The molecular basis of many CHD syndromes has been identified. Monogenic syndromes can include, among others, Holt-Oram, Char, Ellis-van Creveld, Adams-Oliver and Kabuki syndrome. Holt-Oram syndrome is an autosomal dominant disorder most commonly involving the atrial or ventricular septum (ASD or VSD). 70% of cases are caused by a heterozygous pathogenic variant in TBX5. Char syndrome is autosomal dominantly inherited with patent ductus arteriosus (PDA) as the primary cardiac finding, but also other heart defects such as VSD have been reported. ~50% of families with a clinical diagnosis for Char syndrome have a heterozygous pathogenic variant in TFAP2B. Ellis-van Creveld syndrome (EVC) is an autosomal recessive skeletal dysplasia associated with a primary atrial septation defect resulting in a common atrium. Two-thirds of cases of EVC are caused by homozygous or compound heterozygous variants in EVC or EVC2. Adams-Oliver syndrome (AOS) can be inherited autosomal dominantly or recessively. Malformations can include heart, scalp and limbs. Pathogenic variants in ARHGAP31, DOCK6, RBPJ, EOGT, NOTCH1, and DLL4 have been reported. Kabuki syndrome (KS) has both X-linked and autosomal dominant pathogeneses. CHDs occur in 40% to 70% of individuals with KS. The most common cardiac malformations are coarctation of the
aorta, ASD, and VSD. KS is mainly caused by pathogenic variants in the KMT2D and KDM6A genes.
Pierpont et al. 2018, Circulation. Nov 20;138