– Genetics of Congenital Heart Disease




The field of medical genetics is rapidly expanding into other areas of medicine, particularly pediatric cardiology. Over the last several decades, hundreds of genetic variations have been discovered to produce changes in sarcomere proteins, conduction systems, mineral regulation, energy production, transcription factors, and signaling proteins that result in cardiomyopathies, arrhythmias, and structural malformations. In finding the cause of these lesions, the field of cardiology has been able to further elaborate pathophysiology and improve classification of disease for more accurate diagnosis. Understanding the etiology has improved the understanding of prognosis and disease progression, and provides an opportunity for therapeutic advancement in managing current disease and preventing the development of disease.

This chapter has been written to provide the practicing pediatric cardiologist and neonatologist with a logical way to approach the genetics of congenital heart disease (CHD) and incorporate the concepts into clinical practice. It is assumed that the basic principles and concepts of cardiovascular molecular biology and genetics are familiar to the reader. In this chapter, we will categorize the syndromes associated with congenital heart problems for concise generation of differential diagnosis, explain appropriate workup, and review conditions that are commonly encountered in the neonate.

Categorizing CHD

As a physician taking care of the newborn, whether a pediatrician, pediatric cardiologist, or neonatologist, the practice of expanding the differential diagnosis beyond the heart lesion establishes a foundation for elevated clinical suspicion for underlying genetic etiology. Much like genetic syndromes have a recurring pattern of presentation, heart lesions with genetic etiology can have a similar pattern. Establishing an accurate diagnosis has many benefits to the physician caring for the neonate and the baby that will be discussed later in this chapter.

A comprehensive list of syndromes with significant cardiac involvement and categorized by type of heart lesion is provided in Table 15.1. There are several syndromes with specific lesions and many syndromes that have nonspecific lesions that overlap into several categories. For purposes of convenience, the syndromes that overlap into other categories have been listed in a mixed category. The major categories include aneurysms, arrhythmias, dilated cardiomyopathies, hypertrophic cardiomyopathies, metabolic cardiomyopathies, structural abnormalities, tumors, and syndromes with specific lesions. These categories have been broken down into subcategories to further refine differential diagnosis.

Table 15.1. List of syndromes associated with cardiac abnormalities

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Sep 8, 2016 | Posted by in CARDIOLOGY | Comments Off on – Genetics of Congenital Heart Disease
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Name of condition Other names Etiology Type of heart defect Associated features Testing available Inheritance
Structural defects
Septal defects
2q37 Deletion syndrome Albright hereditary osteodystrophy-like syndrome, brachydactyly mental retardation syndrome 2q37 deletion ASD, VSD, PDA Dysmorphic, intellectual disability, short stature, brachymetaphalangy, hypotonia, obesity, seizures, CNS abnormalities, gastrointestinal abnormalities Yes Autosomal dominant, 95% de novo
Beckwith–Wiedemann syndrome
Paternal uniparental disomy 11p15, loss of maternal methylation IC2 of 11p15, gain of maternal methylation IC1 of 11p15 ASD, VSD Macrosomia, macroglossia, visceromegaly, embryonal tumors, omphalocele, hypoglycemia, ear creases/pits, adrenocortical cytomegaly, renal abnormalities, hemihyperplasia Yes Autosomal dominant in 15% of cases
Char syndrome
TFAP2B mutation PDA, VSD Dysmorphic, Polydactyly, Hypoplasia of third fingers Yes Autosomal Dominant
Chondrodysplasia punctata 2, X-linked Conradi–Hunermann syndrome, Happle syndrome EBP mutation ASD, VSD Dysmorphic, chondrodysplasia punctata, rhizomelic shortening, polydactyly, ectodermal defects, ophthalmologic anomalies, Dandy-Walker, cryptorchidism, hypospadias Yes X-linked
Cornelia de Lange syndrome Brachmann–de Lange syndrome NIPBL, SMC1A, SMC3 mutation Septal defects Dysmorphic, growth retardation, hirsuitism, upper-limb anomalies, mental impairment, behavioral abnormalities, GI dysfunction, hearing loss, myopia, crytorchidism Yes Autosomal dominant, 99% de novo; SMC1A X-linked
Ellis–van Creveld (EVC) syndrome Chondroectodermal dysplasia EVC, EVC2 mutation ASD Polydactyly, natal teeth, short stature, short ribs, short limbs, cleft palate, fusion of the hamate and capitate Yes Autosomal recessive
Feingold syndrome 1 Oculodigitoesophagoduodenal syndrome MYCN mutation Minor cardiac anomalies Digital anomalies, microcephaly, short palpebral fissures, GI anomalies Yes Autosomal dominant
Fryns syndrome
Unknown ASD, VSD Diaphragmatic defect, dysrmorphic, distal digital hypoplasia, pulmonary hypoplasia, polyhydramnios, cloudy cornea, orofacial cleft, brain anomalies, renal dysplasia, GI malformation, GU malformation No Autosomal recessive
Holt–Oram syndrome Heart and hand syndrome TBX5 mutation ASD, VSD, conduction abnormalities Upper-limb anomalies Yes Autosomal dominant, 85% de novo
Jourbert syndrome with cardiac involvement
CEP290, TMEM216, KIF7, TCTN3 mutation VSD, situs inversus Molar tooth sign, hypotonia, developmental delay, breathing abnormalities, truncal ataxia, variable intellectual disability, oculomotor apraxia, renal disease, hepatic fibrosis, polydactyly, oral hamartomas Yes Autosomal recessive
KAT6B-related disorders Genitopatellar syndrome, Say-Barber-Biesecker variant of Ohdo syndrome KAT6B mutation ASD, VSD, PFO Long thumbs/great toes, mask-like face, blepharophimosis/ptosis, lacrimal duct anomalies, patellar hypoplasia/agenisis, dental anomalies, hearling loss, thyroid anomalies, cleft palate, hypotonia, global developmental delay Yes Autosomal dominant, most de novo
McKusick-Kaufman syndrome
MKKS mutation Atrioventricularis communis with left-sided superior vena cava, ASD, VSD, AV canal defects, hypoplastic left heart, tetralogy of fallot, PDA Hydrometrocolpos, postaxial polydactyly, GU anomalies Yes Autosomal recessive
MED12-related disorders FG syndrome Type 1, Opitz–Kaveggia syndrome, Lujan syndrome, Lujan–Fryns syndrome, mental retardation X-linked with marfanoid habitus MED12 mutation Septal defects, AV canal defects, hypoplastic left heart, MV prolapse, PDA Dysmorphic, short stature, intellectual disability, behavioral anomalies, hypotonia, seizures, ophthalmologic anomalies, GI abnormalities, broad thumbs and halluces Yes X-linked
NSDHL-related disorders CHILD syndrome, CK syndrome NSDHL mutation Septal defects, unilateral ventricle, single coronary ostium Unilateral ichthyosiform lesions and ipsilateral limb defects, cartilagionous calcifications, CNS anomalies, lung hypoplasia, intellectual disability, dysmorphic, microcephaly Yes X-linked
Primary ciliary dyskinesia Immotile cilia syndrome, Kartagener syndrome DNAI1, DNAAF3, DNAH5, HYDIN, NME8, DNAH11, DNAI2, DNAAF2, RSPH4A, RSPH9, DNAAF1, CCDC39, CCDC40, DNAL1, CCDC103, HEATR2, LRRC6 mutation Situs inversus, heterotaxy Respiratory distress, chronic airway infection, recurrent sinus infection, recurrent ear infection, infertility Yes, panel available Autsomal recessive
Roberts syndrome Roberts-SC phocomelia syndrome, pseudothalidomide syndrome, SC-phocomelia syndrome ESCO2 mutation ASD, VSD, PDA Growth retardation, limb malformations, dysmorphic, GU anomalies Yes Autosomal recessive
Rubinstein–Taybi syndrome Broad thumbs-hallux syndrome CREBBP or EP300 mutation ASD, VSD Dysmorphic, talon cusps, broad thumbs/great toes, undescended testicles, GU anomalies, short stature, mental impairment Yes Autosomal dominant, most de novo
Smith–Lemli–Opitz syndrome RSH syndrome, SLO syndrome DHCR7 mutation AV canal defects, anomalous pulmonary return Failure to thrive, hypotonia, GI anomalies, intellectual disability, behavioral abnormalities, GU anomalies, dysmorphic, cataracts Yes Autosomal recessive
Smith–Magenis syndrome del(17)(p11.2) 17p11.2 deletion, RAI1 mutation ASD, VSD Dysmorphic, hypotonia, feeding difficulties, FTT, short stature, brachydactyly, ophthalmologic anomalies, otolaryngologic anomalies, hearing loss, peripheral neuropathy, developmental delay, cognitive impairment, neurobehavioral anomalies, sleep disturbances Yes Autosomal dominant, most de novo
Sotos syndrome Cerebral gigantism NSD1 mutation ASD, VSD, PDA Dysmorphic, learning disability, overgrowth, behavior problems, advanced bone age, joint laxity, renal anomalies, scoliosis, seizures Yes Autosomal dominant, 95% de novo
Thrombocytopenia absent radius syndrome Radial aplasia amegakaryocytic thrombocytopenia, radial aplasia thrombocytopenia syndrome, TAR syndrome 1q21.1 200kb deletion, RBM8A mutation ASD, VSD Bilateral absent radii, present thumbs, thrombocytopenia, skeletal anomalies, cow’s milk allergy, GU anomalies Yes Autosomal recessive
Trisomy 13 Patau syndrome 47, XX, +13; 47, XY, +13 ASD, VSD Severe intellectual disability, dysmorphic, microphthalmia, polydactyly, brain anomalies, spine anomalies, cleft lip/palate, hypotonia, early death Yes Nondisjunction; unbalanced translocation
Trisomy 18 Edward syndrome 47, XX, +18; 47, XY, +18 ASD, VSD Severe intellectual disability, growth retardation, microcephaly, dysmorphic, clenched fists with overlapping fingers, early death Yes Nondisjunction; unbalanced translocation
Trisomy 21 Down syndrome 47, XX, +21; 47, XY, +21 ASD, VSD Intellectual disability, dysmorphic, hypotonia, duodenal atresia, hypothyroidism Yes Nondisjunction; unbalanced translocation
X-linked Opitz G/BBB syndrome Opitz syndrome MID1 mutation ASD, VSD, PDA, persistent left superior vena cava Hypertelorism, hypospadias, laryngotracheoesophageal abnormalities, intellectual disability, developmental delay, imperforate anus, midline defects Yes X-linked
Conotruncal defects
22q11.2 deletion syndrome DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome, autosomal dominant G/BBB syndrome, Sedlackova syndrome, Cayler cardiofacial syndrome 22q11.2 deletion Conotruncal malformations: Tetralogy of fallot, interrupted aortic arch, VSD, truncus arteriosus Palatal abnormalities, hypocalcemia, immune deficiency, learning difficulties, dysmorphic, dysphagia, growth hormone deficiency, autoimmune disease, hearing loss, polydactyly, GU anomalies, laryngotracheoesophageal anomalies, ophthalmologic anomalies, CNS anomalies, GI anomalies, preauricular tags/pits, neoplasms Yes Autosomal dominant, 93% de novo
CHARGE syndrome
CHD7 mutation Conotrucal malformations: Tetralogy of fallot, AV canal defects, aortic arch anomalies Ocular coloboma, choanal atresia, cranial nerve I/VII/VIII/IX/X dysfunction, ear anomalies, genital hypoplasia, developmental delay, growth deficiency, cleft lip/palate, tracheoesophageal fistula, dysmorphic Yes Autosomal dominant, most de novo
Cytochrome P450 oxidoreductase deficiency Antley-Bixler syndrome Elevated metabolites of pregnenolone and progesterone associated with 17 and 21 hydroxlase deficiencies. POR mutation Transposition of the great vessels, VSD, ASD, PFO, hypoplastic right atrium Craniosynostosis, brachycephaly, severe midface hypoplasia, radiohumeral synostosis, multiple joint contractures Yes Autsomal recessive
Coarctation of the aorta
Kabuki syndrome Kabuki makeup syndrome, Niikawa–Kuroki syndrome, KMT2D-related Kabuki, and KDM6A-related Kabuki KMT2D (MLL2) and KDM6A mutation Left-sided obstructive lesions especially coarctation, septal defects Dysmorphic, spinal column abnormalities, brachydactyly, clinodactyly, persistent fetal fingertip pads, cleft lip/palate, GU anomalies, GI anomalies, ophthalmologic anomalies, dental anomalies, ear pits, microcephaly Yes Autosomal dominant, most de novo
Turner syndrome Monosomy X syndrome 45, X Coarctation Short stature, premature ovarian failure, webbed neck, lymphedema, skeletal anomalies Yes Nondisjunction
Mixed structural defects
1p36 deletion syndrome Monosomy 1p36 syndrome 1p36 deletion ASD, VSD, PDA, coarcation of the aorta, valvular anomalies, PDA, tetralogy of fallot, infundibular stenosis of the right ventricle, Ebstein anomaly Dysmorphic, developmental delay, hypotonia, ophthalmologic anomalies, skeletal anomalies, hearing anomalies, GU anomalies, feeding difficulties, seizures, intellectual disability Yes Autosomal dominant, most de novo
1q21.1 deletion syndrome
1q21.1 deletion Coarctation, interrupted aorta, PDA, ASD, VSD, truncus arteriosus Dysmorphic, microcephaly, short stature, ophthalmologic anomalies, intellectual disability, failure to thrive, joint laxity, seizures, hypotonia Yes Autosomal dominant, 18%–50% de novo
Bardet–Biedl syndrome
BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, CEP290, WDPCP, SDCCAG8 mutation Aortic stenosis, PDA, ASD, VSD Cone-rod dystrophy, postaxial polydactyly, truncal obesity, learning disabilities, hypogonadism, renal anomalies, developmental delay, behavioral abnormalities, ophthalmologic anomalies, ataxia, orodental abnormalities, dysmorphic, Yes Autosomal recessive
Branchio-oculo-facial syndrome BOF syndrome TFAP2A mutation ASD, tetralogy of fallot Branchial defect, ocular anomaly, dysmorphic, ectopic thymus, renal anomalies, ectodermal anomalies, growth restriction Yes Autosomal dominant, 50%–60% de novo
Cranioectodermal dysplasia Sensenbrenner syndrome, cranioectodermal dysplasia 1,2,3,4 IFT122, WDR35, IFT43, WDR19 mutation PDA, ASD, VSD, mitral/tricuspid valve thickening, ventricular hypertrophy, peripheral pulmonary stenosis Dysmorphic, hand/foot anomalies, pectus abnormality, rib deformities, short stature, ectodermal defects, GU anomalies, GI anomalies, brain anomalies Yes Autosomal recessive
Diamond-Blackfan anemia Congenital hypoplastic anemia of Blackfan and Diamond RPS19, RPL5, RPS10, RPL11, RPL35A, RPS26, RPS24, RPS17, RPS7, RPL26, GATA1 mutation VSD, ASD, coarctation of aorta Microcephaly, dysmorphic, ophthalmologic anomalies, webbed neck, upper-limb and hand anomalies, GU anomalies Yes Autosomal dominant, 55%–60% de novo; GATA1 X-linked
Emanuel syndrome Supernumerary der(22)5(11;22) syndrome 47, XX or 47, XY +der(22)t(11;22)(q23;q11) ASD, VSD, tetralogy of fallot, truncus arteriosus, tricuspid atresia, coarctation of the aorta, aberrant subclavian artery, persistent left superior vena cava, PDA Growth retardation, dysmorphic, GU anomalies, GI anomalies, hypotonia, congenital hip dislocation, arachnodactyly, cleft palate, microcephaly, developmental delay, intellectual disability Yes All product of balanced translocation carriers (recurrence 5.6%)
Fanconi anemia Fanconi pancytopenia FANCA, FANCB, FANCC, BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, BRIP1, FANCL, FANCM, PALB2, RAD51C, SLX4 mutation PDA, ASD, VSD, coarctation of the aorta, truncus arteriosus, situs inversus Short stature, abnormal skin pigmentation, malformations of the thumb, skeletal anomalies, ophthalmologic anomalies, hearing loss, developmental delay, GI anomalies, renal anomalies, hypogonadism, progressive bone marrow failure Yes Autosomal recessive, FANCB X-linked
KANSL1-related intellectual disability syndrome 17q21.31 microdeletion syndrome KANSL1 mutation or 17q21.21 deletion ASD, VSD, valve disease, aortic root dilatation, pulmonary stenosis Dysmorphic, developmental delay, hypotonia, epilepsy, nevi, hair abnormalities, dental anomalies, long/slender fingers, joint laxity, CNS anomalies, GU anomalies, skeletal anomalies Yes Autosomal dominant, most de novo
Kleefstra syndrome 9q subtelomeric deletion syndrome, 9q34.3 microdeletion syndrome EHMT1 mutation or 9q34.3 deletion ASD, VSD, tetralogy of fallot, aortic coarctation, bicuspid aortic valve, pulmonic stenosis Intellectual disability, dysmorphic, renal anomalies, genital anomalies, hypotonia, seizure disorder, brain anomalies Yes Autosomal dominant, Most de novo
Lymphedema-distichiasis syndrome Lymphedema with distichiasis FOXC2 mutation ASD, VSD, PDA, tetralogy of fallot, arrhythmia Lower-limb lymphedema, distichiasis, ocular abnormalities, ptosis Yes Autosomal dominant, 25% de novo
Otopalatodigital spectrum disorders Frontometaphyseal dysplasia, Melnick–Needles syndrome, otopalatodigital syndrome Type I and II, terminal osseous dysplasia with pigmentary skin defects, myxomatous cardiac valvular dystrophy FLNA mutation Cardiac valve disease, septal defects, right ventricular outflow obstruction Short stature, dysmorphic, thoracic hypoplasia, hypoplastic thumbs, scoliosis, cleft palate Yes X-linked
Peters Plus syndrome
B3GALTL mutation ASD, VSD, subvalvular aortic stenosis, pulmonary stenosis, bicuspid pulmonary valve Anterior chamber anomalies of the eye, short stature, dysmorphic, cleft palate, pscyhomotor delay Yes Autsomal recessive
ROR2-related Robinow syndrome Fetal face syndrome ROR2 mutation Pulmonary valve stenosis, ASD, VSD, coarctation of the aorta, tetralogy of fallot, tricuspid atresia Dysmorphic, dental anomalies, skeletal anomalies, urogenital anomlaies, growth hormone deficiency Yes Autosomal recessive
SALL4-related disorders Acro-renal-ocular syndrome, Duane-radial ray syndrome, Okihiro syndrome, SALL4-related Holt–Oram syndrome SALL4 mutation ASD, VSD, tetralogy of fallot Duane anomaly, radial ray malformation, ophthalmologic anomalies, GU anomalies, GI anomalies, dysmorphic Yes Autosomal dominant, 40% to 50% de novo
Simpson-Golabi-Behmel syndrome GPC3 related, GP4 related GPC3 and GPC4 mutation Septal defects, pulmonic stenosis, coarctation, transposition, PDA, PFO Macrosomia, macrocephaly, dysmorphic, ophthalmologic anomalies, ear abnormalities, cystic hygroma, supernumerary nipples, GU anomalies, GI anomalies, skeletal anomalies Yes X-linked
Townes–Brocks syndrome
SALL1 mutation ASD, VSD, tetralogy of fallot, truncus arteriosus, pulmonary valve atresia, PDA Imperforate anus, dysplastic ears, hearing impairment, thumb malformations, GU anomalies, foot malformations, Duane anomaly, Arnold-Chiari malformation, growth retardation, intellectual disability Yes Autosomal dominant, 50% de novo
Wolf–Hirschhorn syndrome 4p-syndrome, monosomy 4p, Pitt-Rogers-Danks syndrome 4p16.3 deletion ASD, pulmonary stenosis, VSD, PDA, aortic insufficiency, tetralogy of fallot Dysmorphic, IUGR, intellectual disability, hypotonia, seizures, feeding difficulties, skeletal anomalies, immunodeficiency Yes Autosomal dominant, 45% with unbalanced translocation
Hypertrophic cardiomyopathy
Cardiofaciocutaneous syndrome
BRAF, KRAS, MAP2K1, MAP2K2 mutation Pulmonic stenosis, ASD, VSD, hypertrophic cardiomyopathy, heart valve anomalies Dysmorphic, macrocephaly, ectodermal anomalies, musculoskeletal anomalies, ophthalmologic anomalies, growth hormone deficiency, developmental delay, hypotonia, GU anomalies Yes Autosomal dominant
Costello syndrome