Holt-Oram syndrome (HOS) is characterized by upper-limb defects, congenital heart malformation, and cardiac conduction disease. Upper-limb malformations may be unilateral, bilateral/symmetric, or bilateral/asymmetric and can range from triphalangeal or absent thumb(s) to phocomelia. Other upper-limb malformations can include unequal arm length caused by aplasia or hypoplasia of the radius, fusion or anomalous development of the carpal and thenar bones, abnormal forearm pronation and supination, abnormal opposition of the thumb, sloping shoulders, and restriction of shoulder joint movement. An abnormal carpal bone is present in all affected individuals and may be the only evidence of disease. A congenital heart malformation is present in 75% of individuals with HOS and most commonly involves the septum. Atrial septal defect and ventricular septal defect can vary in number, size, and location. Complex congenital heart malformations can also occur in individuals with HOS. Individuals with HOS with or without a congenital heart malformation are at risk for cardiac conduction disease. While individuals may present at birth with sinus bradycardia and first-degree atrioventricular (AV) block, AV block can progress unpredictably to a higher grade including complete heart block with and without atrial fibrillation.

A rare congenital heart malformation with characteristics of underdevelopment of the right ventricle associated with patent foramen ovale or interauricular communication and normally developed tricuspid and pulmonary valves. Manifests with severe cyanosis, congestive heart failure, and in severe cases, death in early infancy.

Autosomal visceral heterotaxy-7 is an autosomal recessive developmental disorder characterized by complex congenital heart malformations and/or situs inversus and caused by defects in the normal left-right asymmetric positioning of internal organs. The phenotype is variable (summary by Guimier et al., 2015). For a discussion of the genetic heterogeneity of visceral heterotaxy, see HTX1 (306955).

Cardiac valvular dysplasia-1 (CVDP1) is characterized by congenital malformations of the pulmonic, tricuspid, and mitral valves. Structural cardiac defects, including atrial and ventricular septal defects, single left ventricle, and hypoplastic right ventricle have also been observed in affected individuals (Ta-Shma et al., 2017). Genetic Heterogeneity of Cardiac Valvular Dysplasia CVDP2 (620067) is caused by mutation in the ADAMTS19 gene (607513) on chromosome 5q23.