP*NOTCH1*NPPA*OBSL1*OPA3*PDLIM3*PERP*PKP4*PPP1R13L*PTRF*SGCA*SGCB*ZFHX3*

General Panels

Cardiomyopathies General Panel

Diseases involved: It covers the entire spectrum of cardiomyopathy presentations (hypertrophic, dilated, restrictive, arrhythmogenic, and non-compaction). It also includes RASopathies, storage diseases, and some mitochondrial disorders of nuclear DNA origin, which may present a cardiomyopathy as one of the main manifestations.


This panel is aimed at the diagnosis of cases presenting some degree of myocardial involvement, but where the phenotype is not completely clear or there are some diagnostic uncertainties. It should also be considered when there is overlapping between phenotypes either in the patient or in the family, which is not infrequent in clinical practice. It is useful since:

• The genetic study allows confirming the clinical suspicion and is also an important tool for differential diagnosis of the disease.

• Proper and correct diagnosis of the disease allows for risk stratification.

• When a pathogenic mutation is detected, it can be used as a predictive test. It is useful for genetic counselling, since it allows detecting carriers at risk who should undergo appropriate clinical monitoring.

• It includes 173 genes covering the whole presentation spectrum of cardiomyopathies (hypertrophic, dilated, restrictive, and non-compaction), also including RASopathies, storage diseases, and congenital heart diseases.

• It includes priority genes that have a clear association with the development of these diseases. It also includes secondary genes, which have sporadically been associated to them, as well as candidate genes gathered from a systematic review of the literature.


173 genesCardiomyopathies General Panel


173 Genes

www.healthincode.com [email protected] 03/2016

ACTC1BAG3DESDMDDSC2DSG2DSPEMDFLNCGLAJUPLAMP2LMNAMYBPC3MYH7

MYL2MYL3PKP2PLNPRKAG2PTPN11RBM20TAZTMEM43TNNC1TNNI3TNNT2TPM1TTNTTR

A2ML1AARS2ABCC9ACAD9ACADVLACTA1ACTN2AGKAGLAGPAT2ALMS1ANK2ANKRD1ANO5ATP5E

ATPAF2BRAFBSCL2CALR3CAV3CHRM2COA5COA6COL7A1COQ2COX15COX6B1CRYABCSRP3CTNNA3

DLDDNAJC19DOLKDTNAELAC2EYA4FAHFHL1FHL2FHOD3FKRPFKTNFOXD4FOXRED1FXN

GAAGATA4GATA6GATAD1GFM1GLB1GNPTABGUSBHCN4HFEHRASJPH2KRASLAMA2LAMA4

LDB3LIASLZTR1MAP2K1MAP2K2MIB1MLYCDMRPL3MRPL44MRPS22MTO1MURCMYH6MYOM1MYOT

MYOZ2MYPNNEBLNEXNNF1NKX2-5NNTNRASOBSCNPDHA1PHKA1PMM2PRDM16PSEN1PSEN2

RAF1RASA2RIT1RRASRYR2SCN5ASCO2SDHASGCDSHOC2SLC22A5SLC25A3SLC25A4SOS1SOS2

SPEGSPRED1SURF1SYNE1SYNE2TBX20TCAPTGFB3TMEM70TMPOTOR1AIP1TRIM63TSFMTXNRD2VCL

XKCASQ2*CTNNB1*DNM1L*GATA5*IDH2*ILK*KCNH2*KCNJ2*KCNJ8*KCNQ1*KLF10*MYLK2*NOTCH1*OBSL1*

OPA3*PDLIM3*PERP*PKP4*PPP1R13L*SGCA*SGCB*TNNI3K*

General Panels

Arrhythmias General Panel

Diseases involved: It includes all diseases that can produce arrhythmias (high predisposition to sudden death), either with or without the presence of structural heart disease. As such, it includes all cardiomyopathies, channelopathies, and cardiac conduction diseases.


• This panel is mainly aimed at the diagnosis of cases where it is not possible to establish a clearly defined phenotype, but where cardiac arrhythmias are the main manifestation.

• It is mainly intended for subjects with personal or familial history of sudden death with unknown origin or subjects with ventricular fibrillation of unknown origin that meet the above-mentioned characteristics.

• It includes priority genes with a clear association with these diseases, secondary genes where the evidence is lower, and candidate genes gathered from a systematic literature review.


218 genesArrhythmias General Panel


218 Genes


ACTC1BAG3BRAFCACNA1CCASQ2DESDMDDSC2DSG2DSPEMDFLNCGLAJUPKCNE1KCNE2KCNH2KCNJ2KCNJ8

KCNQ1KRASLAMP2LMNAMYBPC3MYH7MYL2MYL3NF1PKP2PLNPRKAG2PTPN11RAF1RBM20RYR2SCN1BSCN5ASOS1

SOS2TAZTMEM43TNNC1TNNI3TNNT2TPM1TTNTTRA2ML1AARS2ABCC9ACAD9ACADVLACTA1ACTN2AGKAGLAGPAT2

AKAP9ALMS1ANK2ANKRD1ANO5ATP5EATPAF2BSCL2CACNA1DCACNA2D1CACNB2CALM1CALM2CALM3CALR3CAPN3CAV3CHRM2COA5

COA6COL7A1COQ2COX15COX6B1CRYABCSRP3CTNNA3DLDDNAJC19DOLKDTNAELAC2EYA4FAHFHL1FHL2FHOD3FKRP

FKTNFOXD4FOXRED1FXNGAAGATA4GATA6GATAD1GFM1GJA1GJA5GLB1GNPTABGPD1LGUSBHCN4HFEHRASJPH2

KCND2KCND3KCNE5KCNE3KCNJ5KCNK17LAMA2LAMA4LDB3LDLRLIASLZTR1MAP2K1MAP2K2MIB1MLYCDMRPL3MRPL44MRPS22

MTO1MURCMYH6MYOM1MYOTMYOZ2MYPNNEBLNEXNNKX2-5NKX2-6NNTNRASOBSCNPDHA1PHKA1PITX2PMM2PRDM16

PSEN1PSEN2RANGRFRASA2RIT1RRASSCN10ASCN2BSCN3BSCN4BSCO2SDHASGCDSHOC2SLC22A5SLC25A3SLC25A4SLMAPSNTA1

SPEGSPRED1SURF1SYNE1SYNE2TBX20TBX5TCAPTGFB3TMEM70TMPOTNNI3KTOR1AIP1TRDNTRIM63TRPM4TSFMTXNRD2VCL

XKANK3*CTNNB1*DNM1L*FGF12*GATA5*GREM2*IDH2*ILK*IRX3*KCNA5*KCNK3*KLF10*MYH11*MYLK2*NOS1AP*NOTCH1*NPPA*OBSL1*

OPA3*PDLIM3*PERP*PKP4*PPP1R13L*PTRF*SGCA*SGCB*ZFHX3*

General Panels

Ventricular Arrhythmia and Sudden Death without Structural Heart Disease General Panel

Diseases covered: It includes diseases that can cause ventricular arrhythmias and sudden death as their first clinical manifestation. Therefore channelopathies and some genes associated with cardiomyopathies but capable of producing ventricular arrhythmias without any apparent cardiac involvement are included.


• This panel is mainly oriented at diagnosing of phenotypes that present ventricular arrhythmias as a primary manifestation of the disease without apparent structural heart disease and not clearly defined phenotype.

• It is intended for those individuals whose clinical or anatomopathological study does not show structural alterations, and would be the testing of choice in cases of sudden death with negative autopsy.

• It should be especially considered in patients with personal or family history of sudden death, subjects with a history of syncope of undetermined origin, or individuals with idiopathic ventricular fibrillation without structural heart disease.

• This panel includes priority genes that have a clear association with these diseases, secondary genes where there is a lesser degree of evidence, and candidate genes gathered from a systematic literature review.


77 genesVentricular Arrhythmia and Sudden Death without Structural Heart Disease General Panel

77 Genes



03/2016

CACNA1CCASQ2DESDSC2DSG2DSPFLNC

JUPKCNE1KCNE2KCNH2KCNJ2KCNJ8KCNQ1

LMNAPKP2PLNPRKAG2RYR2SCN1BSCN5A

TMEM43TNNC1TNNI3TNNT2ABCC9ACTC1AKAP9

ANK2CACNA1DCACNA2D1CACNB2CALM1CALM2CALM3

CAV3EMDFGF12FHL2GAAGJA5GLA

GPD1LHCN4HFEKCND2KCND3KCNE5KCNE3

KCNJ5KCNK17LAMP2MURCNKX2-5RANGRFSCN10A

SCN2BSCN3BSCN4BSLMAPSNTA1TBX5TNNI3K

TRDNTRPM4TTRANK3*IRX3*KCNA5*LDB3*

MYH6*MYH7*NOS1AP*NPPA*PTRF*SYNE1*SYNE2*

Cardiomyopathies

Yield of genetic testing: 60% The probability of detecting a likely causal mutation in a patient under suspicion of familial hypertrophic cardiomyo-pathy with our basic 17-gene panel is close to 60%, which can be increased by using our extended 104-gene panel. In any case, diagnostic yield depends on multiple variables such as number of relatives affected, clinical suspicion, age, race, institution of origin, etc.

Hypertrophic CardiomyopathyHypertrophic cardiomyopathy (HCM) is a genetic disease characterized by cardiac muscle wall thickening in the absence of an apparent cause. Early diagnosis is important since the disease is associated with a significant risk of sudden death and (other) cardiovascular complications. • The incidence of the disease is approximately 1 in 500 individuals.


The genetic testing is indicated in clinical practice guidelines upon suspicion of the disease: • It allows confirming the clinical suspicion and is also an important tool for differential diagnosis of the disease. • An adequate and correct diagnosis of the disease allows for risk stratification. The identification of the responsible mutation also provides prognostic information about the disease, with our group in the lead of this genetic field.• The test has a predictive value for the disease when a pathogenic mutation is found. It then becomes the basis for genetic counseling, constituting a cost-effective strategy for family monitoring: carriers should undergo appropriate monitoring and risk strati-fication of the disease; non-carriers present the same risk as the general population.

• Our basic HCM panel is indicated as the first diagnostic approach upon clinical suspicion of HCM. • It includes 9 main sarcomeric genes associated with the disease, and it also contains 8 disease-associated genes whose clinical presentation can be indistinguishable from classic HCM (phenocopies).

It includes both the primary sarcomeric genes and all phenocopies of the disease, as well as secondary and candidate genes gathered from a systematic literature review. It is indicated when: • The basic panel study is negative and there is a clear HCM phenotype, since it improves diagnostic yield.• Severe phenotypes or phenotypes associated with syndromes and other rare genetic diseases are detected. • An exhaustive genetic testing of this pathology is intended, since this is the most complete panel for HCM on the market.

104 genes

Health in Code panels

17 genesHypertrophic Cardiomyopathy Panel

Hypertrophic Cardiomyopathy Extended Panel

• Elliott PM, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J. 2014; 35(39):2733-2779. • Gersh BJ, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: A report of the American College of cardiology foundation/American heart association task force on practice guidelines. Circulation. 2011;124(24). • Charron P, Arad M, Monserrat L, et al. Genetic counselling and testing in cardiomyopathies: A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2010;31(22):2715-2728.

Study extension: Other panels that include hypertrophic cardiomyopathy genes

• Cardiovascular Diseases General Panel [380]

• Arrhythmias General Panel [218]• Cardiomyopathies General Panel [173]

17/104 Genes


ACTC1DES

FLNCGLA

LAMP2MYBPC3

MYH7MYL2

MYL3 PLN PRKAG2 PTPN11 TNNC1 TNNI3 TNNT2 TPM1 TTR

ACTC1DESFLNCGLALAMP2MYBPC3MYH7MYL2

MYL3PLNPRKAG2PTPN11TNNC1TNNI3TNNT2TPM1

TTRAARS2ACAD9ACADVLACTA1ACTN2AGKAGL

AGPAT2ANK2ANKRD1ATP5EATPAF2BRAFBSCL2CALR3

CAV3COA5COA6COQ2COX15COX6B1CRYABCSRP3

DLDDSPELAC2FAHFHL1FHL2FHOD3FOXRED1

FXNGAAGFM1GLB1GNPTABGUSBHRASJPH2

KRASLDB3LIASLZTR1MAP2K1MAP2K2MLYCDMRPL3

MRPL44MRPS22MTO1MYH6MYOM1MYOZ2MYPNNEXN

NF1NRASOBSCNPDHA1PHKA1PMM2RAF1SCO2

SHOC2SLC22A5SLC25A3SLC25A4SOS1SURF1TAZTCAP

TMEM70TRIM63TSFMTTNVCLBAG3*CASQ2*IDH2*

KCNJ8*KLF10*LMNA*MURC*MYLK2*OBSL1*PDLIM3*RYR2*

Cardiomyopathies


• This panel includes all genes related to cardiomyopathies and channelopathies.• It is recommended in case of sudden death with an unknown or unclear cause, or where previous findings cannot completely explain the severity of the symptoms. Likewise, it should also be considered in cases where, despite the fact that the patient presented a pre-existing condition, it is suspected that another aggravating genetic cause might exist (for example, the presence of a channelopathy associated with a pre-existing cardiomyopathy).

Arrhythmias General Panel 218 genes

• This panel includes 173 genes covering the whole presentation spectrum of cardiomyopathies (hypertrophic, dilated, restrictive, arrhythmogenic and non-compaction), also including RASopathies, storage diseases, and congenital heart diseases. • This panel is suitable when the patient shows evidence of myocardial affection, but the phenotype is not completely clear or there are some diagnostic uncertainties. It should also be considered when there is overlapping between these phenotypes either in the patient or in the family, which is not infrequent in clinical practice.

Cardiomyopathies General Panel 173 genes

• This panel includes all genes associated or potentially associated with the development of inherited cardiovascular diseases that can present sudden death as a major adverse event.• It includes all genes associated to cardiomyopathies and their differential diagnoses, cardiac arrhythmias, early atherosclerosis (dyslipidemias), and aortic diseases. It includes priority genes with a clear association with the disease, secondary genes where the evidence is lower, and candidate genes (highly interesting panel for research projects).• It should be considered when an exhaustive study of all genes related to cardiovascular pathologies is intended, especially in cases of sudden death where clinical or pathological information is incomplete or the diagnosis is unclear.

Cardiovascular Diseases General Panel 380 genes

Cardiomyopathies

Yield of genetic testing: 50%

The probability of detecting a likely causal mutation of the disease in a patient under suspicion of familial dilated cardiomyopathy is close to 50%. In any case, diagnostic yield depends on multiple variables such as number of relatives affected, clinical suspicion, age, race, origin, etc.

Dilated CardiomyopathyDilated cardiomyopathy (DCM) is a disease characterized by an increase in ventri-cular volume (mainly of the left ventricle) associated with wall thinning and deterioration of systolic function. It is one of the main causes of heart failure and heart transplantation, and it presents a high risk of cardiac sudden death. For many years, the cause was thought to be exclusively autoimmune or viral, where endomyocardial biopsy plays an essential role. However, genetic causes are nowadays known to represent 30%-50% of cases.• The prevalence of the disease was estimated to be 1 in 2,500 individuals, although recent studies suggest that it could be much higher.


The genetic test is indicated when there is a suspicion of familial dilated cardiomyopathy: • It can identify the causal mutation, which confirms the diagnosis of the disease and constitutes an important tool for differential diagnosis since its presentation frequently overlaps with other cardiomyopathies. • Not all mutations in different genes show a similar behavior-they are usually associated with a specific set of symptoms and with a different prognosis. This helps performing the appropriate risk stratification for the disease and foreseeing possible complications.• In case a pathogenic mutation is detected, the test can be used with predictive value, constituting the cornerstone of genetic counseling. It is a cost-effective strategy for family monitoring since it allows detecting carriers at risk who must follow appropriate clinical monitoring (given that they are highly likely to develop the disease in the future). Contrarily, non-carriers present the same risk as the general population.

• This panel is indicated as the first diagnostic approach upon clinical suspicion of familial or idiopathic DCM. • It is the most complete panel on the market for this pathology, including genes that can also be associated with cardiac conduction diseases and/or muscle alterations, both in clinical and subclinical phase. • It includes priority genes recommended in clinical practice guidelines and clearly associated with this disease. Sporadically associated secondary genes are also included, along with candidate genes gathered from a systematic literature review.

Health in Code panel

96 genesDilated Cardiomyopathy Panel

• Charron P, Arad M, Monserrat L, et al. Genetic counselling and testing in cardiomyopathies: A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2010;31(22):2715-2728.• Rapezzi C, et al. Diagnostic work-up in cardiomyopathies: Bridging the gap between clinical phenotypes and final diagnosis. A position statement from the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2013;34(19):1448-1458. • Hershberger RE, MD, Siegfried JD. Clinical and Genetic Issues in Familial Dilated Cardiomyopathy. J. Am Coll Cardiol. 2011 April 19; 57(16): 1641–1649.

Study extension: Other panels that include dilated cardiomyopathy genes

96 Genes




ACTC1BAG3DESDMDDSPFLNCLMNAMYBPC3

MYH7PKP2PLNRBM20TAZTNNC1TNNI3TNNT2

TPM1TTNABCC9ACTA1ACTN2ALMS1ANKRD1ANO5

CAV3CHRM2COL741CRYABCSRP3DNAJC19DOLKDSC2

DSG2EMDEYA4FHL2FHOD3FKRPFKTNFOXD4

GAAGATA4GATA6GATAD1GLB1HFEJUPLAMA2

LAMA4LAMP2LDB3MURCMYH6MYL2MYL3MYOT

MYPNNEBLNEXNPRDM16PSEN1PSEN2RAF1RYR2

SCN5ASDHASGCDSLC22A5SPEGSYNE1SYNE2TBX20

TCAPTMEM43TMPOTOR1AIP1TTRTXNRD2VCLXK

BRAF*DNM1L*GATA5*GLA*IDH2*ILK*KCNJ2*KCNJ8*

NKX2-5*OBSCN*OPA3*PDLIM3*PTPN11*SGCA*SGCB*TNNI3K*

Cardiomyopathies








Cardiomyopathies

Yield of genetic testing: 50%-60%

The probability of detecting a likely causal mutation of the disease in a patient under suspicion of arrhythmogenic cardiomyo-pathy is variable, depending on factors such as geographic location. It is generally around 50%-60%. It is common to find more than one probably pathogenic mutation.

Arrhythmogenic Cardiomyopathy Arrhythmogenic Righ Ventricular Dysplasia

Arrhythmogenic cardiomyopathy (ACM) is an inherited genetic disease characterized by a progressive atrophy of the cardiac muscle, which is replaced by fibroadipose tissue, leading to clinical ventricular dysfunction and to the development of malignant cardiac arrhythmias. Although the disease has been traditionally known as right ventricular arrhythmogenic cardiomyopathy/dysplasia, there can be a concomitant or predominant compromise of the left ventricle. Clinical criteria have been defined for the disease, and the presence of a pathogenic mutation is one of them. Disease detection is important, since it its presence is associated with a significant risk of sudden death, especially in young subjects.• The prevalence of the disease was estimated to be 1 in 5,000 individuals.


The genetic test is indicated upon suspicion of the disease: • It is part of the diagnostic criteria of the disease as well as an important tool for differential diagnosis. • A correct diagnosis of the disease allows for appropriate risk stratification. In addition, the identification of certain types of mutations in some genes provides prognostic information in carriers.• The test has a predictive value for the disease when a pathogenic mutation is found. It is very important for genetic counseling and useful for familial monitoring. It allows identifying the carriers at risk of developing the disease, who must follow appropriate clinical monitoring. It is worth noting that the disease has variable expressivity and penetration, with the presence of additional genetic and/or environmental factors being important in many cases.

• This panel is indicated as the first diagnostic approach upon clinical suspicion of arrhythmogenic cardiomyopathy (patients with possible or borderline diagnosis). • It should also be requested in cases with an established diagnosis of the disease (in case diagnostic criteria are met) in order to facilitate the familial study. • It includes all desmosomal genes, as well as other priority genes that have been clearly associated with the disease. Secondary and candidate genes gathered from a systematic literature review are also included.


21 genesArrhythmogenic Cardiomyopathy Panel

• Charron P, Arad M, Monserrat L, et al. Genetic counselling and testing in cardiomyopathies: A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2010;31(22):2715-2728.• Marcus FI, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/Dysplasia: Proposed modification of the task force criteria. Circulation. 2010;121(13):1533-1541.• Rapezzi C, et al. Diagnostic work-up in cardiomyopathies: Bridging the gap between clinical phenotypes and final diagnosis. A position statement from the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2013;34(19):1448-1458.

Study extension: Other panels that include arrhythmogenic cardiomyopathy genes

21 Genes




DSC2DSG2

DSPFLNC

JUPPKP2

PLNTMEM43

CTNNA3DES

LMNARYR2

TGFB3TTN

CASQ2*CTNNB1*

LDB3* PERP* PKP4* PPP1R13L* SCN5A*

Cardiomyopathies








Cardiomyopathies


The probability of identifying a likely causal mutation in a patient under suspicion of non-compaction cardiomyopathy varies due to the clinical heterogeneity of the disease. The diagnostic yield is higher in cases with a clear phenotype and family history of the disease. It is generally about 50%.

Non-Compaction Cardiomyopathy

Non-compaction cardiomyopathy is a clinically heterogeneous disease, which is charac-terized by the presence of excessively prominent trabeculations in the myocardium accompanied by crypts and a very thin layer of compacted heart muscle. Mutations in genes that are associated with other types of cardiomyopathies (particularly hyper-trophic and dilated) can cause this pathology. However, genes specifically related to non-compaction cardiomyopathy have also been described as well.


The progression of the disease may present deteriorating cardiac function with the development of cardiac insufficiency, as well as malignant arrhythmias. Therefore, early diagnosis is important. Genetic testing is useful since:

• It is able to identify the causal mutation, confirming the diagnosis of the disease. Due to the clinical heterogeneity with much overlap between different phenotypes, it is very important for differential diagnosis.• In case a pathogenic mutation is detected, it can be used as a predictive test. It is useful in genetic counseling since it can detect carriers at risk who should undergo adequate clinical monitoring.

• This panel is indicated as the first diagnostic approach in patients with a clear phenotype of non-compaction cardiomyopathy. It is a panel designed specifically for this pathology. • It includes priority genes, which are genes that have been clearly associated with the disease. Some of them are also associated with other cardiomyopathies. Genes that have been sporadically associated with the disease are listed as secondary genes, and candidate genes gathered from a systematic literature review are also included.


37 genesNon-Compaction Cardiomyopathy Panel

• Rapezzi C, et al. Diagnostic work-up in cardiomyopathies: Bridging the gap between clinical phenotypes and final diagnosis. A position statement from the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2013;34(19):1448-1458. (doi:10.1093/eurheartj/ehs397)• Charron P, Arad M, Monserrat L, et al. Genetic counselling and testing in cardiomyopathies: A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2010;31(22):2715-2728.

Study extension: Other panels that include non-compaction cardiomyopathy genes

• Arrhythmias General Panel [218] Long QT / Short QT / Brugada / Catecholaminergic Polymorphic Ventricular Tachycardia / Cardiac Conduction Disease / Cardiomyopathies

• Cardiomyopathies General Panel [173]Cardiomyopathies (hypertrophic, dilated, non-compaction, restrictive, arrhythmogenic, RASopathies) / Congenital Heart Diseases


Cardiomyopathies / Channelopathies / Congenital Heart Diseases / Aortic Diseases / Skeletal Myopathy / Pulmonary Hypertension / Familial Dyslipidemias

37 Genes


ACTC1MYBPC3MYH7

TAZACTN2DMD

DNAJC19DTNAFHL1

HCN4LDB3LMNA

MIB1MYH6MYL2

NKX2-5NNTPLN

PRDM16RYR2TNNT2

TPM1ANKRD1*BAG3*

CASQ2*CSRP3*DSP*

FLNC*KCNH2*KCNQ1*

MLYCD*MYL3*NOTCH1*

PTPN11*TNNC1*TNNI3*

TTN*

Cardiomyopathies








Cardiomyopathies


The probability of identifying a likely causal mutation in a patient under suspicion of restrictive cardiomyo-pathy is approximately 50%. The diagnostic yield is higher in cases with a clear phenotype and family history of the disease.

Restrictive Cardiomyopathy

Restrictive cardiomyopathy is a heart disease characterized by impaired ventricular filling in the absence of myocardial hypertrophy or significant impairment of systolic function. Patients usually present signs and symptoms of heart failure and increased mortality rate, requiring heart transplantation in many cases. Although many of the genes associated with this disease are associated with other types of cardiomyopa-thies (particularly hypertrophic and dilated), there are some predominantly related to this phenotype.


• It is able to identify the causal mutation, confirming the diagnosis of the disease. Due to the clinical heterogeneity and overlapping of different phenotypes, it is very important for differential diagnosis.• In case a pathogenic mutation is detected, it can be used as a predictive test. It is useful in genetic counseling since it can detect carriers at risk that should be under adequate clinical monitoring.

• This panel is indicated as the first diagnostic approach to a patient with a clear phenotype of restrictive cardiomyopathy, as it has been designed specifically for this condition. • It includes priority genes, which are genes that have been clearly associated with the disease. Some of them are also associated with other cardiomyopathies. • Genes that have been sporadically associated with the disease are listed as secondary genes, and candidate genes gathered from a systematic literature review are also included.


20 genesRestrictive Cardiomyopathy Panel

• Charron P, Arad M, Monserrat L, et al. Genetic counselling and testing in cardiomyopathies: A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2010;31(22):2715-2728. • Rapezzi C, Arbustini E, Caforio A, et al. Diagnostic work-up in cardiomyopathies: Bridging the gap between clinical phenotypes and final diagnosis. A position statement from the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2013;34(19):1448-1458.

Study extension: Other panels that include restrictive cardiomyopathy genes


• Arrhythmias General Panel [218] Long QT / Short QT / Brugada / Catecholaminergic Polymorphic Ventricular Tachycardia / Cardiac Conduction Diseases / Cardiomyopathies



20 Genes


ACTC1DES

GLAMYBPC3

MYH7MYL2

MYL3TNNI3

TNNT2TPM1

TTRFLNC

ACTN2FHL1

HFEMYPN

TNNC1TTN

LMNA*BAG3*

Cardiomyopathies








Cardiomyopathies

• Noonan Syndrome: Judith E Allanson and Amy E Roberts. 2011 August 4. GeneReviews.• Noonan Syndrome: Van der Burgt I. Orphanet J Rare Dis. 2008 June.• Noonan Syndrome with Multiple Lentigines (LEOPARD Syndrome): Bruce D Gelb and Marco Tartaglia. 2015 May 14. GeneReviews. • Costello Syndrome: Karen W Gripp and Angela E Lin. 2012 January 12. GeneReviews. • Legius Syndrome (Neurofibromatosis Type 1-Like Syndrome): David Stevenson, David Viskochil and Rong Mao. 2015 January 15.• Cardiofaciocutaneous Syndrome: Katherine A Rauen. 2012 September 6. GeneReviews.

Yield of genetic testing: >70%

The probability of identifying a causal mutation when a patient has been diagnosed with one of these syndromes is high, over 70% in all cases. It can range from 70%-80% for one mutation or relevant variant in case of Noonan syndrome to 88%-98% in the case of Legius syndrome.

RASopathies Noonan, LEOPARD, Costello

RAS genes play an important role in the mitogen-activated protein kinase-dependent signaling pathway (MAPK), a metabolic pathway that regulates cell proliferation, diffe-rentiation, survival and death or apoptosis. Germinal mutations described in some of these genes cause developmental anomalies in the subject (depending on the affected gene), which often overlap clinically, with an autosomal dominant inheritance pattern. Therefore, all patients share a variable degree of intellectual disability, cardiac anomalies, facial dysmorphism, skin anomalies, and predisposition to develop cancer (RASopathies).• The most widely known pathology in this group is Noonan syndrome, with an estimated incidence between 1/1,000 and 1/2,500 live births.


• Subjects under suspicion or clinical diagnosis of Noonan, LEOPARD, Costello, Legius or cardiofaciocutaneous syndrome. There is frequent clinical overlapping among these syndromes (these patients share a variable degree of intellectual disability, cardiac anomalies, facial dysmorphism, skin anomalies, and predisposition to develop cancer); therefore the genetic study would facilitate differential diagnosis. All these syndromes share an autosomal dominant pattern of inheritance.• Familial study: A search for the mutation previously identified in a proband (relatives of patients with Noonan, LEOPARD, Costello, Legius or cardiofaciocutaneous syndrome, in which a mutation has been previously identified).

• This panel is indicated when there is a suspicion of any RASopathy in the patient, having been specifically designed for this group of symptoms. It includes priority genes, which have been clearly associated with these diseases, and secondary genes, which have been sporadically associated with them.


18 genesRASopathies Panel

Study extension: Other panels that include RASopathies genes


• Hypertrophic Cardiomyopathy Extended Panel [104]

• Cardiomyopathies General Panel [173 ]

Main sarcomeric genes / Phenocopies / Secondary genes / Candidate genes / RASopathies genes

Cardiomyopathies (hypertrophic, dilated, LV non compaction, restrictive, arrhythmogenic, RASopathies) / Congenital Heart Diseases


18 Genes


BRAFKRAS

NF1PTPN11

RAF1SOS1

SOS2A2ML1

HRASLZTR1

MAP2K1 MAP2K2 NRAS RASA2 RIT1 RRAS SHOC2 SPRED1

Cardiomyopathies

It includes both the primary sarcomeric genes and all phenocopies of HCM, as well as secondary and candidate genes gathered from a systematic literature review. It includes all the genes that are included in the RASopathies panel as well. It is indicated when: • There is a clear HCM phenotype in the patient and, although there is a suspicion of RASopathy, this phenotype is not clear. • Severe phenotypes or phenotypes associated with syndromes and other rare genetic diseases are detected. • An exhaustive genetic study of this pathology is intended, since this is the most complete panel for HCM in the market.

Hypertrophic Cardiomyopathy Extended Panel 104 genes






Channelopathies


The yield of genetic testing in correctly characterized subjects is approximately 75%-80%. The clinical specificity of the test is close to 95%. The positive clinical predictive value (possibility of carriers developing the disease throughout their life) depends on the identified variant, with an average of 60%. Around 5% of cases can be carriers of more than one variant in the same or different genes.

Long QT SyndromeLong QT syndrome is a genetic disease associated with abnormal cardiac ion channel function, which manifests itself through the lengthening of the QT interval on the electrocardiogram. This abnormality predisposes to the development of ventricular arrhythmias that can lead to syncope, cardiac arrest and sudden death; these can be the first manifestations of the disease at any age. The transmission pattern is generally autosomal dominant, with the recessive form of the disease being much rarer (Jervell and Lange-Nielsen syndrome, where it is associated with neurosensorial loss of hearing).


• Patients with diagnosed long QT syndrome (Schwartz score >3 or QTc >500 ms).• Patients under clinical suspicion of long QT syndrome:

Asymptomatic subjects with serial ECGs showing QTc values >460 ms (prepubescent) or >480 ms (adults). Subjects with a personal or family history of sudden death. Subjects with a history of syncope of unknown origin. Subjects with ventricular fibrillation of unknown origin.

• Relatives of patients with genetic diagnosis of long QT syndrome.

• This panel includes the genes where most mutations with clinically proven association responsible for long QT syndrome are identified.

• This panel includes priority genes that are most frequently associated with the development of long QT syndrome. It also includes secondary genes associated with this entity, although with a lower level of evidence, as well as candidate genes of which only functional evidence of association exists.• It is indicated in those cases where an unequivocal clinical diagnosis of long QT syndrome exists and no mutations were identified by the 8-gene panel. This allows identifying variants potentially associated with the phenotype in those genes where the responsible mutations are less prevalent.• It should be considered as a first approach when an exhaustive genetic study of this pathology is intended, since this is the most complete panel on the market. The extended study can also be useful in families under suspicion of complex genotypes, with an important variability in phenotypic expression among its members.

28 genes


8 genesLong QT Syndrome Panel

Extended Long QT Syndrome Panel

• HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Priori SG et al. Heart Rhythm. 2013 Dec;10(12):1932-63. • HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Ackerman MJ, Priori SG, et al. Europace. 2011 Aug;13(8):1077-109.• Recommendations for the use of genetic testing in the clinical evaluation of inherited cardiac arrhythmias associated with sudden cardiac death: Canadian Cardiovas-cular Society/Canadian Heart Rhythm Society joint position paper. Gollob MH et al, Can J Cardiol. 2011 Mar-Apr;27(2):232-45. • Clinical utility gene card for: long-QT syndrome (types 1-13). Beckmann BM1, Wilde AA, Kääb S.et al. Eur J Hum Genet. 2013 Oct;21(10).• Genetic testing for long QT syndrome and the category of cardiac ion channelopathies. Modell SM, Bradley DJ, Lehmann MH. PLoS Curr. 2012 May 3.

Study extension: Other panels that include long QT syndrome genes


• Ventricular Arrhythmia and Sudden Death without Structural Heart Disease General Panel [77]

• Arrhythmias General Panel [218]

8/28 Genes


KCNQ1 KCNH2 SCN5A KCNE1 KCNE2 KCNJ2 CACNA1C RYR2

CACNA1CKCNE1KCNE2

KCNH2KCNJ2KCNQ1

SCN5AAKAP9

ANK2CALM1

CALM2CALM3

CAV3KCND2

KCNJ5RYR2

SCN4BSNTA1

TRDNFHL2*

HCN4*KCNA5*

KCND3*KCNE5*

KCNE3*NOS1AP*

PTRF*SCN1B*

Channelopathies


• This panel is mainly oriented at the diagnosis of cases where it is not possible to establish a clearly defined phenotype, but where cardiac ventricular arrhythmias are the main manifestation. • It is designed for subjects whose clinical or anatomopathological study does not reveal cardiac structural alterations. It should be especially considered for those patients with personal or familiar history of sudden death, subjects with a history of syncope of unknown origin, or subjects with idiopathic ventricular fibrillation that fulfil the above-mentioned characteristics.

Ventricular Arrhythmia and Sudden Death without Structural Heart Disease General Panel 77 genes



• This panel includes all genes associated or potentially associated with the development of inherited cardiovascular diseases that can present sudden death as a major adverse event.• It includes all genes associated to cardiomyopathies and their differential diagnoses, cardiac arrhythmias, early atherosclerosis (dyslipidemias), and aortic diseases. It includes priority genes with a clear association with the disease, secondary genes where the evidence is lower, and candidate genes (highly interesting for research projects).• It should be considered when an exhaustive study of all genes related to cardiovascular pathologies is intended, especially in cases of sudden death where clinical or pathological information is incomplete or the diagnosis is unclear.


Channelopathies

• HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Priori SG et al. Heart Rhythm. 2013 Dec;10(12):1932-63. • HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Ackerman MJ, Priori SG, et al. Europace. 2011 Aug;13(8):1077-109.


The probability of detecting a patho-genic mutation when a patient has been diagnosed with short QT syndrome has not been clearly established, although it is estimated to be close to 25%.

Short QT syndrome is a very rare genetic entity generally caused by an increase in function in some cardiac ion channels, which leads to an abnormal shortening of cardiac repolarization. It is associated with a high predisposition to ventricular arrhythmias, and patients may present syncope, cardiac arrest or sudden death. As in the case of long QT syndrome, these can be the first manifestations of the disease and can occur at any age.


• Patients with diagnosis of short QT syndrome (QTc <330 ms).• Patients under diagnostic suspicion of short QT syndrome (QTc <360 ms) who present any of the following characteristics:

Personal or familial history of sudden death. History of syncope of unknown origin. Ventricular fibrillation of unknown origin.

• Relatives of patients with genetic diagnosis of short QT syndrome.

• The panel includes those genes with proven association with this phenotype, with evidence gathered from the most relevant publications up to date.


7 genesShort QT Syndrome Panel

Short QT Syndrome

KCNH2 KCNJ2 KCNQ1 CACNA1C CACNA2D1 CACNB2 CACNA1D*

Study extension: Other panels that include short QT syndrome genes

7 Genes


• Cardiovascular Diseases General Panel [380]• Ventricular Arrhythmia and Sudden Death without Structural Heart Disease General Panel [77]

Cardiomyopathies / Long QT / Short QT / Brugada / Catecholaminergic Polymorphic Ventricular Tachycardia


03/2016

Channelopathies






Channelopathies


Catecholaminergic polymorphic ventricular tachycardia is a rare genetic condition characterized by the development of typical ventricular arrhythmias triggered by physical or emotional stress. The development of ventricular arrhythmias can lead to syncope, cardiac arrest or sudden death, occurring especially in children or young adults with no background of cardiac abnormalities. The inheritance pattern is autosomal dominant, although a significant proportion of cases present de novo mutations (mutations absent in both parents).


• Patients diagnosed with or under diagnostic suspicion of catecholaminergic polymorphic ventricular tachycardia: probands or relatives who, having a structu-rally normal heart and normal ECG, develop bidirectional ventricular tachycardia or polymorphic extrasystoles induced by catecholamines or exercise.• It might be considered for subjects with personal or familial history of sudden death or syncope of unknown origin.• Subjects with ventricular fibrillation of unknown origin.• Relatives of patients with genetic diagnosis of catecholaminergic polymorphic ventricular tachycardia.

• This panel includes the two genes associated with the development of catecholaminergic polymorphic ventricular tachy-cardia and another group of genes associated with phenotypes that, since they present bidirectional or polymorphic ventricular arrhythmia, constitute differential diagnoses of this entity.


9 genesCatecholaminergic Polymorphic Ventricular Tachycardia Panel

Catecholaminergic Polymorphic Ventricular Tachycardia

Study extension: Other panels that include catecholaminergic polymorphic ventricular tachycardia genes


The test yield is high in patients with a clearly established clinical diagnosis is around 70%-80%. Clinical specificity is 95%. The predictive value of the test (probability of carriers developing the disease throughout their life) is 80%. Within this group, it is estimated that 30% of subjects may present sudden death in the absence of treatment.

9 Genes





03/2016

RYR2 KCNJ2 CASQ2 CALM1 CALM2 CALM3 ANK2 TRDN SCN5A*

Channelopathies






Channelopathies


The probability of detecting a likely causal mutation in a patient under suspicion of Brugada syndrome is approximately 30%. As for J wave syndrome, the probability has not been clearly established.

Brugada Syndrome J Wave Syndrome

These two diseases are caused by abnormal functioning of some cardiac ion channels. They are included together in this panel because their pathophysiological mechanism is very similar; some authors even suggest that they are part of the same spectrum of diseases. They manifest themselves by abnormalities in ECG surface with a predispo-sition to the development of ventricular arrhythmias that may produce syncope, cardiac arrest, or sudden death; these often being the first manifestations of the disease.


• Patients with an electrocardiographic pattern compatible with Brugada syndrome (ST segment elevation ≥2 mm in more than one right precordial lead (V1-V3), followed by a negative T waves) or a diagnosis of early repolarization (J point elevation of ≥1 mm in ≥2 contiguous inferior and/or lateral leads).• Patients under diagnostic suspicion of the disease presenting some of the following characteristics:

Subjects with a personal or familiar history of sudden death. Subjects with a history of syncope of unknown origin. Subjects with ventricular fibrillation of unknown origin.

• Relatives of patients with a genetic diagnosis of Brugada or J wave syndrome (familiar screening).

• The panel includes the main gene associated with Brugada syndrome (SCN5A), as well as a group of genes with clinical and functional evidence of association with the entity. • Certain cases of Brugada syndrome in which mutations in SCN5A are not identified can present potentially pathogenic mutations in the group of genes additionally included in this panel.


25 genesBrugada Syndrome Panel_ J Wave Syndrome Panel


Study extension: Other panels that include Brugada syndrome genes




25 Genes


SCN5ACACNA1C

CACNA2D1CACNB2

KCNJ8SCN1B

SCN10AABCC9

ANK2FGF12

GPD1LHCN4

KCND2KCND3

KCNE5KCNE3

PKP2RANGRF

SCN2BSCN3B

SLMAPTRPM4

ANK3*CACNA1D*

KCNH2*

Channelopathies






Channelopathies

Yield of genetic testing:

The probability of finding a pathogenic mutation when a patient presents cardiac conduction disorders has not been clearly established. However, the probability could be higher in cases where there is a family history of these disorders, and when it occurs in young subjects without a clear cause.

Cardiac Conduction Disease

There is a large number of genes associated with the development of cardiomyopathies whose first clinical manifestation can be the presence of cardiac conduction disorders, such as atrioventricular blocks. The same is true for some channelopathies. Many of these pathologies may be undiagnosed because their clinical expression can be very mild in the early stages.


• The genetic study confirms the clinical suspicion, and is itself an important tool in the differential diagnosis of the disease. • The proper and correct diagnosis of the disease allows risk stratification. Some mutations in certain genes (for example LMNA) might provide prognosis information about the disease.• This test has a predictive value of the disease when a pathogenic mutation is detected:

It might be useful in genetic counseling. It allows detecting carriers at risk that should be under adequate clinical monitoring. The detection of non-carriers constitutes a cost-effective strategy, as they present a similar risk as the general population.

• This panel is indicated as a first diagnostic approach for a patient with cardiac conduction disorders, especially when there is family history (usually frequent history of pacemaker implantation in several members of the family), and in younger patients where there is no heart disease to explain the disorder. • The panel includes priority genes that are clearly related to the disease, some of which are also associated with other cardiomyopathies and channelopathies. Other secondary genes that have been associated with the disease sporadically and candidate genes arising from a systematic review of the literature are included.


34 genesCardiac Conduction Disease Panel

Study extension: Other panels that include cardiac conduction disease genes

34 Genes


• Charron P, Arad M, Monserrat L, et al. Genetic counselling and testing in cardiomyopathies: A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2010;31(22):2715-2728. • Rapezzi C, Arbustini E, Caforio A, et al. Diagnostic work-up in cardiomyopathies: Bridging the gap between clinical phenotypes and final diagnosis. A position statement from the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2013;34(19):1448-1458.

03/2016

DESEMDGLA

LAMP2LMNAPRKAG2

SCN5AACTC1CACNA1D

GAAGJA5HCN4

HFEKCNJ2KCNK17

MURCNKX2-5SCN10A

SCN1BTBX5TNNI3K

TRPM4TTRIRX3*

KCNE2*KCNH2*

KCNQ1*LDB3*

MYH6*MYH7*

NPPA*SCN4B*

SYNE1*SYNE2*





Channelopathies

Priority genes: Genes where there is sufficient evidence (clinical and functional) to consider them as associated with the disease; they are included in clinical practice guidelines. Secondary genes: Genes related to the disease but with a lower level of evidence or constituting sporadic cases. *Candidate genes: Without sufficient evidence in humans but potentially associated with the disease







Channelopathies


The probability of finding a pathogenic mutation when a patient presents atrial fibrillation has not been clearly established. The yield could be higher in cases where there is a family history of this disorder and when it occurs in young subjects without a clear cause.

Atrial Fibrillation

Atrial fibrillation (AF) is a common heart arrhythmia in the general population with prevalence increasing with age, affecting nearly 6% of individuals over 65 years. There are many cardiac conditions that may predispose to the development of this arrhythmia, although it was observed in the recent years that genetics may be the cause in 5%-15% of cases diagnosed with isolated AF.


• Patients with a family history of atrial fibrillation in the absence of predisposing factors such as hypertension, ischemic cardiomyopathy, or structural heart diseases.

• The panel includes genes with clinical and functional evidence of association with familial atrial fibrillation. • Many of the included genes are associated with defined electrophysiological phenotypes or even structural heart diseases in which the development of atrial fibrillation may be the first or the main manifestation of the disease. This allows for differential diagnosis of familial atrial fibrillation.


43 genesAtrial Fibrillation Panel

• 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. January CT, et al. Circulation. 2014 Dec 2;130(23):2071-104.

Study extension: Other panels that include atrial fibrillation genes

43 Genes





03/2016

ABCC9ACTC1EMDGATA4

GATA5GATA6GJA1GJA5

HCN4KCNA5KCND3KCNE1

KCNE5KCNE2KCNE3KCNJ2

KCNQ1LMNANKX2-5

NKX2-6NPPAPITX2

RYR2SCN10ASCN1B

SCN2BSCN3BSCN4B

SCN5ATBX5TTR

CACNB2*GREM2*JPH2*

KCNH2*KCNJ5*KCNJ8*

KCNK3*TNNI3*TNNI3K*

TNNT2*TPM1*ZFHX3*

Channelopathies



Inherited Cardiovascular Diseases and Sudden Death General Panel 380 genes

• This panel includes all genes related to cardiomyopathies and channelopathies.• It is recommended in case of sudden death where the cause is unknown or unclear or previous findings do not fully explain the severity of the disease. It should be considered in cases where, even though the patient had a pre-existing condition, it is suspected that there might be another aggravating genetic cause (e.g. the presence of a channelopathy associated with a previous cardiomyopathy).


This panel includes a group of diseases of genetic origin associated with the presence of aneurysms and dissections of the aorta or other branches of the arterial tree, even though the physiopatholo-gical mechanism associated with the development of such diseases can be different. Among these pathologies are diseases of the connective tissue, such as Marfan, Loeys-Dietz, Ehlers-Danlos, and Shprintzen-Goldberg genetic syndromes, and thoracic aortic aneurysms and dissections (TAAD). All of them are inherited in an autosomal dominant pattern. Their penetrance and expressivity depend on the syndrome type and the affected gene, as well as on the age of disease onset, the degree of dilatation, and the location of the manifestations in the arterial tree.

• 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interven-tional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Hiratzka LF et al. Circulation. 2010 Apr 6; 121(13):e266-369.• Marfan Syndrome. Harry C Dietz. GeneReviews. 2014 June 12. • Thoracic Aortic Aneurysms and Aortic Dissections. GeneReviews. 2014 June 12. • Loeys-Dietz Syndrome (Loeys-Dietz Aortic Aneurysm Syndrome). GeneReviews. 2013 July 11. • Ehlers-Danlos Syndrome Type IV (EDS Type IV; EDS, Vascular Type). Melanie G Pepin and Peter H Byers. GeneReviews. 2011 May 3. • Shprintzen-Goldberg Syndrome (Marfanoid-Craniosynostosis Syndrome). Marie T Greally. GeneReviews. 2012 January 12.

• This panel is indicated when aortic vascular diseases (aneurysms or dissections) are present without a clear cause, and especially if they present a familial pattern or any of the above-mentioned syndromes is suspected. • It includes all genes associated with these pathologies gathered from a systematic literature review.


35 genesAortic Diseases Panel

Study extension: Other panels that include aortic diseases genes

• Cardiovascular Diseases General Panel [380]Cardiomyopathies / Channelopathies / Congenital Heart Diseases / Aortic Diseases / Skeletal Myopathy / Pulmonary Hypertension / Familial Dyslipidemias

Aortic Diseases Marfan, TAAD, Loeys-Dietz, Ehler-Danlos, Shprintzen-Goldberg, etc.

35 Genes


The probability of identifying a variant associated with familial thoracic aortic aneurysms and dissections depends on how distinct the clinical manifestations of the disease are and on the suspected syndrome. It can range from over 90%-95% in cases with Marfan or Ehlers-Danlos syndromes with well-established diagnostic criteria, to lower values for other etiologies such as familial thoracic aortic aneurysms and dissections.


• Subjects under suspicion or clinical diagnosis of familial thoracic aortic aneurysms and dissections, whether in their syndromic (i.e. associated with a set of clinical characteristics including vascular involvement, as is the case of Marfan syndrome) or non-syndromic forms (when vascular involvement occurs in isolation).• Familial study: A search for a mutation previously identified in a proband (relatives of affected patients in which a pathogenic mutation associated with the familial disease has been previously identified).


ACTA2 ADAMTSL4 B3GAT3

CBSCOL1A1COL1A2

COL3A1COL5A1COL5A2

EFEMP2ELNFBN1

FBN2FLNAGAA

GATA5HRASKCNJ8

MED12MYH11MYLK

NKX2-5NOTCH1PLOD1

PRKG1PTPN11SKI

SLC2A10SMAD3SMAD4

TGFB2TGFB3TGFBR1

TGFBR2ZDHHC9


• This panel includes all genes associated or potentially associated with the development of inherited cardiovascular diseases that can present sudden death as a major adverse event.• It includes all genes associated with cardiomyopathies and their differential diagnoses, cardiac arrhythmias, early atherosclerosis (dyslipidemias), and aortic diseases. It includes priority genes with a clear association with the disease, secondary genes where the evidence is lower, and candidate genes (highly interesting for research projects).• It should be considered when an exhaustive study of all genes related to cardiovascular pathologies is intended, especially in cases of sudden death where clinical or pathological information is incomplete or the diagnosis is unclear.



It is recommended to rule out chromo-somal abnormalities (karyotype, CGH-array, SNP arrays) in order to improve the yield of the test, especially when other malformations are present.The NGS panel allows identifying mutations in some of the genes previously associated with the develo-pment of syndromic or non-syndromic congenital heart diseases.Case analysis using whole-exome sequencing can be considered in cases where there is suspicion of a genetic cause for a congenital heart disease without an identified molecular cause, but the individual yield over our NGS panels is low.

Congenital Heart Diseases

Health in Code offers the most complete genetic study for the assessment of patients with congenital heart diseases:

NGS Panel with 114 genes related to congenital heart diseases Copy number variation analysis through SNP arrayWhole-Exome Sequencing

• Congenital heart diseases are the most frequent cause of congenital malformations in newborns, and are the first cause of infant death related to congenital malformations. Their prevalence is 8 to 14 out of every 1000 live births. Most congenital heart diseases have a multifactorial etiology. It is estimated that in 8%-10% of cases the cause is a chromosomal abnormality, and 3%-5% present within the context of a monogenic syndrome.• Specific molecular diagnosis for a genetic syndrome allows for appropriate advice and early medical follow-up. The American Heart Association (AHA) and the American Academy of Pediatrics have pointed out the main reasons to determine the genetic cause of congenital heart diseases: (1) identifying other organs and systems suscep-tible of medical follow-up; (2) obtaining specific information about the prognosis; (3) informing families about risks of recurrence; and (4) identifying relatives at risk and providing them with the necessary studies, including genetic study.


• Individuals suspected or clinically diagnosed with a syndromic or non-syndromic (i.e. isolated) congenital heart disease. Upon familial history of congenital heart disease with a risk of recurrence, it is always necessary to try to determine its molecular etiology.• Familial study: relatives of patients with a syndromic or non-syndromic congenital heart disease in which a causal mutation has been previously identified.

114 Genes

• Genetics of congenital heart disease: the glass half empty. Fahed AC, Gelb BD, Seidman JG, Seidman CE. Circ Res. 2013 Feb 15; 112(4):707-20.• Genetic basis of congenital cardiovascular malformations. Lalani SR, Belmont JW. Eur J Med Genet. 2014 Aug; 57(8):402-13.


Diagnostic approach:

Complete clinical history (family history, prenatal history, etc.)

Detailed physical examComplementary exams

(image, ECG, etc.)

CONGENITAL HEART DISEASE

SYNDROMICMultiple malformations

NON-SYNDROMICIsolated

Karyotype SNP arrayCGH array

FISHMLPA massive sequencing_WHOLE EXOME

massive sequencing_ NGS PANEL

• The use of this panel should be considered:In case of isolated congenital heart diseaseIn case of syndromic congenital heart disease related to genes included in the panelIn case other causes for congenital heart disease (e.g. presence of chromosomal abnormalities) have been ruled out through another method, such as SNP arrays.

Health in Code Panel

114 genesCongenital Heart Diseases Panel

ACTA2 ACTC1 ACVR1 ACVR2B ACVRL1 ANKRD1 B3GAT3 BMPR2 BRAF

CBLCFC1 CITED2 COL1A1 COL1A2 COL3A1 COL5A1 COL5A2 CREBBP

CRELD1 CHD7 DTNA EFEMP2 EHMT1 ELNENG EP300 EVC

EYA4 FBN1 FBN2 FLNA FOXC1 FOXF1 FOXH1 FOXP1 GAA

GATA4 GATA5 GATA6 GDF1 GJA1 GJA5 HAND2 HRAS IRX4

ISL1 JAG1KANSL1KCNA5 KCNJ8 KCNK3 KMT2D KRAS LEFTY2

MAP2K1/MEK1 MAP2K2 MCTP2 MED12 MED13L MFAP5 MIB1 MYBPC3

MYH11 MYH6 MYH7 MYLK NEXNNF1 NKX2-5 NKX2-6 NODAL

NOTCH1 NOTCH2 NOTCH3 PHP4 NRAS PDGFRA PITX2 PLOD1 PRKG1

PTPN11 RAF1 RASA1 RASA2 RIT1 SALL4 SHOC2SKI SLC2A10

SMAD1 SMAD3 SMAD4 SMAD6 SMAD9 SOS1 SOS2 SPRED1 TAB2

TBX1 TBX20 TBX5 TDGF1 TFAP2B TGFB2 TGFB3 TGFBR1 TGFBR2

TNNI3 TNNI3K TOPBP1 UPF3B ZDHHC9 ZFPM2 ZIC3

Diagnostic approach:

• In the case of a congenital heart disease associated with other malformations, it is possible that the cause is a genetic syndrome. For this reason, karyotype study is indicated upon suspicion of chromosomal abnormalities. • SNP array analysis can detect copy number variations (CNVs) in the whole genetic material, allowing to confirm or rule out micro-deletion or microduplication syndromes, such as deletion 22q11 (velocardiofacial syndrome), deletion 7q11 (Williams syndrome), etc. • NGS panel (massive sequencing) allows for the study of 114 genes related to congenital heart diseases, either for some monogenic syndromes such as Holt-Oram syndrome (TBX5), Alagille syndrome (JAG1 and NOTCH2), CHARGE syndrome (CDH7), Rubinstein-Taybi syndrome (CREBBP and EP300), RASopathies, Marfan syndrome (FBN1), among others; as well as mutations in genes related to non-syndromic or isolated congenital heart diseases.• Health in Code also offers the possibility to perform whole exome sequencing studies in cases where there is suspicion of a genetic cause for a congenital heart disease without an identified molecular cause, but its additional yield over our NGS panels is low.

• This panel includes all genes associated or potentially associated with the development of inherited cardiovascular diseases that can present sudden death as a major adverse event. • It includes all genes associated to cardiomyopathies and their differential diagnoses, cardiac arrhythmias, early atherosclerosis (dyslipidemias), and aortic diseases. It includes priority genes with a clear association with the disease, secondary genes where the evidence is lower, and candidate genes (highly interesting for research projects).• It should be considered when an exhaustive study of all genes related to cardiovascular pathologies is intended, especially in cases of sudden death where clinical or pathological information is incomplete or the diagnosis is unclear.


Study extension: Other panels that include congenital heart diseases genes

SNP-arrays

Over 290 microdeletion/microduplication syndromes

Array analyses allow evaluating a gain or loss in the number of DNA copies in the whole genetic material of the patient1.It is considered a first-line study in cases of patients with cognitive deficiency, autism, and/or congenital malformations1,2.

Cytogenetic studies using microarrays allow interrogating a large amount and variety of loci compared to classic techniques. Its great versatility and yield have led to its rapid implementation in the clinical environment5.

Health in Code provides high-resolution microarray-based molecular cytogenetic services, combining the qualities of genotyping probes with probes for structural variant detection. Only in this way it is possible to detect non-balanced chromosomal abnorma-lities, uniparental disomy, loss of heterozygosity, etc. in a single assay.

In addition, the high probe density of our platform (>2.6 millions) guarantees a high sensitivity (>99%) and resolution (up to 25kb), making it possible to bridge the gap between the approaches of molecular genetics and classic cytogenetics6.

With SNP-array analysis, it is possible to analyze over 290 microdeletion/microduplication syndromes.

Health in Code Panel


Indicación 1:• It is considered a first-line study for postnatally evaluated individuals:

Multiple non-specific congenital anomalies, and/or Mental retardation/Intellectual disability

Advantages 1,2:• Analyzing DNA in virtually every tissue, including non-cultured tissue.• Detection of cytogenetic abnormalities not detected by conventional analyses.• Determining breakage points in chromosomal rearrangements.• Detection of loss of heterozygosity (SNP array only).

Yield of testing:

In cases of multiple congenital malformations, mental retardation, and/or autism, diagnosis rate is 19% 3.Different studies have demonstrated that up to 20%-41% of individuals with balanced translocations present losses or gains of genetic material at breakage points4.

CNV-SNP array study


Limitations 1:• It does not detect balanced chromosomal rearrange-ments (balanced translocations or inversions); however, it can determine if rearrangements present losses or gains at breakage points.• Low-level mosaicism.• Triploidies, tetraploidies or other levels of polyploidies and some aneuploidies such as XYY.• CNV for genomic regions not covered by the platform.• The level of detection depends of the study density.• It does not detect point mutations, gene expression, or methylation analysis.• Trisomy secondary to a translocation (trisomies 13 and 21).

1 ACMG Standards and Guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013. South ST, Lee C, Lamb AN, Higgins AW, Kearney HM; Working Group for the American College of Medical Genetics and Genomics Laboratory Quality Assurance Committee. Genet Med. 2013 Nov;15(11):901-92 Professional Practice and Guidelines Committee. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Manning M, Hudgins L; Genet Med. 2010 Nov;12(11):742-53 Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, et al. Am J Hum Genet. 2010 May 14;86(5):749-64.4 Clinical utility of array CGH for the detection of chromosomal imbalances associated with mental retardation and multiple congenital anomalies. Edelmann L, Hirschhorn K. Ann NY Acad Sci 2009; 1151:157- 166. 5 Clinical impact of copy number variation analysis using high-resolution microarray technologies: advantages, limitations and concerns. Coughlin, C. R. II, et al., Genome Medicine 4:80 (2012).6 Density matters: comparison of array platforms for detection of copy-number variation and copy-neutral abnormalities. Mason-Suares H, et al. Genet Med. 2013 Sep;15(9):706-12


The probability of identifying a mutation related to the disease depends on the presentation and findings suggesting a genetic inheritance pattern. Our panel has a higher yield in pathologies where there is a concomitant heart muscle involvement.For dystrophinopathies, thanks to our bioinformatic analysis of coverages (with which we can identify large deletions or duplications of the DMD gene), we can reach 90%-95% yield for the identification of pathogenic mutations.The probability of identifying pathogenic mutations in subjects under suspicion of Emery-Dreifuss muscular dystrophy with a familiar X-linked transmission pattern is 70%, and 45%-50% for the autosomal dominant pattern. The probability of identifying a pathogenic mutation in genes associated with limb-girdle muscular dystrophies is 60%-70% in case there is an affected individual and a recessive familial pattern is suspected.

Skeletal Myopathy

Skeletal myopathies are a group of diseases characterized by progressive muscle atrophy and weakness, generally due to the degeneration of skeletal, smooth, and cardiac muscles. Some of the most representative diseases in this group are Duchenne and Becker muscular dystrophies (DMD/BMD), which follow an X-linked trans-mission pattern; limb-girdle muscular dystrophies, of which both autosomal dominant (Emery-Dreifuss muscular dystrophy and LMNA mutations) and recessive forms (some types of Charcot-Marie-Tooth disease) have been described.

Indication for the genetic testing:

• Subjects under suspicion or with a clinical diagnosis of the disease (physical examination findings, electromyography, immunohistochemical study, or anatomopathological alterations in skeletal muscle).• Familial study: A search for a pathogenic mutation previously identified in a proband (relatives of patients diagnosed with skeletal myopathy in which one or two mutations associated with the disease have been previously identified, depending on the inheritance pattern). • In case of identifying a likely pathogenic or pathogenic variant in the FXN gene, which raises suspicion of Friedreich’s ataxia, a GAA triplet expansion study in this gene is recommended in order to confirm or rule out the disease. This service can be requested additionally.

• Dystrophinopathies. Basil T Darras, David T Miller, and David K Urion. GeneReviews. 2014 November 26. • Limb-Girdle Muscular Dystrophy Overview. Elena Pegoraro, and Eric P Hoffman. GeneReviews. 2012 August 30.

• It is indicated as a first approach upon clinical suspicion of myopathy of genetic origin, particularly when the phenotype is compatible with any of the described pathologies, which generally manifest themselves through progressive muscle weakness.• This panel does not include all genes related to inherited cardiomyopathies, which are usually present from birth or childhood and are generally not progressive.


57 genesSkeletal Myopathy Panel


57 Genes


ACTA1AGKAGLANO5BAG3

CAPN3CAV3COQ2CRYABDES

DMDEMDFHL1FKRPFKTN

FLNCFXNGAAHRASKCNE3

KCNJ2LAMA2LAMP2LDB3LMNA

MURCMYH7MYL2MYL3MYOT

PHKA1PRKAG2PTRFSCO2SDHA

SGCASGCBSGCDSLC22A5SLC25A3

SLC25A4SPEGSURF1SYNE1SYNE2

TAZTCAPTNNI3TOR1AIP1TTN

XKBSCL2*CACNA1C*DLD*DOLK*

PMM2*TMEM43*

Yield of genetic testing:The performance of this panel is optimal for genetic confirmation of HHT, increasing with the number of clinical criteria of the disease. It is estimated that the probability of detecting a mutation in ENG or ACVRL1 genes is over 85% in patients who meet the four Curaçao criteria. However, other secondary genes need to be considered in those patients who do not meet all of these criteria or in those with an atypical presentation, e.g. without epistaxis. The current panel includes all these priority and secondary genes and, thereby, avoids the need to repeat new genetic studies and speeds up the delivery of results.

The yield of the offered panel allows the diagnosis of any of the genes defined for HHT so far. It also includes the study of the RASA1 gene, causative of the capillary malformation-arteriovenous malformation syndrome (CM-AVM). Mutations in this gene have also been described as causative of a clinical picture overlapping with and clinically indistinguishable from HHT. Mutation detection in these genes is done by Next Generation Sequencing (NGS), which is the currently recommended method and can also detect previously undefined mutations. Both the clinical setting and the cosegregation study in relatives are of utmost importance for this, as they would support the pathological value of the detected mutation. In addition, knowing the cases described in the literature with a particular mutation will also contribute to its clinical interpretation.

Hereditary Hemorrhagic Telangiectasia Rendu-Osler-Weber syndromeHereditary Hemorrhagic Telangiectasia (HHT) is a disease characterized by the presence of multiple arteriovenous malformations (AVMs). Clinical expression is age-dependent: it starts in infancy and may present a possible subsequent progression of AVMs, until it reaches a stationary phase around age 50. Its diagnosis is based on the presence of epistaxis, skin or mucosal telangiectasia, visceral AVMs, family history, or presence of a pathogenic mutation in some of the disease-related genes.


• Patients with any of the four Curaçao criteria that define the disease: 1) spontaneous recurrent epistaxis, 2) cutaneous or mucosal telangiectasias, 3) visceral AVMs, or 4) first-degree relatives with those characteristics.• It is especially useful in patients with probable (two Curaçao criteria present) or unlikely (less than two criteria present) diagnosis, as well as in patients with an atypical presentation of the disease, which could suggest a mutation in genes other than ENG or ACVRL1. • The genetic test can help to confirm or rule out the clinical diagnosis in these individuals.• In addition, knowing the molecular diagnosis of the disease may provide information about prognosis, appropriate type of monitoring, and management of the disease.• Identifying the causal mutation is also useful in familial genetic screening, allowing for the early detection of affected patients, who which can help selecting appropriate clinical study and follow-up.• Finally, having identified the causal mutation allows for preimplantation genetic diagnosis, i.e. detecting said mutation in embryos prior to their implantation in order to prevent disease in progeny.

• International guidelines for the diagnosis and management of Hereditary Hemorrhagic Telangiectasia. J Med Genet 2011;48:73-87.• McDonald J, et al. Hereditary Hemorrhagic Telangiectasia: genetics and molecular diagnostics in a new era. Front Genet 2015 Jan 26;6:1.

Includes:• The two priority genes encompassing most mutations that have been identified in connection with HHT: the ENG (defines HHT type 1, more related to pulmonary arteriovenous fistulas) and ACVRL1 (defines HHT type 2, with higher frequency of liver invol-vement) genes.• Other priority genes are SMAD4 and BMPR1A, which determine an HHT affectation associated with juvenile colonic polyposis syndrome.• Other secondary genes are SMAD1, GDF2 (BMP9), BMP10, BMPR2, and RASA1.


9 genesHereditary Hemorrhagic Telangiectasia Panel


9 Genes


ENG ACVRL1 SMAD4 BMPR1A SMAD1 GDF2 (BMP9) BMP10 BMPR2 RASA1


The yield of the genetic testing on PAH through the use of massive sequencing panels has not been completely assessed. It is generally around 55%, being higher in cases with familial PAH or PAH related to other disorders (HHT), where it can reach values of over 80%.


• Patients with suspected diagnosis of idiopathic or familial PAH, since it allows confirming the clinical diagnosis if a pathogenic mutation is identified.• Performing an adequate and correct diagnosis allows for risk stratification in some cases. For example, patients who are carriers of pathogenic mutations in BMPR2 or ACVRL1 genes present a worse prognosis than non-carriers.• For familial genetic screening when a pathogenic mutation is identified in the proband. This allows detecting carrier relatives at risk of developing the disease, while monitoring of non-carriers may be discontinued. The clinical variability and the incomplete penetrance of this disease need to be taken into account: carriers must undergo appropriate clinical monitoring, although not all cases will develop the disease.

• Aepc C, Society I, Uk SG, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2015:ehv317. doi:10.1093/eurheartj/ehv317.McDonald J, et al. • Chung WK, Austin ED, Hunter Best D, Brown LM, Gregory Elliott C. Training/Practice When to Offer Genetic Testing for Pulmonary Arterial Hypertension. Can J Cardiol. 2015;31:544-547. doi:10.1016/j.cjca.2014.11.005.

Includes:• BMPR2, the main gene associated with PAH, responsible for 75% of familial PAH cases and 25% of idiopathic PAH cases.• Genes linked to PAH associated with other disorders such as hemorrhagic hereditary telangiectasia. • Other secondary genes which have been recently associated with the disease, as well as candidate genes arising from a systematic review of the literature.


16 genesPulmonary Hypertension Panel

16 Genes

Pulmonary hypertension is characterized by an increase in pulmonary pressure in the absence of a secondary cause explaining it (absence of associated pulmonary, cardiac, or thromboembolic disease). It is a progressive disease associated with poor prognosis. The main cause is pulmonary arterial hypertension (PAH), which includes idiopathic PAH, familial (inherited) PAH, and PAH related to other disorders (such as hemorrhagic hereditary telangiectasia, HHT).In recent years, significant advances have been made regarding physiopathology and application of genetics in the management of patients suspected of the disease: many of the cases believed to be idiopathic are currently considered to have a genetic cause. The inheritance pattern in familial cases is autosomal dominant.


Pulmonary Hypertension


BMPR2 ACVRL1 BMPR1B CAV1 EIF2AK4 ENG FOXF1 GDF2 KCNA5 KCNK3 NOTCH3 RASA1 SMAD1

SMAD4 SMAD9 TOPBP1


Disease-causing mutations are usually “point mutations”, approximately in 70% of cases, but small or large rearrangements have been described in up to 30% of cases. Using NGS (which allows for the detection of possible deletions), the probability of detecting a positive genetic study when the disease is well characterized clinically is close to 100%.

Fabry DiseaseFabry disease (or Anderson-Fabry disease) is due to the partial or total absence of the alpha-galactosidase A enzyme activity, which is in charge of degrading globotriaosylceramide (GL-3 or GB3). Since this fatty substance cannot be eliminated, it is accumulated and causes a malfunction of those sites in which it is deposited, affecting blood vessels, heart, kidney, liver, skin, and brain tissues.It is inherited following an X-linked pattern and therefore affects men more frequently than women (these can also be affected, although generally by a later and milder form). It is estimated that 1 in 50,000 males are affected, with a prevalence in the general population of 1 in 100,000 people.Since Fabry disease is uncommon and causes a wide range of symptoms, it can be confused with other diseases. Therefore, patients suffering from Fabry disease can go for long periods of time without a correct diagnosis. The main cardiac condition is left ventricular hypertrophy. Many of these patients are referred to doctors with a diagnosis of hypertrophic cardiomyopathy (actually, Fabry disease being the cause in 0.5%-1% of patients with hypertrophic cardiomyopathy).Early diagnosis of Fabry disease is essential, since nowadays there are specific treatments available: intravenous administration of the deficitary enzyme.


• Subjects under suspicion or clinical diagnosis of Fabry disease:Children and adolescents: Acute or chronic limb pain unresponsive to the usual analgesics (acroparesthesias), recurring fever of unknown origin, intolerance to heat, cold, or exercise, chronic intestinal disorders of uncertain origin, diffuse angiokeratomas, hipohydrosis, proteinuria, growth retardation, corneal opacities (cornea verticillata).Adults: Persistence of the above-mentioned symptoms, renal insufficiency of uncertain origin, left ventricular hypertrophy (hypertrophic cardiomyopathy), dyspnea, low tolerance to exercise, angina, thoracic pain, palpitations, arrhythmia, early cerebrovascular disease, loss of hearing, and tinnitus.

• Familial study: A search for a mutation previously identified in a proband (families of patients with Fabry disease in which a mutation has been previously identified).

• Biegstraaten M, Arngrímsson R, Barbey F et al. Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document. Orphanet J Rare Dis. 2015 Mar 27;10:36.• Smid BE, van der Tol L, Cecchi F et al. Uncertain diagnosis of Fabry disease: consensus recommendation on diagnosis in adults with left ventricular hypertrophy and genetic variants of unknown significance. Int J Cardiol. 2014 Dec 15;177(2):400-8.• Laney DA, Bennett RL, Clarke V et al. Fox A, Hopkin RJ, Johnson J, O’Rourke E, Sims K, Walter G. Fabry disease practice guidelines: recommendations of the National Society of Genetic Counselors.J Genet Couns. 2013 Oct;22(5):555-64. • Gal A, Beck M, Winchester B. Clinical utility gene card for: Fabry disease. Eur J Hum Genet. 2012 Feb;20(2).

Study extension: Other panels that include Fabry Disease genes


• Hypertrophic Cardiomyopathy Panels [17 / 104]

• Cardiomyopathies General Panel [173]

• This is the study of choice upon clinical suspicion of Fabry disease. • It is performed through NGS, by the method of amplification of the GLA gene. It includes all exons and non-coding regions (UTRs, introns, and adjacent regions). It allows for the evaluation of possible structural variants and copy-number variation (CNVs), which increases its diagnostic yield with respect to the traditional Sanger method technique.


1 geneMassive parallel sequencing method after amplification of GLA gene

GLA

1 Gene


• It includes both the main sarcomeric genes and all phenocopies of the disease, as well as secondary and candidate genes gathered in a systematic literature review. It is indicated:

If the basic panel study is negative and there is a clear HCM phenotype, since this panel improves diagnostic yield. In case severe phenotypes or phenotypes associated with syndromes and other rare genetic diseases are detected. If an exhaustive genetic study of this pathology is intended, since this is the most complete panel for HCM in the market.

Hypertrophic Cardiomyopathy Extended Panel 104 genes





• Fabry disease is one of the main phenocopies of hypertrophic cardiomyopathy, and patients are usually referred to doctors with this diagnosis. In case the suspicion of Fabry disease is not high, or if there are data of cardiac involvement not explained by this disease (pattern of hypertrophy not suggesting Fabry, hypertrophy at an early age or without involvement of other organs, etc.), we recommend starting the evaluation by any of the hypertrophic cardiomyopathy panels:

Hypertrophic Cardiomyopathy Panels

• Our basic HCM panel is indicated as a first diagnostic approach upon clinical suspicion of HCM. It includes the 9 main sarcomeric genes associated with the disease and also contains 8 disease-associated genes whose clinical presentation can be indistinguishable from classic HCM (phenocopies), including GLA gene associated with Fabry disease.

17 genes



In case a clear diagnosis of familial TTR amyloidosis exists, the genetic study allows identifying the causal mutation in over 99% of cases. The great majority of them are point mutations, with no deletion/duplica-tion-type structural variants having been described in this gene.

Amyloidosis is a generic term referring to a group of diseases characterized by extracellular deposition of amyloid material in various organs, either in isolation or generalized. Clinical manifestations depend on the affected organ and the amount of deposited amyloid. Amyloidosis is estimated in 1 in 60,000 people, with 0.8% preva-lence in autopsies.The deposition of amyloid is common on the cardiac level, and it may be the first manifestation of the disease. The presentation is usually left ventricular hypertrophy, therefore patients may be initially diagnosed as suffering from hypertrophic cardiom-yopathy. There is a familial amyloid cardiomyopathy (autosomal dominant inheritance pattern) caused by mutations in the transthyretin gene (TTR). Over 100 mutations associated with different phenotypes, including neuropathic, cardiac, renal and ocular forms, have been described in this gene. The prevalence of this disease is unknown.


• Patients with clinical diagnosis and positive anatomopathologic study for familial amyloidosis in which transthyretin/prealbumin (TTR) protein has been found responsible.• Patients under suspicion of familial amyloidosis related to TTR.• Familial study: A search for the mutation previously identified in a proband (relatives of patients with familial TTR amyloidosis in which a pathogenic mutation has been previously identified).

• Familial Transthyretin Amyloidosis. Yoshiki Sekijima, Kunihiro Yoshida, Takahiko Tokuda and Shu-ichi Ikeda. GeneReviews. 2012 January 26.

• TTR gene sequencing is recommended for individuals with a clear suspicion of familial amyloidosis.


1 geneFamilial Amyloidosis Related to TTR Panel

TTR


1 Gene


Familial Amyloidosis Related to transthyretin [TTR]

Sample Collection and Shipping

www.healthincode.com

All samples must be accompanied by the application form, available on our website www.healthincode.com. If the request comes from a public hospital, an authorization for the study released by the center’s management must be attached.

Where can you find us?

Sample requirements

How should samples be collected?

Where to send samples?Send the package to the address below (contact us for any questions regarding shipping at: HEALTH IN CODE S. L. Edificio El Fortín, As Xubias s/n. 15.006 A Coruña, Spain.

How should samples be packaged?

Genomic DNA: Minimum amount for NGS > 5-10 μg (A260/280 = 1.8-1.9) and for Sanger sequencing > 1 μg (A260/280 = 1.8-1.9); shipped at 4-8ºC (recommended) or at room temperature (in this case the sample must be in our lab within 24/48 hours).

Saliva sample: Saliva kit shipped at room temperature. Kits can be ordered at [email protected].

Peripheral blood: 3 to 5 ml of peripheral blood in EDTA in one lavender-top tube shipped at 4-8°C (recommended) or at room temperature (in this case the sample must be delivered to our laboratory within the next 24-48 hours.

@ [email protected] [email protected] +34 881 600 003 Ed. El Fortín As Xubias s/n A Coruña 15006 Spain

Triple layer.

Primary receptacle: watertight, leak-proof receptacle containing the specimen.Secondary packaging: watertight. Absorbent material must be used to cushion primary receptacles.Outer packaging: minimum size 100×100mm. Rigid container for blood and tissue sample.

Contact us for any question or information regarding shipping.

Sample collection and transportation are under client´s responsability. However, we recommend to follow the guidelines below to ensure samples arrival upon quality and quantity requisites that guarantee optimal analytic processing.

Price list 2016

NGS General Panels

NGS Specific Panels

Hypertrophic Cardiomyopathy Basic Panel [17 genes] Extended Panel [104 genes]Dilated Cardiomyopathy [96 genes]Arrhythmogenic Cardiomyopathy [21 genes]Non-Compaction Cardiomyopathy [37 genes]Restrictive Cardiomyopathy [20 genes]RASopathies (Noonan, LEOPARD, Costello) [18 genes]

950 €1,450 €1,450 €1,150 €1,250 €1,150 €1,150 €

Aortic Diseases [35 genes]Congenital Heart Diseases [114 genes] SNP arraysSkeletal Myopathy [57 genes]Hereditar y Hemorrhagic Telangiectasia [9 genes]Pulmonary Hypertension [16 genes]Fabry Disease [1 gene]Familial Amyloidosis [1 gene]

1,150 €1,250 €

750 €1,250 €

950 €950 €360 €240 €

Long QT Syndrome Basic Panel [8 genes] Extended Panel [28 genes]Short QT Syndrome [7 genes]Catecholaminergic Polymorphic Ventricular Tachycardia [9 genes]Brugada Syndrome_J Wave Syndrome [25 genes]Cardiac Conduction Disease [34 genes]Atrial Fibrillation [43 genes]

950 €1,250 €

950 €1,150 €

950 €1,250 €1,250 €

1,950 € 1,750 € 1,750 € 1,250 €

Cardiovascular Diseases General Panel [380 genes]Cardiomyopathies General Panel [173 genes] Arrhythmias General Panel [218 genes]Ventricular Arrhythmia & Sudden Death without Structural Heart Disease General Panel [77 genes]

lndex case evaluated 2 Without index case

Study of Relatives 1

240 €340 €440 €540 €

170 €255 €340 €425 €

One variant Two variants Three variants Four variants

1 For structural variants (gross rearrangements, copy-number variation [insertions, deletions and duplications], inversions, translocations, etc.) contact [email protected] for a quote2 Index case previously evaluated by Health in Code

[email protected]@healthincode.com+34 881 600 003Ed. El FortínAs Xubias s/n A Coruña 15006 Spain

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