KEY POINTS

• 1.
  

  Birth defects are among the leading causes of morbidity and mortality in children and are present in 3% to 6% of births.

  
  
• 2.
  

  The most common birth defects, which account for nearly half of the birth defects in the United States, are congenital heart disease, neural tube defects, oral facial clefts, and hypospadias.

  
  
• 3.
  

  Causes of birth defects include genetic causes such as chromosome disorders, copy number variants, monogenic disorders, epigenetics, and common variants, in addition to environmental contributions.

  
  
• 4.
  

  For each type of birth defect, there is a long list of possible genetic causes.

  
  
• 5.
  

  Many genetic variants can cause different birth defects or other associated medical or neurodevelopmental issues in different patients.

  
  
• 6.
  

  For syndromic birth defects, genetic testing should include chromosome microarray with reflex testing to exome sequencing.

  
  
• 7.
  

  For isolated birth defects in newborns, all the features may not yet be recognized. Chromosome microarray is routine, and exome sequencing is increasingly used as the cost of clinical sequencing decreases and as clinical utility is demonstrated.

Summary

Birth defects are among the leading causes of morbidity and mortality in children and are present in 3% to 6% of births. The majority of birth defects are thought to be isolated and nonsyndromic at birth; however, as the child grows and develops, many are appreciated to be associated with other medical problems, difficulty with growth, and/or neurodevelopmental and behavioral issues. The etiologies for most birth defects are unknown and are likely multifactorial. However, as genomic technologies have matured and been used to interrogate large cohorts of individuals with birth defects, a range of genetic causes have been identified, including chromosome disorders, copy number variants (CNVs), monogenic disorders, epigenetics, and common variants. In some cases, there may be contributions from both the maternal and fetal genomes because the mother’s genotype influences the metabolism of cofactors such as folate that may be critical to certain birth defects including neural tube defects. A limitation to the systematic analysis of the etiology of birth defects has been the limited availability of unbiased prospective data from mothers during pregnancy along with birth and long-term outcomes paired with comprehensive genomic data to assess the contribution of genes and environment and their interactions. Advances in genomic tools have now made it possible to genomically assess fetuses and newborns with birth defects to diagnose the 20% to 30% of cases with identifiable genetic etiologies and provide more accurate prognostic information and tailored surveillance as well as intervention to those infants likely to have associated medical and neurodevelopmental issues. In addition to supporting the care of the infant, this genetic information can provide important information to parents to accurately estimate the risk of recurrence and provide families with informed reproductive strategies for future pregnancies.

Introduction

Nearly 8 million children are born each year with a serious birth defect worldwide. The incidence of structural birth defects ranges from approximately 3% to 6% of all live births. Birth defects are a leading cause of infant mortality. The most common birth defects, which account for nearly half of the birth defects in the United States, are congenital heart disease (CHD), neural tube defects, oral facial clefts, and hypospadias. Most structural birth defects develop during the first trimester, and the majority of these defects are isolated and affect only one organ system. When birth defects are not isolated they are often referred to as syndromic, and in some but not all such cases, genetic etiologies can be identified. When birth defects are isolated, they are often termed nonsyndromic, and the etiology is more complex and thought to include an interaction between maternal and fetal genes and environment, including folic acid levels, maternal smoking, alcohol, obesity, diabetes, and teratogenic exposures.

CHD is the most common type of birth defect and is present in approximately 1% of all live births. ^, CHD often requires at least one if not multiple surgeries. Neural tube defects result from incomplete closure of the vertebrae or skull, leading to exposed portions of the brain or spinal cord. The incidence of neural tube defects varies widely around the world, and the incidence has been decreased by folic acid supplementation. Oral facial clefts are a result of disturbed facial development, are present in approximately 2 in 1000 births, and are associated with problems feeding, speaking, and hearing. Hypospadias is present in approximately 3 in 1000 births and is often repaired by a simple surgical procedure.

Human development requires coordination of cell migration, proliferation, and cell death that ultimately determines embryonic form and function. The complexity of these developmental processes requires coordinated interaction of multiple genes in biologic pathways that can be disturbed by germline mutations, somatic mutations, epigenetics, stochastic events, and environmental agents. There are challenges to studying each of these mechanisms given that access to the appropriate cells or tissues at the appropriate time in development is often not possible in humans. Nonetheless, we have been able to advance our understanding of constitutional genomic causes of birth defects with advances in sequencing technology and capacity and the ability to readily identify de novo genetic events on a genome-wide basis.

In the following sections we will review the most common birth defect, CHD, as a representative birth defect. Other birth defects are similar in the types of genetic contributions, although the relative frequency of different classes of genetic variants and specific environmental exposures differ by birth defect.

Congenital Heart Disease

Chromosomal Aneuploidies

Aneuploidy is an abnormal number of chromosomes such as a trisomy. The risk of most aneuploidies increases with increasing maternal age. In the Baltimore–Washington Infant Study, chromosomal abnormalities were identified more than 100 times more frequently in patients with CHD compared with normal controls, with a total of 12.9% of CHD cases having chromosomal abnormalities. The following sections review some of the most common aneuploidy syndromes associated with CHD. Table 78.1 contains further details on some of these syndromes.

Copy Number Variations

CNVs consist of deletions or duplications of contiguous regions of DNA that affect approximately 12% of the genome and can impact either a single gene or multiple contiguous genes. Pathogenic CNVs tend to be de novo and large and to disrupt coding portions of genes that are dosage sensitive. These are found more frequently in patients with CHD compared with controls. CNVs are observed more frequently in patients with CHD and extracardiac features compared with those with isolated CHD. In 2007, Thienpont et al. used array-comparative genomic hybridization in patients with CHD and associated extracardiac anomalies and identified likely pathogenic CNVs in 17% of patients. In 2014, Glessner et al. performed whole exome sequencing (WES) in 538 patients with CHD and found that 9.8% of patients without a previous genetic diagnosis had a rare de novo CNV. Table 78.1 lists several of the CNVs associated with CHD.

Recent data have demonstrated that CNVs are not only causative of CHD, but they also impact clinical outcomes. In 2013, Carey et al. compared neurocognitive and growth outcomes in patients with single-ventricle physiology and found that patients with pathogenic CNVs had decreased linear growth, and those with CNVs associated with known genomic disorders had the poorest neurocognitive and growth outcomes. Kim et al. examined CNVs in 422 cases of nonsyndromic CHD and found that the presence of a likely pathogenic CNV was associated with significantly lower transplant-free survival after surgery. The increased risk of morbidity in patients with large CNVs may be due to additional genes that are impacted or due to pleiotropic effects of single genes within the region. Some of the most common syndromes caused by CNVs and associated with CHD are described below.

Single-Gene Defects

In addition to CNVs, de novo sequence variants in single genes have been identified using ES in patients with CHD, both in syndromic and nonsyndromic cases. Patients with CHD have an excess burden of de novo protein-altering variants in genes that are expressed during cardiac development. A European study using ES in 1891 patients found that in patients with nonisolated CHD, there were an increased number of de novo protein-truncating variants and deleterious missense variants in known autosomal-dominant CHD-associated genes and in non-CHD genes associated with developmental delay. In patients with isolated CHD, there was a much lower frequency of de novo deleterious variants, but there was an increase in rare, inherited protein-truncating variants in CHD-associated genes, likely representing mutations that are incompletely penetrant.

Monogenic Conditions Causing Syndromic CHD

As sequencing techniques have improved, the genetic causes of several well-characterized clinical syndromes have been discovered. The following section describes examples of the most common monogenic syndromes associated with CHD. These syndromes are inherited in an autosomal-dominant manner. Some are caused by variants in one gene and others are genetically heterogeneous. Table 78.2 contains additional details for selected syndromes.

Table 78.2

Common Monogenic Conditions Associated With Syndromic Congenital Heart Disease

Syndrome	Gene(s)	Loci	Live Birth Prevalence	Common Clinical Features	Associated Congenital Heart Disease	Patients With the Genetic Condition Who Have CHD, %	References
Adams-Oliver	DLL4 DOCK6 EOGT NOTCH1	15q15.1 19p13.2 3p14.1 9q34.3	Unknown (rare)	Aplasia cutis congenital, transverse terminal limb defects	BAV, PDA, PS, VSD, ASD, TOF	20	Hassed et al.
Alagille	JAG1 NOTCH2	20p12.2 1p12-p11	1 in 100,000	Bile duct paucity, cholestasis, posterior embryotoxin, butterfly vertebrae, renal defects	Branch pulmonary artery stenosis, TOF, PA	90–95	McElhinney et al., Emerick et al., McDaniell et al., Turnpenny et al.
Axenfeld-Rieger	FOXC1	6p25.3	1 in 200,000	Ocular anomalies including glaucoma, dental anomalies, redundant periumbilical skin	ASD, AS, PS, TOF, BAV, TA	Unknown	Gripp et al.
Baller-Gerold and Rothmund- Thomson	RECQL4	8q24.3	Unknown (rare)	Radial hypoplasia, craniosynostosis, poikiloderma, growth deficiency, malignancy	VSD, TOF, subaortic stenosis	25	Van Maldergem et al., Fradin et al.
Bardet-Biedl	BBS2 BBS6	16q13 20p12.2	1 in 100,000 to 1 in 160,000	Retinal dystrophy, polydactyly, obesity, genital anomalies, renal dysfunction, learning difficulties	AS, PS, PDA, cardiomyopathies	7–50	Forsythe et al., Suspitsin et al.
Cantu	ABCC9	12p12.1	Unknown (rare)	Congenital hypertrichosis, osteochondroplasia, macrocephaly, coarse facial features	Cardiomegaly, ventricular hypertrophy, PDA, BAV	60–75	Grange et al., Scurr et al.
Carpenter	RAB23	6p11.2	Unknown (rare)	Craniosynostosis, polysyndactyly, obesity	ASD, VSD, TOF, PDA, PS	18–50	Kadakia et al., Jenkins et al.
Cardiofaciocutaneous	BRAF KRAS MAP2K1 MAP2K2	7q34 12p12.1 15q22.31 19p13.3	1 in 810,000	Curly hair, sparse eyebrows, feeding difficulty, developmental delay	PS, ASD, VSD, HCM	75	Jhang et al., Pierpont et al.
Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	CDK13	7p14.1	Unknown (rare)	Intellectual disability, hypertelorism, upslanted palpebral fissures, wide nasal bridge and narrow mouth, seizures	ASD, VSD, PS	56	Sifrim et al., Hamilton et al., Bostwick et al.
Char	TFAP2B	6p12.3	Unknown (rare)	Dysmorphic facies, abnormal fifth digit, strabismus, hearing anomalies	PDA, VSD	26–75	Satoda et al., Satoda et al.
CHARGE	CHD7	8q12	1 in 10,000 to 1 in 15,000	Coloboma, choanal atresia, growth retardation, genital hypoplasia, ear anomalies, intellectual disability	TOF, PDA, DORV, AVSD, VSD	75–85	Trider et al., Corsten-Janssen et al.
Coffin-Siris	ARID1B SMARCA4	6q25 22q11	Unknown (rare)	Intellectual disability, feeding difficulty, coarse facies, hypoplastic distal phalanges, hypertrichosis	ASD, VSD, PS, AS, dextrocardia, CoA, PDA, TOF	44	Kosho et al., Nemani et al.
Cornelia de Lange	NIPBL	5p13	1 in 10,000 to 1 in 30,000	Growth retardation, dysmorphic facies, hirsutism, limb deficiency	VSD, ASD, PS, PDA	13–70	Selicorni et al.
Costello	HRAS	11p15.5	1 in 300,000 to 1 in 1,250,000	Short stature, feeding difficulties, coarse facial features, skin abnormalities, intellectual disability	PS, ASD, VSD, HCM, arrhythmias	50–60	Abe et al., Lin et al.
Ellis–van Creveld	EVC EVC2	4p16.2 4p16.2	1 in 60,000 to 1 in 200,000	Short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth	Common atrium	60–75	O’Connor et al., Ruiz-Perez et al., ,
Fragile X	FMR1	Xq27.3	1 in 4000 males, 1 in 8000 females	Intellectual disability, autism spectrum disorder, macrocephaly, macroorchidism, seizures, prominent forehead, large ears, hyperflexibility	MVP, aortic dilation	10–20	Kidd et al.
Genitopatellar or Ohdo/SBBYS	KAT6B	10q22.2	Unknown (rare)	Intellectual disability, genital and patellar anomalies	ASD, VSD, PFO	50	Campeau et al.
Heterotaxy	GDF1 NODAL ZIC3	19p13.11 10q22.1 Xq26.3	1 in 10,000	Biliary atresia, abdominal situs abnormality, spleen abnormality, isomerism of lungs and bronchi, systemic venous anomalies	Pulmonary venous anomalies, atrial anomalies, AVSD, PS, AS, conotruncal anomalies	>90	Belmont et al., Jin et al., Lin et al.
Holt-Oram	TBX5	12q24.1	1 in 100,000	Upper limb anomalies	ASD, VSD, AVSD, conduction defects	75	McDermott et al., Basson et al.
Johanson-Blizzard	UBR1	15q15.2	Unknown (rare)	Pancreatic insufficiency, hypoplastic/aplastic nasal alae, cutis aplasia, developmental delay, intellectual disability	Dysplastic mitral valve, PDA, VSD, ASD, dextrocardia	10	Alpay et al., Almashraki et al.
Kabuki	KDM6A KMT2D	Xp11.3 12q13	1 in 32,000	Growth deficiency, wide palpebral fissures, arched eyebrows, protruding ears, clinodactyly, intellectual disability	CoA, BAV, VSD	30–50	Hannibal et al., Wessels et al.
Kleefstra	EHMT1	9q34.3	Unknown (rare)	Microcephaly, hypotonia, neuropsychiatric anomalies, broad forehead, synophrys, midface hypoplasia, depressed nasal bridge, short nose, ear anomalies, intellectual disability	ASD, VSD, TOF, PDA, CoA, BAV	40–45	Kleefstra et al., Ciaccio et al.
Koolen–De Vries	KANSL1	17q21.31	1 in 16,000	Hypotonia, friendly behavior, long face, upslanting palpebral fissures, narrow/short palpebral fissures, ptosis, epicanthal folds, bulbous nasal tip (88%), everted lower lip, large prominent ears, intellectual disability, epilepsy, kidney anomalies	ASD, VSD, PDA, BAV, PS	39	Koolen et al. ,
Loeys-Dietz	TGFBR1 TGFBR2 SMAD3	9q22.33 3p24.1 15q22.33	Unknown (rare)	Aortic and peripheral arterial aneurysms, pectus excavatum, scoliosis, talipes equinovarus, hypertelorism, cleft palata/bifid uvula	BAV, PDA, ASD, MVP	30–50	MacCarrick et al., Loughborough et al.
Mandibulofacial dysostosis, Guion-Almeida type	EFTUD2	17q21.31	Unknown (rare)	Microcephaly, midface hypoplasia, micrognathia, choanal atresia, hearing loss, cleft palateintellectual disability	ASD, VSD, PDA	30–60	Lines et al., Lehalle et al.
Marfan	FBN1	15q21.1	1 in 5000	Ocular anomalies (ectopia lentis), skeletal anomalies (arachnodactyly, loose joints), vascular anomalies	AR, MVP	80	Thacoor
Mental retardation, autosomal dominant	KAT6A	8p11.21	Unknown (rare)	Microcephaly, global developmental delay, craniofacial dysmorphism, hypotonia, feeding difficulty, ocular anomalies	PDA, ASD, VSD	Unknown	Tham et al., Arboleda et al.
Mowat-Wilson	ZEB2	2q22.3	Unknown (rare)	Short stature, microcephaly, hypertelorism, pointed chin, Hirschsprung disease, intellectual disability, seizures	VSD, CoA, ASD, PDA, PS	50	Garavelli et al., Zweier et al.
Myhre	SMAD4	18q21.2	Unknown (rare)	Short stature, dysmorphic facies, hearing loss, laryngeal anomalies, arthropathy, intellectual disability	ASD, VSD, PDA, PS, AS, CoA	60	Lin et al.
Nephronophthisis and Meckel- Gruber–like syndrome	NPHP3	3q22.1	Unknown (rare)	Nephronoophthisis, CNS malformations, cystic kidneys, polydactyly, situs inversus	AS, ASD, PDA	20	Bergmann et al., Salonen et al., Tory et al.
Neurofibromatosis	NF1	17q11.2	1 in 3000 to1 in 4000	Changes in skin pigmentation, tumor growth, macrocephaly, scoliosis, hypertension	PS, CoA, MR, PDA, VSD, AS, AR, ASD	2–15	Incecik et al., Lin et al., Leppävirta et al.
Noonan	PTPN11 SOS1 RAF1 KRAS NRAS RIT1 SHOC2 SOS2 BRAF LZTR1	12q24.13 2p22.1 3p25.2 12p12.1 1p13.2 1q22 10q25.2 14q21.3 7q34 22q11.21	1 in 1000 to1 in 2500	Dysmorphic facies, short stature, chest deformities, lymphatic anomalies, skeletal anomalies, hematologic defects	PS, HCM, ASD, TOF, AVSD, VSD, PDA	75–90	Romano et al., , Marino et al., Jhang et al.
Noonan syndrome with multiple lentigines	PTPN11	12q24.13	Unknown (rare)	Multiple lentigines, hearing loss, mild learning issues	HCM, conduction abnormalities	80	Aoki et al., Limongelli et al., Sarkozy et al.
Oculofaciocardiodental (OFCD)	BCOR	Xp11.4	Unknown (rare)	Congenital cataracts, microphthalmia, dysmorphic features, dental anomalies, syndactyly, flexion deformities, intellectual disability	ASD, VSD, PS, AS, PDA, dextrocardia, DORV	66–74	Hilton et al., Horn et al.
Orofaciodigital	OFD1	Xp22.2	Unknown (rare)	Ciliary defects, facial anomalies, abnormal digits, brain and kidney anomalies	ASD, AVSD, HLHS	33–100	Bouman et al.
Peter’s plus	B3GLCT/B3GALTL	13q12.3	Unknown (rare)	Anterior eye anomalies, developmental delay, cleft lip and palate, short statues, broad hands and feet	ASD, VSD, PS, subvalvar AS	25–30	Lesnik et al., Maillette de Buy Wenniger-Prick
Polycystic kidney disease, autosomal dominant	PKD1	16p13.3	1 in 1000	Polycystic kidneys, hypertension, extrarenal cysts	MVP, ASD, PDA	10–20	Dell, Ivy et al.
Renal-hepatic-­pancreatic dysplasia/nephronopthisis	NEK8	17q11.2	Unknown (rare)	Ciliary dysfunction, renal, hepatic and pancreatic anomalies	Cardiomegaly, HCM, septal defects, PDA	Unknown	Grampa et al., Rajagopalan et al.
Roberts	ESCO2	8p21.1	Unknown (rare)	Growth retardation, cleft lip/palate, hypertelorism, sparse hair, symmetric limb reduction, cryptorchidism, intellectual disability	ASD, AS	20–50	Van Den Berg et al., Goh et al.
Robinow	ROR2	9q22.31	Unknown (rare)	Mesomelic limb shortening, hypertelorism, nasal anomalies, midface hypoplasia, brachydactyly, clinodactyly, micropenis, short stature, scoliosis	PS, VSD, ASD, DORV, TOF, CoA, TA	15–30	Al-Ata et al., Mazzeu et al.
Rubinstein-Taybi	CBP EP300	16p13.3 22q13.2	1 in 100,000 to 1 in 125,000	Growth retardation, microcephaly, highly arched eyebrows, long eyelashes, down-slanting palpebral fissures, broad nasal bridge, beaked nose, highly arched palate, broad thumbs, large toes, intellectual disability	PDA, VSD, ASD	30	Stevens et al., Hennekam
Sifrim-Hitz-Weiss	CHD4	12p13.31	Unknown (rare)	Developmental delay, hearing loss, macrocephaly, palate abnormalities, ventriculomegaly, hypogonadism, intellectual disability	PDA, ASD, VSD, BAV, TOF, CoA	Unknown	Sifrim et al., Weiss et al.
Smith-Lemli-Opitz	DHCR7	11q12–13	1 in 15,000 to 1 in 60,000	Growth retardation, dysmorphic facial features, genital anomalies, limb anomalies, intellectual disability	AVSD, ASD, VSD	50	Lin et al., Digilio et al., Waterham et al.
Sotos	NSD1	5p35.3	1 in 10,000 to 1 in 50,000	Tall stature, macrocephaly, high anterior hairline, frontal bossing, thin face, downslanting palpebral fissures, advanced bone age, developmental delay	ASD, PDA, VSD	8–50	Leventopoulos et al.
Syndromic microphthalmia/pulmonary hypoplasia- diaphragmatic hernia-anophthalmia- cardiac defect (PDAC)	STRA6	15q24.1	Unknown (rare)	Pulmonary hypoplasia, diaphragmatic defects, bilateral anopthalmia, contractures, camptodactyly	ASD, VSD, PS, PDA, PA, TOF, CoA, TA	50	Marcadier et al.
Townes-Brocks	SALL1	16p12.1	1 in 250,000	Imperforate anus, dysplastic ears, thumb malformations, renal agenesis, multicystic kidneys, microphthalmia	VSD, ASD, PA, TA	20–30	Liberalesso et al., Miller et al.
Weill-Marchesani	ADAMTS10	19p13.2	Unknown (rare)	Short stature, brachydactyly, joint stiffness, microspherophakia, ectopia lentis	MVP, AS, PS	50	Dagoneau et al., Kojuri et al.

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