Congenital Heart Defects

Question 1

What do all truncal defects have in common?

Answer 1

defects in neural crest migration

Question 2

What are the features of DiGeorge Syndrome?

Answer 2

cardiac: conotruncal defect
immune: thymic aplasia or hypoplasia
hypocalcemia: parathyroid absence/hypoplasia
dysmorphism: hypertelorism, short philtrum, cupid’s bow mouth, ear anomalies

Question 3

Name the cardiac lesions associated with DiGeorge syndrome.

Answer 3

interrupted aortic arch
truncus arteriosus
tetralogy of fallot
isolated VSD

Question 4

What are the features associated with Velocardiofacial syndrome?

Answer 4

cardiac: VSD, tetrology of fallot, R aortic arch
cleft palate (overt or submucosal)
developmental delay (mild to moderate, especially speech)
dysmorphology: slender tapering fingers, prominent nose, abnormal ears, abundant hair

Question 5

What is the genetic etiology of DG/VCF?

Answer 5

unbalanced translocations with monosomy 22q11
18% of DiGeorge patients have chromosomal defects (monosomy 22q11 or monosomy 10p13)
85-90% of DiGeorge patients have 22q11 microdeletions
>80% of VCF patients have 22q11 microdeletions
10% of these cases are inherited

Question 6

What testing is available to look for DG/VCF?

Answer 6

FISH
MLPA
aCGH
(detects 85-90% of cases)

Question 7

What are the “hidden risks” of DG/VCF?

Answer 7

genetic risk (parents with mild phenotype)
medical risks (speech/language delays, palatal surgery, hypocalcemia, late-onset psychiatric disorders in the schizo-effective range)
cardiac risk (risk of blood transfusion and open chest, worse surgical outcomes)

Question 8

What are the major features of Noonan syndrome?

Answer 8

short stature
facial dysmorphisms
cardiovascular disease (pulmonic stenosis, hypertrophic cardiomyopathy, septal defects, aortic coarctation)
skeletal (pectus cavinatum/excavatum, vertebral abnormalities, cubitus valgus)
webbed/short neck
cryptorchidism
bleeding diasthesis
intellectual disability

Question 9

What is the genetic cause of Noonan Syndrome?

Answer 9

PTPN11 missence changes that alter the N-SH2 switching mechanism of the SHP-2 protein tyrosine phosphatase locking it in the active form (gain of function)
many mutations due to APA
more affected males

Question 10

Name the Ras pathway disorders and their genes.

Answer 10

Noonan syndrome (KRAS, NRAS, SOS1, SOS2, FAF1, BRAF, MEK1, SHOC2, CBL, RITI)
Noonan with multiple lentigines (RAF1)
Costello syndrome (HRAS)
Cardiofaciocutaneous (KRAS, BRAF, MEK1, MEK2)

Question 11

What hidden features are associated with Noonan syndrome?

Answer 11

genetic risk (parents with mild phenotypes)
medical risks (developmental delay, complications of bleeding diathesis, utility of growth hormone treatment, leukemia)
cardiac risk (occult hypertrophic cardiomyopathy)

Question 12

What are the genetic causes of teralogy of fallot?

Answer 12

CNVs (10%):

1q21. 1
3p25. 1
7p21. 3

Question 13

How does the precision medicine approach to CHD genetic testing improve patient care?

Answer 13

genotype-specific cardiac outcomes improved with altered cardiac care
genotype-specific non-cardiac outcomes resulting in neurodevelopmental interventions
reproductive decision making (offspring risk and offspring outcomes)