GENETICS Which Syndrome; Which Test

Valerie Watiker, MS, CGC, MD

Disclosures

http://blogs.nature.com/

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• The Basic 46 • Chromosome

disorders • Micro deletions • Single gene

disorders

CHROMOSOMES The Basics & The Nitty Gritty

Anatomy of a Chromosome

Array Technology

http://humupd.oxfordjournals.org/content/18/5.cover-expansion

Three Questions to Ask

» 1. What Group ? » 2. What Disorder? » 3. What is the Best Test?

■ 1 month old female ■ Normal birth history ■ Normal NIPT screen ■ Feeding issues ■ PE:

■ Small mouth and ears ■ Redundant neck folds ■ Noisy breathing ■ Somewhat hypotonic

■ Cardiac: VSD

emedicine.medscape.com/article/943216-clinical

Three Questions to Ask

1. What Group ? 2. What Disorder? 3. What is the Best Test?

1. Chromosomal 2. Trisomy 21 3. Karyotype

Chromosomal Microarray is First Line Test

Trisomy 18

» IUGR » Weak cry » Low set ears » Short pf. » Small mouth » Clenched hand

(index finger over 3rd finger)

» Cardiac: VSD, ASD,PDA

Orphanet J Rare Dis. 2012; 7: 81.

newborn and 1 year of age

Trisomy 13

» Holoprosencephaly » Scalp defect » Micropthalmia » Low set ears » Cleft lip +/- palate » Polydactyly » Clenched hand

(thumb over fingers) » Cardiac: VSD, PDA

ASD, Dextroposition

Orphanethttps://pedclerk.bsd.uchicago.edu/page/trisomy-18-edwards-trisomy-13-patau.

diseasespictures.com

Common Chromosomal Disorders

» Turner Syndrome ,(45, X) » Klinefelter, (47XXY) » Deletion 1p36 » Wolf Hischorn (4p-) » Cri Du Chat (5p-)

■ IQ variable ■ Learning disabilities ■ Hypernasal speech ■ cleft palate ■ Facial features

■ hooded eyes ■ tubular nose

■ Short stature

■ Cardiac: TOFhttp//dempsterfamilyfoundation.org

Three Questions to Ask

1. What Group?

2. What Disorder ?

3. What is the Best Test?

1. Chromosomal Microdeletion

2. 22q11.2 deletion 3. Microarray-

(FISH will miss some deletions)

Chromosomal Microarray is First Line Test

22q11.2 Duplication 22q11.2 Triplication

22q11.2 deletionhttp//dempsterfamilyfoundation.org

Williams Syndrome

» Developmental delay

» Cocktail party personality

» Cardiac: 60-80% » Supervalvular AS » Supervalvular PS

newborn and 1 year of age

https://infograph.venngage.com/p/106191/williams-syndrome-infographic

http://www.forgottendiseases.org/assets/WilliamsSyn.html

Down Syndrome Critical region 21q22.3

Fragile X Xq27.3

Duchenne Xp21

Alagille 20p11.23-12.1

Smith-Magenis 17p11.2

Miller-Dieker Lissencephaly 17p13.3

Angelman/ Prader-Willi 15q12

Retino Blastoma 13q14

DiGeorge 2 10p13

Langer Gideon 8q24.11

Williams 7q11.23

cru-du-chat 5p15

Wolf- Hirschorn 4p16.3

Cornelia de Lange (duplication) 3q26.1

DiGeorge 22q11.21-11.23

Rubenstein- Taybi 16p13.3

Aniridia 11p13

Beckwith- Wiedemann (duplication) 11p15.5

» Thumb abnormalities

» Absent radius/Ulna

» Cardiac: ASD VSD

Three Questions to Ask

1. What Group ?

2. What Disorder?

3. What is the Best

Test?

1. Single Gene

2. Holt -Oram

3. TBX5, (AD)

Gene sequencing

with del. /dup.

Evaluate parents for hand anomalies (XRAY)

Single Gene Disorders

» Marfan Syndrome ( AD) FBN1 gene

» Tuberous Sclerosis (AD), TSC1 and TSC2

» Charge Syndrome (AD), CHD7, » TAR syndrome (AR) , unknown, some del 1q21

» Algille Syndrome (AD) - JAG1, NOTCH2

Three Questions to Ask

1. What Group?

2. What Disorder ?

3. What is the Best Test?

Microarray is First Line Test

?

Parental Screening» NT: >3.5mm, risk aneuploidy

and cardiac defects » Add Serum, NB,& ductus flow

95% T-21 detection, 3% FP » NIPT: high sensitivity for

Trisomy 21, 18, and 13. and XY disorders

» Remember these are screening not diagnostic.

https://fetalmedicine.org

NIPT

Table 1. Cell-free DNA Test Performance Characteristics in Patients Who Receive an Interpretable Result*

      Age 25years

Age 40years

  Sensitivity (%) Specificity (%) PPV (%) PPV (%)

Trisomy 21 99.3 99.8 33 87

Trisomy 18 97.4 99.8 13 68

Trisomy 13 91.6 99.9 9 57

Sex chromosome aneuploidy 91.0 99.6 --† --

Abbreviation: PPV, positive predictive value.

http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Genetics/Cell-free-DNA-Screening-for-Fetal-Aneuploidy

NIPT

» NIPT no call results results » 15%risk for aneuploidy » ACMG — Offer diagnostic testing for

a no-call NIPS result due to low fetal fraction if maternal blood for NIPS was drawn at an appropriate gestational age. A repeat blood draw is NOT appropriate.

GREGG et al | Noninvasive prenatal screening for fetal aneuploidy: 2016 update

Genetic Resources

• www.genetests.org • OMIM: http://

www.ncbi.nlm.nih.gov/sites/entrez?db=OMIM&itool=toolbar

• ACMG • NSGC • ACOG • Laboratory

websites • NIPT calculator