Birth defects are among the leading causes of morbidity and mortality in children and are present in 3% to 6% of births.
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.
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.
For each type of birth defect, there is a long list of possible genetic causes.
Many genetic variants can cause different birth defects or other associated medical or neurodevelopmental issues in different patients.
For syndromic birth defects, genetic testing should include chromosome microarray with reflex testing to exome sequencing.
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.
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.
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.
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.
|Syndrome||Genetic Change||Prevalence in Live Births||Common Clinical Features||Associated Congenital Heart Disease||Patients With the Condition Who Have CHD, %||References|
|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.|
|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.|
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.
Turner syndrome is a sex chromosome disorder that results from a complete or partial loss of an X chromosome, resulting in the 45, X karyotype. Those with mosaicism or structural abnormalities of the X chromosome tend to have less severe phenotypes compared with those with complete loss. , The most common cardiac lesions associated with Turner syndrome are left-sided lesions, including bicuspid aortic valve in 30% of patients and coarctation of the aorta in 10% of patients. More serious lesions such as partial anomalous pulmonary venous return and hypoplastic left heart syndrome are less common. ,
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.
22q11.2 deletion syndrome is the most common microdeletion syndrome associated with CHD. The majority of patients clinically diagnosed with DiGeorge or velocardiofacial syndrome have a microdeletion of 22q11.2. Of patients with 22q11.2 deletion, 75% to 80% have CHD, with conotruncal defects being the most common lesions. The prevalence of 22q11.2 deletion in patients with CHD is highest in patients with type B interrupted aortic arch, truncus arteriosus, TOF, and isolated aortic arch anomalies. Among patients with conotruncal lesions, up to 50% have a 22q11.2 deletion.
Williams-Beuren syndrome, or Williams syndrome, is caused by a contiguous gene deletion at 7q11.23 that encompasses the elastin gene ELN. , Similar to 22q11.2 deletion syndrome, deletions are often sporadic but can be inherited. Between 50% and 80% of patients with Williams syndrome have CHD, most commonly supravalvar aortic stenosis, supravalvar pulmonic stenosis, and branch pulmonary artery stenosis.
Mutations in ELN , a critical component of vascular tissue, are observed in patients with autosomal-dominant isolated supravalvar aortic stenosis, leading to the conclusion that haploinsufficiency of this gene is the etiology of CHD in patients with Williams syndrome. , ,
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.
|Syndrome||Gene(s)||Loci||Live Birth Prevalence||Common Clinical Features||Associated Congenital Heart Disease||Patients With the Genetic Condition Who Have CHD, %||References|
|Unknown (rare)||Aplasia cutis congenital, transverse terminal limb defects||BAV, PDA, PS, VSD, ASD, TOF||20||Hassed et al.|
|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.|
|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.|
|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.|
|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 |
|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.|
|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.|
|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. ,|
|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.|
|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.|
|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.|