Genetics and Congenital Heart Disease
Jonathan N. Johnson
1. A 2-year-old male is referred after the finding of left ventricular noncompaction on cardiac MRI. The patient’s mother reports a family history of left ventricular noncompaction, intellectual disability, and hypotonia in her now deceased brother. The patient’s mother is currently 6 weeks pregnant with her second child. What is the likelihood the fetus is affected by the same genetic disorder?
A. 75% (3/4)
B. 50% (1/2)
C. 25% (1/4)
D. 3% to 5%
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. A 30-year-old healthy male is referred due to a family history of infantile onset dilated cardiomyopathy in two of his siblings. There is no other family history of cardiac disease and he himself has a normal echo. Genetic testing in his siblings revealed homozygous pathogenic mutations in the DNAJC19 gene, associated with 3-methylglutaconic aciduria, type V. This condition has 100% penetrance. What is the likelihood your patient is a carrier of this condition?
A. 100% (1)
B. 66.7% (2/3)
C. 50% (1/2)
D. 25% (1/4)
E. None of the above
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. The pedigree in the image is most consistent with what inheritance pattern (Figure 13.1)?
A. Autosomal dominant
B. Autosomal recessive
C. X-linked recessive
D. De novo
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. A 7-month-old female dies suddenly of sudden infant death syndrome (SIDS). Autopsy is negative for cardiac anomalies. The decedent’s family is motivated to determine cause of death to better understand risk to future children and other family members. Genetic testing on postmortem tissue reveals a variant of uncertain significance in the KCNH2 gene. What do you estimate the risk for future children to also suffer cardiac arrest based on this genetic finding?
A. 100% (4/4)
B. 50% (1/2)
C. 25% (1/4)
D. 3% to 5%
E. Cannot estimate based on genetic finding
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. A 33-year-old male with hypertrophic cardiomyopathy, epilepsy, and hearing loss is found to have a pathogenic mutation in MT-TL1, causative of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS). He has a healthy 3-year-old son and 1-year-old daughter. What do you estimate the likelihood his daughter is also affected by MELAS?
B. 50% (1/2)
C. 25% (1/4)
E. Cannot be determined with data provided
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. A 2-year-old female is diagnosed with Jervell and Lange-Nielsen syndrome due to an abnormal electrocardiogram and profound bilateral sensorineural hearing loss. Based on this diagnosis, you can conclude that:
A. Any siblings of the patient will also be affected by Jervell and Lange-Nielsen
B. The patient’s parents would be unaffected carriers of this condition
C. The patient’s parents are at risk for prolonged QT
D. This condition is most likely de novo in the patient
E. The patient will also have visual impairment
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. An 18-year-old male is seen due to diagnosis of hypertrophic cardiomyopathy (HCM). His family history is significant for his paternal aunt, paternal uncle, and paternal grandmother with HCM. The patient’s father has had normal echocardiograms. What is the most likely inheritance pattern in this family?
A. X-linked recessive
B. Autosomal recessive
C. Autosomal dominant, full penetrance
D. Autosomal dominant, reduced penetrance
E. Mitochondrial pattern
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. A 2-month-old male infant is referred for failure to thrive and is diagnosed with supravalvar pulmonary stenosis and supravalvar aortic stenosis on echocardiography. The child is described as having an “elfin” face, with flared eyebrows, bright stellate irides, and a wide mouth. A deletion on which of the following chromosomes can lead to this presentation?
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. A 10-month-old male infant is referred to you with a history of atrial septal defect. On examination, you note that the patient has a missing thumb on his right hand. The patient’s father also has a similar missing thumb. On further evaluation, all laboratory values, including CBC and electrolytes, are normal. Genetic analysis reveals a mutation in the TBX5 gene. Which of the following is the most likely diagnosis?
A. Thrombocytopenia-absent radii (TAR) syndrome
B. LEOPARD syndrome
C. Holt-Oram syndrome
D. CHARGE association
E. Rubenstein-Taybi syndrome
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. A neonate is diagnosed with truncus arteriosus. Which of the following genetic syndromes is most likely in this patient?
A. Down syndrome
B. Turner syndrome
C. DiGeorge syndrome
D. Klinefelter syndrome
E. Holt-Oram syndrome
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. A 5-day-old female is diagnosed with a moderate-sized ventricular septal defect. On physical examination, she has hypotonia, microcephaly, hypertelorism, low set ears, and a high-pitched cry. There is no family history of any genetic disorders. Which of the following is the best diagnostic test from genetic standpoint?
A. No testing needed
C. Fluorescent in situ hybridization
D. Single gene sequencing
E. Gene panel testing
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. A 13-year-old female is seen for a heart murmur. Her parents note that she has numerous dark-brown freckle-like spots throughout her body, which seem to have increased in number as she has gotten older. She has a prior diagnosis of sensorineural deafness, as well as short stature. Her parents report that a murmur was heard in many well-child visits, but was always thought to be benign. An ECG is performed and shows first-degree AV block. Which of the following is most likely to be seen on echocardiography?
A. Coarctation of the aorta and bicuspid aortic valve
B. Atrial and ventricular septal defects
C. Pulmonary stenosis and left ventricular hypertrophy
D. Double aortic arch
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. A 14-year-old male is referred to your clinic. He has a history of recurrent sinusitis for which he has undergone numerous courses of antibiotics. A chest x-ray is performed which shows evidence of dextrocardia. In addition, the stomach bubble is located on the right side of the x-ray. A CT scan of the chest reveals bronchiectasis. Which of the following is the most likely diagnosis?
A. Carney complex
B. Kartagener syndrome
C. DiGeorge syndrome
D. Wiskott-Aldrich syndrome
E. Turner 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 5-year-old female presents with fatigue and is found to have complete heart block. Echocardiography reveals a moderate-sized secundum atrial septal defect. A mutation in which gene is most likely to be found in this patient?
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. A 17-year-old male basketball player is referred to you for a murmur. On examination, you note that he has significant scoliosis, pectus carinatum, and pes planus (flat feet). His height is 190 cm, and his arm span is 210 cm. He has positive “thumb” and “wrist” signs. His aortic root measures 45 mm in diameter (Z-score = 5.2). His carotid arteries, aortic arch, and descending aorta are normal. There is no significant family history. He admits to being admitted twice in the past with spontaneous pneumothoraces. Which of the following is true regarding this young man’s diagnosis?
A. He has Loeys-Dietz syndrome
B. He should have a repeat echocardiogram in 5 years
C. He does not need an eye examination
D. He has Marfan syndrome
E. He needs an ECG to assess for a prolonged QT interval
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. An echo performed on a 2-day-old male infant demonstrates severe tricuspid and mitral valve dysplasia with prolapse. He is diagnosed with congenital polyvalvular dysplasia. Which of the following is the most likely genetic diagnosis in this patient?
A. Down syndrome
B. Noonan syndrome
C. Trisomy 18
D. DiGeorge syndrome
E. Alagille syndrome
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. Which of the following genetic syndromes are associated with an increased incidence of partial anomalous pulmonary venous return?
A. Trisomy 18 and trisomy 21
B. Holt-Oram and Marfan
C. Turner and trisomy 21
D. Turner and Noonan
E. Noonan and Alagille
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. A 5-year-old male has progressive limb ataxia and weakness, dysarthria, nystagmus, and loss of proprioception requiring a wheelchair for mobility. His molecular and genetic testing has revealed a mutation in the frataxin (FXN) gene. Which of the following is the likely cardiovascular phenotype?
A. High-grade atrioventricular block
B. Thickening of aortic and mitral valve
C. Concentric left ventricular hypertrophy
D. Dilation of the left ventricle
E. Reverse curve hypertrophy of the septum
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. A 9-year-old female presents to you for evaluation of a murmur. The patient is asymptomatic, but does not participate in any athletic activity. Her family history is significant for a paternal uncle, grandfather, and great grandfather who had “thick heart muscle.” On examination, she has short stature, a triangular face, pectus excavatum, and a webbed neck. Her heart examination reveals an RV lift and a soft short systolic ejection murmur at the LUSB. What are you most likely to find on her echocardiogram?
A. Bicuspid aortic valve with or without coarctation
B. Thickened pulmonary valve with mild stenosis
C. Discrete supravalvular pulmonary stenosis
D. Bilateral pulmonary branch stenosis
E. Right aortic arch
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. As part of an evaluation for short stature, a 12-year-old female is noted to have streaked gonads on abdominal and pelvic ultrasound examination. A karyotype determines that she has Turner syndrome. Which of the following is most likely to be found on echocardiography?
A. Bicuspid aortic valve
B. Mitral valve stenosis
C. Subaortic membrane
D. Aortic root dilatation
E. Atrial septal defect
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. A 6-week-old female infant with biliary atresia is found to have a murmur on examination. When you see the patient, you note that she has a broad forehead, deep-set eyes, and a pointed chin, which give her face a triangular appearance. She is significantly jaundiced. Auscultation reveals a 2/6 systolic murmur heard best at the left upper sternal border and radiating to the axillae bilaterally. Which of the following is the most likely diagnosis?
A. CHARGE association
B. Alagille syndrome
C. Williams syndrome
D. Noonan syndrome
E. DiGeorge syndrome
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.
22. You have been consulted on an 11-year-old male admitted to the pediatric intensive care unit after being diagnosed with Mobitz type II second degree heart block due to symptoms of dizziness and syncope. On echocardiographic evaluation, his left ventricle is severely dilated with reduced ejection fraction estimated at 25%. There is no mitral valve regurgitation and the intracardiac anatomy is normal without any shunt lesions. He has no recent history of any viral infections and has generally been healthy except symptoms of fatigue over the last few years. On physical examination, he has mild skeletal muscle weakness in lower extremities. The family history is positive for a pacemaker in patient’s father and a paternal uncle who had sudden death with no known etiology. Which of the following mutations is most likely to be found in this patient?
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