1. (C) The condition in this family is Barth syndrome which is an X-linked recessive condition that mainly affects males and causes syndromic left ventricular noncompaction, intellectual disability, and hypotonia. In the current case, 2-year-old male has Barth syndrome and his maternal uncle also had Barth syndrome, suggesting mother is a carrier of the disease. Therefore, likelihood the fetus is affected is based on the likelihood the mother (an obligate carrier) passes on the mutation (50%) multiplied by the likelihood that the fetus is male (50%), so 25% or 1/4. Therefore, a carrier mother in X-linked disorders has a 25% chance of having an unaffected son, unaffected daughter, unaffected daughter who also is a carrier, and an affected son (Figure 13.2).

2. (B) Homozygous pathogenic mutations in the DNAJC19 gene are associated with 3-methylglutaconic aciduria, type V which leads to dilated cardiomyopathy with ataxia (DCMA) syndrome. Since it is a homozygous condition, an affected individual has to inherit the identical mutant allele from both their biological mother and their biological father. In the current case as there is no other family history of cardiac disease other than his two siblings, it suggests that their biological mother and father are both carriers of the disease. There are four possibilities of inheritance if you do not know the patient’s health status: 25% noncarrier, 50% carrier, 25% affected. Since the patient has a normal echo and the family history is consistent with infantile onset dilated cardiomyopathy which should have manifested by this age, there is 1/3 (33.3%) chance that he is a noncarrier and a 2/3 (66.7%) chance that he is a carrier.

3. (B) Autosomal recessive is the most likely answer considering the presence of affected siblings but no other affected family members. Autosomal dominant is less likely due to the unaffected status of parents; X-linked recessive is unlikely since a female is affected; de novo is unlikely given multiple affected siblings; and mitochondrial genes are maternally inherited which is unlikely due to unaffected status of mother.

4. (E) Variants of uncertain significance are inconclusive findings with genetic testing and should not be used to quote recurrence risk unless additional evidence reclassifies the variant to likely pathogenic or pathogenic.

5. (D) MELAS is a condition caused by mutations in the mitochondrial gene MT-TL1. Mitochondria are maternally inherited so only females can pass on the mitochondrial mutations to their children. Given the patient is a male, there is 0% likelihood his daughter inherited his mitochondria and thus, MELAS.

6. (C) Jervell and Lange-Nielsen syndrome is caused by biallelic mutations in the KCNQ1 gene. Heterozygous mutation in this gene cause Long QT Syndrome, so both of the patient’s parents would be at risk for the manifestations of long QT syndrome. Siblings of the patient would have a 25% chance of also having Jervell and Lange-Nielsen; the patient’s parents would be at risk for long QT syndrome. Autosomal recessive conditions, like Jervell and Lange-Nielsen, are rarely de novo due to the requirement of biallelic pathogenic mutation.

7. (D) HCM is typically inherited in an autosomal dominant fashion. This is evident in this family based on the presence of multiple affected individuals spanning multiple generations. X-linked recessive can be ruled out due to the presence of male-to-male transmission; autosomal recessive is unlikely given multiple affected generations; and autosomal dominant with full penetrance is less likely given the patient’s father is unaffected. A person with an autosomal dominant disorder with full penetrance has a 50% chance of passing on the disease to a child (Figure 13.3).

8. (C) This child has Williams syndrome. Of patients with Williams syndrome, 90% have a deletion identifiable at chromosome 7q11. This may not be readily identifiable on routine karyotype but can be seen on FISH or microarray testing. Deletions on chromosome 11q23 cause Jacobsen syndrome. Deletions on chromosome 22q11.2 cause the constellation of disorders including DiGeorge syndrome and velocardiofacial syndrome. Both 1p36 and 8p23.1 are lesser recognized deletion syndromes that may result in patients with congenital heart disease.

9. (C) Holt-Oram syndrome is an autosomal dominant disorder caused by mutations of the TBX5 gene. Patients most often present with abnormalities of the carpal bones of the wrist, which can include a malformed or missing thumb. Around 75% of patients have cardiac manifestations, the most common form being atrial septal defects.

10. (C) Patients with DiGeorge syndrome have an increased risk of conotruncal abnormalities compared to the other syndromes listed, particularly interrupted aortic arch and truncus arteriosus. The most common type of interrupted aortic arch in these patients is the type B interruption, between the second carotid and the ipsilateral subclavian artery.

11. (C) The patient has cri-du-chat syndrome (5p-syndrome) which is caused by deletion of part of the short arm of chromosome 5. Children with cri-du-chat syndrome have microcephaly, round face, hypertelorism, micrognathia, epicanthal folds, low-set ears, hypotonia, and severe psychomotor and mental retardation. One of the characteristic features is a high-pitched cat like cry. The best form of genetic testing for assessing deletion or duplication on the chromosome is microarray or fluorescent in situ hybridization (FISH). Karyotyping is obtained in chromosomal aneuploidies like Down syndrome or Turner syndrome. While Mendelian gene disorders like Noonan syndrome (PTPN1) may require single testing gene, gene panels, or even expanded whole exome sequencing.

12. (C) The vignette is describing a patient with LEOPARD syndrome, characterized by (L) lentigines, (E) electrocardiographic conduction defects, (O) ocular hypertelorism, (P) pulmonary stenosis, (A) abnormal genitals, (R) retarded growth with subsequent short stature, and (D) deafness. LEOPARD syndrome is an autosomal dominant disorder and overlaps in many features with Noonan syndrome. Similar to Noonan syndrome, mutations in PTPN11 and RAF1 have been implicated in LEOPARD syndrome.

13. (B) Kartagener syndrome is an autosomal recessive disorder including situs inversus, bronchiectasis, and immotility of cilia in the respiratory tract. As a result, these patients have poor mucociliary clearance, increasing their risk of having lower and upper respiratory infections, particularly sinusitis, bronchitis, pneumonia, and otitis. Patients with DiGeorge syndrome may have an increased risk of infection secondary to T-cell dysfunction. Wiskott-Aldrich is an X-linked disorder characterized by thrombocytopenia, eczema, and immune deficiency. Carney complex is an autosomal dominant syndrome of skin hyperpigmentation, endocrine overactivity, and myxomas of the skin and heart.

14. (A) The gene NKX2.5 is located on chromosome 5q. Mutations in NKX2.5 have been identified in familial cohorts of patients with atrial septal defects and conduction anomalies including heart block. Mutations in TBX5 cause Holt-Oram syndrome, with associated large atrial septal defects and radial anomalies. Mutations in MLL2 have been implicated in Kabuki syndrome. Mutations in JAG1 cause Alagille syndrome. PTNP11 is one of several genes which have been implicated in Noonan syndrome.

15. (D) The patient has Marfan syndrome, based on his enlarged aortic root/sinus of Valsalva and his systemic features. If he had a positive family history of Marfan syndrome, the aortic enlargement would be all that was needed to make a definitive diagnosis in him, even in the absence of systemic features. He should be followed with serial echocardiography for the remainder of his life (at least annually now that his aorta is dilated) and may be referred for surgery. He should have an eye examination to look for ectopia lentis. The normal extra-aortic vessels indicate that we are not likely dealing with Loeys-Dietz syndrome, though there is considerable overlap between all of the thoracic aortopathies.

16. (C) The patient has been diagnosed with congenital polyvalvular dysplasia, a valvular developmental disorder that results in thickened leaflets with significant regurgitation and prolapse. It typically involves two or more valves but can involve all four valves of the heart. This disorder most commonly occurs in patients with trisomy 18. In fact, at least 90% of patients with trisomy 18 have some form of valvular dysplasia. Many patients will have an associated ventricular septal defect or other congenital lesion.

17. (D) Patients with Turner syndrome and Noonan syndrome have a higher incidence of partial anomalous venous return. Additionally, patients with visceral heterotaxy, polysplenia, and asplenia have a high incidence of anomalous venous return.

18. (C) Friedreich ataxia is an inherited neuromuscular disorder caused by loss of function mutations in the FXN gene located on chromosome 9q13. Patients with Freidreich’s ataxia have neurologic dysfunction that is generally characterized by progressive ataxia of limbs and gait. Patients with Freidreich’s ataxia can also present with left ventricular hypertrophy which is generally symmetric and concentric.

19. (B) The family history is consistent with Noonan syndrome, of whom up to 85% of the patients may have congenital heart disease (most commonly pulmonary valvular stenosis, ASD, partial AV canal, coarctation, and hypertrophic cardiomyopathy). The right ventricular lift and short systolic ejection murmur suggest mild pulmonary valve stenosis, likely secondary to a thickened pulmonary valve. Noonan syndrome can affect both males and females. Bicuspid aortic valves and coarctation are common in Turner syndrome, and supravalvular pulmonary and aortic stenosis are common in Williams syndrome. Pulmonary branch stenosis is seen commonly in Alagille syndrome.

20. (A) Around 30% of patients with Turner syndrome have congenital heart disease, mostly involving the left-sided cardiac structures. Bicuspid aortic valve is the most common (15%), followed by coarctation (10%), and rarely mitral valve anomalies and hypoplastic left heart syndrome (<5%). Aortic root and ascending aorta dilatation are an issue as Turner patients get older, as there is a risk of aortic dissection and sudden death. As such, guidelines for management of patients with Turner syndrome advocate for routine screening with echocardiography, even in the absence of prior congenital heart disease.

21. (B) Alagille syndrome is an autosomal dominant disorder that presents with particular facial features including a triangular-shaped face, broad forehead, and deep-set eyes. They tend to have butterfly vertebrae, a paucity of bile ducts, and many will require liver transplantation. The most common cardiac manifestations include peripheral pulmonary stenosis and tetralogy of Fallot.