Physical Address

304 North Cardinal St.
Dorchester Center, MA 02124

Genetics of Common Birth Defects in Newborns


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

Evidence for the Genetic Basis of Congenital Heart Disease

The etiology of CHD is multifactorial. A genetic or environmental cause can be identified in about 20% to 30% of all cases, and that number is changing as new methods of testing become available.

The overall incidence of CHD is similar between males and females; however, there are differences by type of CHD, with males having a slightly higher incidence of more severe lesions. , There are also differences in incidence of specific lesions based on race and ethnicity. Patent ductus arteriosus (PDA) and ventricular septal defects (VSDs) are more common in Europeans whereas atrial septal defects (ASDs) are more common in Hispanics. , The differences observed based on gender and ethnicity suggest that genetics play an important role in the development of specific types of CHD, with certain populations having increased genetic susceptibility.

The risk of CHD recurrence in the offspring of an affected parent is between 3% and 20%, depending on the lesion. Recurrence risk in the offspring of women with CHD is about twice as high as the recurrence in offspring of men with CHD. Lesions with the highest recurrence risk are heterotaxy (HTX), right ventricular outflow tract obstruction, and left ventricular outflow tract obstruction. Approximately half of siblings with recurrent CHD have a different lesion, supporting the theory that the etiology of CHD is multifactorial.

Overall, twins have an increased risk of CHD compared with singleton pregnancies, which is thought to be due to vascular changes related to a shared placenta for monochorionic twins. A population-based Taiwanese study calculated the adjusted risk ratio for CHD with an affected relative and found that it was 12.03 for a twin, 4.91 for a first-degree relative, and 1.21 for a second-degree relative.

Genetic Testing in Congenital Heart Disease

Genetic testing for a fetus with CHD can start in the prenatal period with either chorionic villus sampling at 10 to 11 weeks’ gestation or amniocentesis after 15 to 16 weeks’ gestation to obtain placental/fetal DNA. More recently, noninvasive prenatal testing has been used to obtain fetal cell-free DNA from maternal blood to screen for aneuploidies and common deletions or duplications, most notably 22q11.2 deletion syndrome. Noninvasive prenatal testing is a screening test, and abnormal findings require confirmatory testing using chorionic villi, amniocytes, or postnatal testing.

Clinical genetic testing in infants with CHD using karyotyping, fluorescence in situ hybridization (FISH), and chromosome microarray analysis (CMA) has an overall clinical yield of 15% to 25%, with a higher likelihood of finding a genetic diagnosis in patients with dysmorphic facial features and extracardiac anomalies. Karyotyping allows for the identification of aneuploidies and large chromosomal rearrangements. CMA is used to detect CNVs across the genome and can reliably detect deletions or duplications as small as approximately 100,000 nucleotides. If a specific deletion or duplication syndrome is suspected, FISH can be used and allows for rapid turnaround and focused testing. It is most commonly used to test for 22q11.2 deletion.

Recent decreases in sequencing cost allow for more comprehensive assessment of the genome and have powered gene panel testing, exome sequencing (ES), and whole genome sequencing (WGS) in CHD. For each of these tests, significant bioinformatics analysis is required after sequencing to determine the significance of the variant in each individual patient, often using data from family members to assess for the inheritance status and segregation with CHD in the family. ES targets the protein-coding regions, which compose about 1.5% of the genome, and it has been particularly useful in assessing patients with CHD and extracardiac features. ES is used increasingly in clinical practice because CHD is so genetically heterogeneous and because our knowledge of CHD genetics is incomplete. The yield of ES for CHD in the clinical setting of a single large genetic reference laboratory was 28%. WGS sequences the entire genome, including noncoding regions, but studies have not yet demonstrated the additional clinical utility of WGS in patients with CHD. WGS in CHD, however, remains an area of active investigation.

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.

Table 78.1
Common Aneuploidies and Copy Number Variants Associated With Syndromic Congenital Heart Disease
Syndrome Genetic Change Prevalence in Live Births Common Clinical Features Associated Congenital Heart Disease Patients With the Condition Who Have CHD, % References
Aneuploidies
Down syndrome Trisomy 21 1 in 800 Hypotonia, flat facies, epicanthal folds, upslanting palpebral fissures, single palmar transverse crease, small ears, skeletal anomalies, intellectual disability AVSD, VSD, ASD, PDA (less commonly TOF, D-TGA) 40–50 de Graaf et al., , Allen et al., Bull et al.
Patau syndrome Trisomy 18 1 in 8000 Clenched hands, short sternum, limb anomalies, rocker-bottom feet, micrognathia, esophageal atresia, severe intellectual disability PDA, ASD, VSD, AVSD, polyvalvular dysplasia, TOF, DORV 80–95 Musewe et al., Embleton et al., , Van Praagh et al., Springett et al.
Edward syndrome Trisomy 13 1 in 20,000 Midline facial defects, scalp defects, forebrain defects, polydactyly, hypotelorism, microcephaly, deafness, skin and nail defects, severe intellectual disability PDA, ASD, VSD, HLHS, laterality defects 57–80 Musewe et al., Lin et al., Springett et al., Wyllie et al., Goldstein et al.
Turner syndrome 45, X 1 in 2500 Short stature, broad chest with wide-spaced nipples, webbed neck, congenital lymphedema, normal intelligence or mild learning disability BAV, CoA, PAPVR, HLHS 35 Sybert et al., Gravholt et al.
Microdeletions/duplications
Deletion 1p36 syndrome 1p36 deletion 1 in 5000 Growth deficiency, microcephaly, deep-set eyes, low-set ears, hearing loss, hypotonia, seizures, genital anomalies, intellectual disability ASD, VSD, PDA, BAV, PS, MR, TOF, CoA, cardiomyopathy 70 Battaglia et al.
1q21.1 deletion 1q21.1 deletion Unknown (rare) Short stature, cataracts, mood disorders, autism spectrum disorder, hypotonia PDA, VSD, ASD, TOF, TA 33 Bernier et al.
1q21.1 duplication 1q21.1 duplication Unknown (rare) Autism spectrum disorder, attention deficit hyperactivity disorder, intellectual disability, scoliosis, short stature, gastric ulcers TOF, D-TGA,PS 27 Bernier et al.
1q41q42 microdeletion 1q41q42 microdeletion Unknown (rare) Developmental delay, frontal bossing, deep-set eyes, broad nasal tip, cleft palate, clubfeet, seizure, short stature, congenital diaphragmatic hernia BAV, ASD, VSD, TGA 40–50 Rosenfeld et al.
2q31.1 microdeletion 2q31.1 microdeletion Unknown (rare) Growth retardation, microcephaly, craniosynostosis, cleft lip/palate, limb anomalies, genital anomalies VSD, ASD, PDA, PS 38 Dimitrov et al., Mitter et al.
2q37 microdeletion 2q37 microdeletion Unknown (rare) Short stature, obesity, intellectual disability, sparse hair, arched eyebrows, epicanthal folds, thin upper lip, small hands and feet, clinodactyly, central nervous system anomalies, ocular anomalies, gastrointestinal anomalies, renal anomalies, genitourinary anomalies CoA, ASD, VSD 14–20 Casas et al., Falk et al.
3p25 deletion 3p25 deletion Unknown (rare) Growth deficiency, microcephaly, hypotonia, polydactyly, renal anomalies, intellectual disability AVSD, VSD 33 Shuib et al.
Wolf-Hirschhorn syndrome 4p16.3 deletion 1 in 20,000 to 1 in 50,000 Feeding difficulty, seizures/epilepsy, microcephaly, wide spaced eyes, broad nasal bridge, intellectual disability ASD, PS, VSD, PDA 50–65 Battaglia et al.
Deletion 4q 4q deletion 1 in 100,000 Growth deficiency, craniofacial anomalies, cleft palate, genitourinary defects, digital anomalies, intellectual disability VSD, PDA, peripheral pulmonic stenosis, AS, ASD, TOF, CoA, tricuspid atresia 50 Xu et al.
Cri-du-chat 5p deletion 1 in 15,000 to 1 in 50,000 Catlike cry, growth retardation, hypotonia, dysmorphic features, intellectual disability PDA, VSD, ASD 15–20 Nguyen et al., Hills et al.
Williams-Beuren syndrome 7q11,23 deletion ( ELN gene) 1 in 20,000 Dysmorphic facial features, connective tissue abnormalities, skeletal and renal anomalies, cognitive defects, mild intellectual disability, growth and endocrine abnormalities including hypercalcemia in infancy Supravalvar AS, supravalvar PS, branch pulmonary artery stenosis 50–80 Morris et al., Kececioglu et al., Morris
8p23.1 deletion 8p23.1 deletion (including GATA4 ) Unknown (rare) Microcephaly, growth retardation, congenital diaphragmatic hernia, developmental delay, neuropsychiatric problems AVSD, ASD, VSD, PS, TOF 50–75 Wat et al.
Deletion 9p syndrome 9p deletion Unknown (rare) Trigonocephaly, midface hypoplasia, long philtrum, hypertelorism, up-slanting palpebral fissures, abnormal ears, abnormal external genitals, hypotonia, seizures, intellectual disability PDA, VSD, ASD, CoA 45–50 Huret et al., Swinkels et al.
Kleefstra syndrome 9q34.3 subtelomeric deletion (including EHMT1 ) Unknown (rare) Intellectual disability, delayed speech hypotonia, microcephaly, brachycephaly, hypertelorism, synophrys, midface hypoplasia, anteverted nares, prognathism, everted lips, macroglossia, behavioral problems, obesity ASD, VSD, TOF, pulmonary arterial stenosis 30–47 Kleefstra et al., Kleefstra et al.
Deletion 10p 10p deletion Unknown (rare) Hypoparathyroidism, immune deficiency, deafness, renal anomalies, intellectual disability PS, BAV, ASD, VSD 42 Lindstrand et al.
Duplication 10q24-qter 10q duplication Unknown (rare) Growth retardation, hypotonia, microcephaly, dysmorphic facies, kidney anomalies, limb anomalies, intellectual disability TOF, AVSD, VSD 20–50 Aglan et al., Carter et al.
Jacobsen syndrome 11q deletion 1 in 100,000 Growth retardation, developmental delay, thrombocytopenia, platelet dysfunction, wide-spaced eyes, strabismus, broad nasal bridge, thin upper lip, prominent forehead, intellectual disability, autism, immunodeficiency VSD, HLHS, AS, CoA, Shone’s complex 56 Grossfeld et al.
15q24 microdeletion 15q24 microdeletion Unknown (rare) Growth retardation, intellectual disability, abnormal corpus callosum, microcephaly, abnormal ears, hearing loss, genital anomalies, digital anomalies PDA, pulmonary arterial stenosis, PS 20–40 Mefford et al.
Koolen-de Vries syndrome 17q21 microdeletion 1 in 16,000 Hypotonia, developmental delay, seizures, facial dysmorphisms, friendly behavior ASD, VSD 27 Koolen et al.
22q11.2 deletion syndrome (DiGeorge, velocardiofacial syndrome) 22q11.2 deletion 1 in 6000 Hypertelorism, broad nasal root, long and narrow face, long, slender fingers, hypocalcemia, immunodeficiency, behavioral problems, autism spectrum disorder, learning disability, psychiatric problems IAA type B, TA, TOF, right aortic arch 75–80 Botto et al., Digilio et al., Peyvandi et al.
22q11.2 duplication 22q11.2 duplication Unknown Velopharyngeal insufficiency, cleft palate, hearing loss, facial anomalies, urogenital abnormalities, mild learning disability, hypotonia, scoliosis, frequent infections VSD, aortic regurgitation, MVP, CoA, TOF, HLHS, IAA, TA, D-TGA 15 Portnoï
Phelan-McDermid syndrome 22q13 microdeletion Unknown (rare) Developmental delay, intellectual disability, hypotonia, absent/delayed speech, autism spectrum disorder, long, narrow head, prominent ears, pointed chin, droopy eyebrows, deep-set eyes TR, ASD, PDA, TAPVR 25 Phelan et al.
a Jones KM, Jones MC, Del Campo M. P. Smith’s recognizable patterns of human malformation. In: Smith’s Recognizable Patterns of Human Malformation . 7th ed. Elsevier Inc; 2013:7–83.
AS, Aortic stenosis; ASD, atrial septal defect; AVSD, atrioventricular septal defect; BAV, bicuspid aortic valve; CoA, coarctation of the aorta; DORV, double outlet right ventricle; D-TGA, d-loop transposition of the great arteries; HLHS, hypoplastic left heart syndrome; IAA, interrupted aortic arch; MR, Mitral regurgitation; MVP, mitral valve prolapse; PAPVR, partial anomalous pulmonary venous return; PDA, patent ductus arteriosus; PS, pulmonary stenosis; TA, truncus arteriosus; TAPVR, total anomalous pulmonary venous return; TOF, tetralogy of Fallot; TR, tricuspid regurgitation, VSD, ventricular septal defect.
Adapted from Pierpont et al., 2018.

Down Syndrome

Down syndrome is the most common chromosomal abnormality found in patients with CHD and is usually caused by complete trisomy 21. CHD is found in 40% to 50% of patients with Down syndrome, most commonly atrioventricular septal defect (AVSD) in approximately 40% followed by VSD, ASD, PDA, and tetralogy of Fallot (TOF). , Down syndrome is also associated with a variety of other dysmorphic features and birth defects.

Trisomy 18 and 13

Many fetuses with trisomy 18 or 13 have multiple birth defects and do not survive to birth; however, among those who do, CHD is common. Ninety-five percent of patients with trisomy 18 have CHD, with PDA and VSD being the most common diagnoses. The majority of trisomy 13 patients have cardiac defects, with PDA, ASD, and VSD being the most common lesions. , Life expectancy is limited in both trisomy 18 and 13, and individuals generally die within the first year of life.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here

Related Posts