Syndrome & Gene

Question 1

Marfan Syndrome

Answer 1

Fibrillin (FBN1), TGFB2

Question 2

Legius Syndrome

Answer 2

SPRED1

Question 3

Non syndromic congenital hearing loss

Answer 3

Connexin 26 (GJB2) and Connexin 30 (GJB6)

Question 4

Osteogenesis Imperfecta

Answer 4

COL1A1, COL1A2, CRTAP, P3HI

COL1A1 and COL1A2 account for 90% of OI

Question 5

Kabuki syndrome

Answer 5

KMT2D and KDM6A

Question 6

Achondroplasia

Answer 6

FGFR3

Question 7

Saethre-Chotzen

Answer 7

TWIST

Question 8

Pfeiffer

Answer 8

FGFR1 and FGFR2

Question 9

Apert

Answer 9

FGFR2

Question 10

Crouzon

Answer 10

FGFR2

Question 11

CCHS

Answer 11

PHOX2B–mutations can result in a polyalanine repeat expansion (PARMs), but non polyalanine repeat expansions (nPARMS) have also been described

Question 12

MUENKE craniosynostosis

Answer 12

FGFR3

Question 13

Cornelia De Lange

Answer 13

NIPBL, SMC1L1, SMC3

Question 14

Rubenstein-Taybi

Answer 14

CBP and EP300

Question 15

Smith Lemli Opitz

Answer 15

DHCR7

Question 16

Williams syndrome

Answer 16

7q11.23 microdeletion

Question 17

Noonan syndrome

Answer 17

PTPN11, SOS1, RAF1, other mutations in MAPK signaling pathway also described

Question 18

Russell Silver syndrome

Answer 18

Genetically heterogeneous

1. hypomethylation of paternal allele imprinting center 1 (IC1) of chromosome 11p15.5 (35-50% of cases)
2. maternal uniparental disomy of chromosome 7

Question 19

Costello syndrome

Answer 19

HRAS

Question 20

Cardio-Facio-Cutaneous syndrome

Answer 20

BRAF, MEK1, MEK2

Question 21

Aarskog

Answer 21

FGD1; X linked recessive

Question 22

WAGR syndrome

Answer 22

=aniridia-wilms tumor

deletion of 11p13 including genes PAX6 (aniridia) and WT1 (Wilms tumor suppressor gene)

Question 23

Cri du Chat syndrome

Answer 23

partial deletion of 5p

Question 24

Wolf-Hirschhorn syndrome

Answer 24

partial deletion of 4p

Question 25

Sotos syndrome

Answer 25

NSD1

Question 26

Alagille syndrome

Answer 26

JAG1, NOTCH2
>89% JAG1 mutations, JAG1 deletions (7%), NOTCH2 (1-2%)
Autosomal dominant, 50-70% de novo
Mechanism: haploinsufficiency

Question 27

Brugada syndrome

Answer 27

SCN5A (15-30% of cases)
pathogenic variants have been reported in 22 other genes, each <1% of Brugada syndrome.
Autosomal dominant
Mechanism: mutations cause lack of expression of or acceleration in the inactivation of cardiac sodium channels

Question 28

Cardio-facio-cutaneous syndrome

Answer 28

BRAF, MAP2K1, MAP2K2, KRAS
Autosomal dominant, mostly de novo
Mechanism: sustained activation of the Ras MAPK pathway downstream effectors

Question 29

Costello syndrome

Answer 29

HRAS
Autosomal dominant, mostly de novo
Mechanism: missense mutations lead to constituitive activation of the abnormal protein product resulting in increased signaling through the Ras MAP Kinase pathway

Question 30

HHT

Answer 30

ACVRL1, ENG, GDF2, SMAD4
Autosomal dominant
Mechanism: assumed to be a result of haploinsufficiency

Question 31

Holt-Oram

Answer 31

TBX5, SALL4
Autosomal dominant (85% de novo)
Mechanism: decreased gene dosage either due to rapid degredation of mutant mRNAs or diminished DNA binding

Question 32

Name 2 conditions caused by abnormalities in the gene PMP22.

Answer 32

1. CMT1 (PMP22 duplications)

2. Hereditary neuropathy with liability to pressure palsies (PMP22 deletions or mutations)

Question 33

Ataxia-Telangiectasia. What is the gene and normal function of the protein? Mechanism of disease?

Answer 33

=ATM

• protein finds double strand DNA breaks and coordinates cell cycle checkpoints prior to repair
• ATM is recessive due to LOF of protein (most pathogenic variants are null variants and no protein is made)

Question 34

Sotos syndrome

Answer 34

NSD1

• either by recurrent 1.9 Mb deletion at 5q35 involving NSD1 or pathogenic variant in NSD1
• microdeletion form is a recurrent microdeletion mediated by non-homologous allelic recombination due to flanking low copy repeats