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Autosomal recessive disorders: Autosomal recessive disorders: the Middle East perspectivethe Middle East perspective
Lihadh Al-GazaliLihadh Al-GazaliFaculty of Medicine and Health Faculty of Medicine and Health
SciencesSciencesUAE UniversityUAE University
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DEFINITION OF THE MIDDLE EAST
Lancet Vol 367, 2006
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UNITED ARAB EMIRATES
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Burj Al Arab in DubaiBurj Al Arab in Dubai
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Faculty of Medicine and Health Sciences United Arab Emirates
University
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Characteristics of the population in the Characteristics of the population in the Middle EastMiddle East
Multi-ethnic & diverseMulti-ethnic & diverse Presence of isolated communities, Presence of isolated communities,
like Bedouins, Druze, Nubianslike Bedouins, Druze, Nubians High mobilityHigh mobility Large family sizeLarge family size High level of consanguinityHigh level of consanguinity
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Consanguinity Rates and Inbreeding Coefficients Consanguinity Rates and Inbreeding Coefficients in the Middle Eastin the Middle East
CountryCountryConsanguinityConsanguinityAverage Inbreeding Average Inbreeding CoefficientCoefficient
BahrainBahrain31.8 – 44.531.8 – 44.50.0152 – 0.01660.0152 – 0.0166
EgyptEgypt29290.01010.0101
IraqIraq46.446.40.02250.0225
Israeli ArabsIsraeli Arabs20.6 – 52.920.6 – 52.90.00993 – 0.02530.00993 – 0.0253
JordanJordan25.6 – 52.125.6 – 52.10.0142 – 0.02840.0142 – 0.0284
KuwaitKuwait54.354.30.02190.0219
LebanonLebanon16.5 – 29.616.5 – 29.60.00880.0088
OmanOman35.935.90.01980.0198
QatarQatar54540.027060.02706
Saudi ArabiaSaudi Arabia41.4 – 51.741.4 – 51.70.0196 – 0.03120.0196 – 0.0312
UAEUAE50.550.50.02220.0222
YemenYemen40 – 44.740 – 44.70.0212 – 0.24420.0212 – 0.2442
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Autosomal Recessive disorders in ArabsAutosomal Recessive disorders in ArabsThe The CCatalogue for atalogue for TTransmission ransmission GGenetics in enetics in AArabs (CTGA)rabs (CTGA)
Number of genetic disorders in Arabs - 806Number of genetic disorders in Arabs - 806 Autosomal disorders - 701Autosomal disorders - 701
AR -513AR -513
AD -206AD -206 X-Linked disorders - 47X-Linked disorders - 47
XR -23XR -23
XD -10XD -10
www.cags.org.ae
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Autosomal Recessive (AR) Disorders in Autosomal Recessive (AR) Disorders in the Middle Eastthe Middle East
Common AR disordersCommon AR disorders Relatively common AR disordersRelatively common AR disorders AR disorders that cluster in certain AR disorders that cluster in certain
communitiescommunities AR disorders which are limited to 1 or AR disorders which are limited to 1 or
2 extended families2 extended families New AR disordersNew AR disorders
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Rates of common single gene disorders in Arab Countries
Up to 27% of males have
G6PD deficiency
Up to 27% of males have
G6PD deficiency
Sickle cell carrier rateUp to 25%
Sickle cell carrier rateUp to 25%
? Deaf-mutism? Congenital adrenal
hyperplasia
? Deaf-mutism? Congenital adrenal
hyperplasia
Alpha thalassemia carrier rateUp to 49%
Alpha thalassemia carrier rateUp to 49%
Familial Mediterranean Fever carrier rate
Up to 18%
Familial Mediterranean Fever carrier rate
Up to 18%
Beta thalassemia carrier rate Up to 15%
Beta thalassemia carrier rate Up to 15%
Common single gene disorders in
Arab countries
Common single gene disorders in
Arab countries
Up to 27% of males have
G6PD deficiency
Up to 27% of males have
G6PD deficiency
Sickle cell carrier rateUp to 25%
Sickle cell carrier rateUp to 25%
? Deaf-mutism? Congenital adrenal
hyperplasia
? Deaf-mutism? Congenital adrenal
hyperplasia
Alpha thalassemia carrier rateUp to 49%
Alpha thalassemia carrier rateUp to 49%
Familial Mediterranean Fever carrier rate
Up to 18%
Familial Mediterranean Fever carrier rate
Up to 18%
Beta thalassemia carrier rate Up to 15%
Beta thalassemia carrier rate Up to 15%
Common single gene disorders in
Arab countries
Common single gene disorders in
Arab countries
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Prevalence of Haemoglobinopathies Prevalence of Haemoglobinopathies in the Middle Eastin the Middle East
CountryCountrythal carrierthal carrierthal carrierthal carrierSickle Cell Sickle Cell TraitTrait
BahrainBahrain2.92.924.224.2 13.813.8
EgyptEgypt4.54.5NANA NANA
IraqIraq4.64.6NANA 6.5 – 166.5 – 16
JordanJordan3 – 5.93 – 5.92 – 3.52 – 3.5 0.5 – 60.5 – 6
KuwaitKuwaitNANA5 – 105 – 10 NANA
LebanonLebanon22NANA 0.30.3
OmanOman2.2 – 42.2 – 4NANA 5.8 – 105.8 – 10
Saudi Saudi ArabiaArabia
1 – 151 – 155 – 105 – 10 1 – 251 – 25
UAEUAE8.38.34949 1.41.4
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Common Genetic Disorders in the Common Genetic Disorders in the UAEUAE
Thalassaemia Thalassaemia
Major health problem in UAEMajor health problem in UAE Mutation analysis: Mutation analysis:
UAE is the most heterogeneousUAE is the most heterogeneous
thalassaemia population in the thalassaemia population in the worldworld
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Most Common Most Common Thalassaemia Thalassaemia Mutations in UAEMutations in UAE
Mediterranean mutationsMediterranean mutationsCd 39 (c>T)Cd 39 (c>T)IVS-11-1 (G>A)IVS-11-1 (G>A)Cd5 ( -ct)Cd5 ( -ct)IVS-1 (G>A)IVS-1 (G>A)Cd 30 (G > C)Cd 30 (G > C)
Indian mutationsIndian mutationsIVS-1-5 (G>C)IVS-1-5 (G>C)Cd 8/9 (+G)Cd 8/9 (+G)Hb DHb D
Iranian and Eastern Arabian Peninsula mutationsIranian and Eastern Arabian Peninsula mutations-25 bpdel-25 bpdelcd 39 c>Tcd 39 c>TIVS-11-1 (G>A)IVS-11-1 (G>A)
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Relatively Common AR disorders in the Relatively Common AR disorders in the Middle EastMiddle East
Disorders that are seen more frequently in Disorders that are seen more frequently in
the population of the Middle east than in the population of the Middle east than in
other populations. Examples:other populations. Examples: Joubert syndromeJoubert syndrome Meckel syndrome Meckel syndrome Bardet-Biedl syndromeBardet-Biedl syndrome
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Joubert SyndromeJoubert Syndrome
Hypoplasia/Hypoplasia/dysplasia of the dysplasia of the cerebellar vermiscerebellar vermis
HyperventilationHyperventilation AtaxiaAtaxia Abnormal eye Abnormal eye
movementmovement Mental retardationMental retardation
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Molar Tooth MalformationMolar Tooth Malformation
Malformed cerebellar Malformed cerebellar vermisvermis
Thick and elongated Thick and elongated cerebellar pedunclescerebellar peduncles
Deep interpeduncular Deep interpeduncular fossafossa
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Joubert Syndrome in UAEJoubert Syndrome in UAE
40 children from 20 families were 40 children from 20 families were
evaluatedevaluated 4 genes were mapped in some of these 4 genes were mapped in some of these
familiesfamilies
JBTS1 – 9q34.3JBTS1 – 9q34.3
JBTS2 – 11p12-q13.3JBTS2 – 11p12-q13.3
JBTS3 - 6q23 [Mutation in AHI1(Jouberin)]JBTS3 - 6q23 [Mutation in AHI1(Jouberin)]
JBTS5- 12q [Mutation in CEP290 gene]JBTS5- 12q [Mutation in CEP290 gene]
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Examples of Genetic Disorders that Cluster in Examples of Genetic Disorders that Cluster in Certain Communities in the Middle EastCertain Communities in the Middle East
DisorderDisorderOMIM OMIM NoNo
CommunityCommunity
Faciodigitogenital SyndromeFaciodigitogenital Syndrome227330227330Bedouin tribe in KuwaitBedouin tribe in Kuwait
Hypophosphataemic rickets and Hypophosphataemic rickets and hypercalcuriahypercalcuria
241530241530Bedouin tribe in Israel Bedouin tribe in Israel and Palestinian and Palestinian territoriesterritories
Canavan’s diseaseCanavan’s disease271900271900Samaritans in West Samaritans in West BankBank
Usher Syndrome Type IUsher Syndrome Type I276900276900Samaritans in West Samaritans in West BankBank
Stuve-Wiedemann SyndromeStuve-Wiedemann Syndrome601559601559Omani and Yemeni Omani and Yemeni isolates in UAEisolates in UAE
Ehlers-Danlos Syndrome VIAEhlers-Danlos Syndrome VIA225400225400UAE BedouinUAE Bedouin
Ataxia TelangiectasiaAtaxia Telangiectasia208900208900DruzeDruze
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Stüve-Wiedemann Syndrome (SWS)Stüve-Wiedemann Syndrome (SWS)
Stüve and Wiedemann 1971Stüve and Wiedemann 1971
CamptomeliaCamptomelia
CamptodactylyCamptodactyly
Contractures of Contractures of
large jointslarge joints
HyperthemiaHyperthemia Respiratory Respiratory
insufficiencyinsufficiency Feeding and Feeding and
swallowing swallowing difficultiesdifficulties
Early lethalityEarly lethality
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Molecular aspect of SWSMolecular aspect of SWS
Caused by Mutations in the LIFR Caused by Mutations in the LIFR gene gene
More than 14 mutations in the LIFR More than 14 mutations in the LIFR gene have been described in the gene have been described in the literatureliterature
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SWS in the UAESWS in the UAE
35 cases from 21 families 35 cases from 21 families
originating from Oman and Yemenoriginating from Oman and Yemen
A founder mutation in LIFR gene A founder mutation in LIFR gene
(653_654 ins T) at exon 6, 2 codons (653_654 ins T) at exon 6, 2 codons
downstream predicting premature downstream predicting premature
termination of translationtermination of translation
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Ehlers-Danlos Syndrome VIA (EDS Ehlers-Danlos Syndrome VIA (EDS VIA) Kyphoscoliotic EDSVIA) Kyphoscoliotic EDS
Severe muscular hypotonia at birthSevere muscular hypotonia at birth
Severe joint hypermobilitySevere joint hypermobility
Progressive kyphoscoliosisProgressive kyphoscoliosis
Fragility of skin with abnormal scarringFragility of skin with abnormal scarring
Deficiency of the enzyme lysyle hydroxylaseDeficiency of the enzyme lysyle hydroxylase
More than 20 mutations in LH (PLOD1) gene More than 20 mutations in LH (PLOD1) gene
have been described in the literaturehave been described in the literature
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EDS VIA in UAEEDS VIA in UAE
16 children with EDS VIA from 12 16 children with EDS VIA from 12 Bedouin UAE families originating Bedouin UAE families originating from 2 tribesfrom 2 tribes
A founder mutation in LH gene was A founder mutation in LH gene was found in affected families (g.23939 found in affected families (g.23939 C>T causing a p.R319X nonsense C>T causing a p.R319X nonsense mutation)mutation)
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Rare AR disorders which are limited to Rare AR disorders which are limited to
1 or 2 extended families1 or 2 extended families
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Donnai – Barrow SyndromeDonnai – Barrow Syndrome
1st described in 1993 ( Donnai & 1st described in 1993 ( Donnai & Barrow)Barrow)
Diaphragmatic herniaDiaphragmatic hernia ExomphalosExomphalos Distinctive faceDistinctive face Absent corpus callosumAbsent corpus callosum Sensorineural hearing lossSensorineural hearing loss 10 cases reported in the literature10 cases reported in the literature
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HypertelorisHypertelorismm
++++++++++
ACCACC----++++
OmphalocelOmphalocelee
++++----++
SNHLSNHL++++++++
CDHCDH----++--CDD, lung CDD, lung hypoplasiahypoplasia
Eye abn.Eye abn.High High myopiamyopia
High myopiaHigh myopiaLarge Large prominent prominent
eyeseyes
Iris coloboma, Iris coloboma, Retinal Retinal
dystrophydystrophy
Retinal Retinal dystrophydystrophy
MiscMiscDilated lat. Dilated lat. ventriclesventricles
Dilated lat. Dilated lat. ventricles, ventricles, AlbinismAlbinism
NND, Large NND, Large AF, No AF, No autopsyautopsy
Speech delaySpeech delayRib/vertebral Rib/vertebral anom, Dev anom, Dev deldel
Brain anom..Brain anom..
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Molecular aspect of DBSMolecular aspect of DBS
Homozygosity mapping in the UAE family Homozygosity mapping in the UAE family
localized the gene on chromosome 2q23.3-q31localized the gene on chromosome 2q23.3-q31
Mutations in the LRP2 gene coding Megalin were Mutations in the LRP2 gene coding Megalin were
identifiedidentified
The mutation in the UAE family – c.7564T>CThe mutation in the UAE family – c.7564T>C
p.Y2522Hp.Y2522H
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New AR disorders diagnosed in New AR disorders diagnosed in the Middle Eastthe Middle East
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I
II
III
A New Autosomal Recessive Mental Retardation Syndrome
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A New Autosomal Recessive Syndrome
Mental Retardation
Ocular Colobomas
Brain Malformation
Endocrine Abnormalities
Ichthyosis/dry skin
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CHIME SyndromeCHIME Syndrome Zunich & Kaye 1983Zunich & Kaye 1983
Ocular Colobomas
Heart Defect
Ichthyosis
Mental Retardation
Abnormal Ears
6 cases reported in the literature
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Molecular study of the CHIME-like Molecular study of the CHIME-like syndromesyndrome
Homozygosity mapping localized the Homozygosity mapping localized the gene to chromosome 4 (LOD score gene to chromosome 4 (LOD score 4.2)4.2)
A mutation in one of the candidate A mutation in one of the candidate genes was identifiedgenes was identified
Functional studies are in progressFunctional studies are in progress
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Mental Retardation Mental Retardation Optic AtrophyOptic Atrophy Iris ColobomaIris Coloboma Dry Itchy SkinDry Itchy Skin
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Larsen-like Syndrome
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Flat faceFlat face HypertelorismHypertelorism Downslanting Palpebral Downslanting Palpebral
fissuresfissures Short webbed neckShort webbed neck
New Larsen-Like SyndromeNew Larsen-Like Syndrome
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Larsen-Like SyndromeLarsen-Like Syndrome
Dislocation of elbowsDislocation of elbows Multiple subluxations of the Multiple subluxations of the
interphalangeal joints of fingers and toesinterphalangeal joints of fingers and toes Metatarsus varusMetatarsus varus
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Molecular study of Larsen-like Molecular study of Larsen-like syndromesyndrome
Homozygosity mapping localized the Homozygosity mapping localized the gene to chromosome 11gene to chromosome 11
Several candidate genes were Several candidate genes were sequencedsequenced
Mutation in one of these genes was Mutation in one of these genes was identifiedidentified
Functional studies are in progressFunctional studies are in progress
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1
4
25
Autosomal Recessive MR SyndromeNoonan-like
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Autosomal Recessive MR SyndromeNoonan-like
Moderate to severe MRMacrocephaly
Short statureFacial Dysmorphism:
arched eyebrowsnose asymmetrydental malocculsionlong face Low-set ears
Short neckChest deformityDry skin
3 of 7 have congenital heart defects
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Molecular study in Noonan-like syndrome
Homozygosity mapping localized the gene to chromosome 20 (LOD Score 6.2)
Several candidate genes were sequenced, no mutation has been identified yet
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Genetic Prevention Programmes of AR Genetic Prevention Programmes of AR Disorders in the Middle EastDisorders in the Middle East
Premarital carrier screeningPremarital carrier screening
Family oriented approachFamily oriented approach
Antenatal scanningAntenatal scanning
Pre-implantation diagnosisPre-implantation diagnosis
EducationEducation
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Causes of Ineffective Genetic Counseling in the Middle East
Cultural – Consanguineous marriages
– Large family size
Local beliefs Legal issues
– Options are not available since they are legally unacceptable
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Attitudes toward Genetic Counseling in UAE
100 couples 50 acknowledge a genetic basis for their child’s
condition 10 only remembered the risk given to them 50 preferred consanguineous marriages for
themselves and their children 10 agreed with prenatal diagnosis and abortion of
affected pregnancies 75 agreed with carrier screening and
preconception diagnosis in affected families
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ConclusionConclusion
AR disorders are common in the Middle EastAR disorders are common in the Middle East Most AR disorders in the Middle East are not Most AR disorders in the Middle East are not
studiedstudied The Middle East will continue to be a source The Middle East will continue to be a source
of new information about AR disorders for of new information about AR disorders for the whole worldthe whole world
More work need to be done in planning and More work need to be done in planning and implementing ways of prevention and implementing ways of prevention and treatment of AR disorders in the Middle Easttreatment of AR disorders in the Middle East
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AcknowledgementAcknowledgement
Christopher Walsh- Harvard medical school, USAChristopher Walsh- Harvard medical school, USA Barbara Pober- Harvard medical school, USABarbara Pober- Harvard medical school, USA Joseph Gleeson- UCSD, USAJoseph Gleeson- UCSD, USA Stefan Mundlos – Max Plank Institute for Stefan Mundlos – Max Plank Institute for
Molecular Medicine, GermanyMolecular Medicine, Germany Kathrin Hoffman-Humboldt university, GermanyKathrin Hoffman-Humboldt university, Germany Valarie Cormier-Daire- INSERM, FranceValarie Cormier-Daire- INSERM, France Beat Steinmann – Children’s hospital, SwitzerlandBeat Steinmann – Children’s hospital, Switzerland Bassam Ali- FMHS,UAEBassam Ali- FMHS,UAE
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Al Ain International Genetics Conference – October 2008
www.fmhs.uae.ac.ae