GENETICS OF CONGENITAL HEART DISEASE
Introduction
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
| 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 |
