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.

Malonyl-CoA decarboxylase deficiency is an uncommon inherited metabolic disease. The characteristic phenotype is variable, but may include developmental delay in early childhood, seizures, hypotonia, diarrhea, vomiting, metabolic acidosis, hypoglycemia, ketosis, abnormal urinary compounds, lactic acidemia, and hypertrophic cardiomyopathy (Sweetman and Williams, 2001).

Left ventricular noncompaction (LVNC) is characterized by numerous prominent trabeculations and deep intertrabecular recesses in hypertrophied and hypokinetic segments of the left ventricle (Sasse-Klaassen et al., 2004). The mechanistic basis is thought to be an intrauterine arrest of myocardial development with lack of compaction of the loose myocardial meshwork. LVNC may occur in isolation or in association with congenital heart disease. Distinctive morphologic features can be recognized on 2-dimensional echocardiography (Kurosaki et al., 1999). Noncompaction of the ventricular myocardium is sometimes referred to as spongy myocardium. Stollberger et al. (2002) commented that the term 'isolated LVNC,' meaning LVNC without coexisting cardiac abnormalities, is misleading, because additional cardiac abnormalities are found in nearly all patients with LVNC. Genetic Heterogeneity of Left Ventricular Noncompaction A locus for autosomal dominant left ventricular noncompaction has been identified on chromosome 11p15 (LVNC2; 609470). LVNC3 (see 605906) is caused by mutation in the LDB3 gene (605906) on chromosome 10q23. LVNC4 (see 613424) is caused by mutation in the ACTC1 gene (102540) on chromosome 15q14. LVNC5 (see 613426) is caused by mutation in the MYH7 gene (160760) on chromosome 14q12. LVNC6 (see 601494) is caused by mutation in the TNNT2 gene (191045) on chromosome 1q32. LVNC7 (615092) is caused by mutation in the MIB1 gene (608677) on chromosome 18q11. LVNC8 (615373) is caused by mutation in the PRDM16 gene (605557) on chromosome 1p36. LVNC9 (see 611878) is caused by mutation in the TPM1 gene (191010) on chromosome 15q22. LVNC10 (615396) is caused by mutation in the MYBPC3 gene (600958) on chromosome 11p11. LVNC can also occur as part of an X-linked disorder, Barth syndrome (302060), caused by mutation in the TAZ gene (300394) on chromosome Xq28.

Dilated cardiomyopathy-1Y (CMD1Y) is characterized by severe progressive cardiac failure, resulting in death in the third to sixth decades of life in some patients. Electron microscopy shows an abnormal sarcomere structure (Olson et al., 2001). In left ventricular noncompaction-9 (LVNC9), patients may present with cardiac failure or may be asymptomatic. Echocardiography shows noncompaction of the apex and midventricular wall of the left ventricle (Probst et al., 2011). Some patients also exhibit Ebstein anomaly of the tricuspid valve (Kelle et al., 2016) and some have mitral valve insufficiency (Nijak et al., 2018).

Some individuals with left ventricular noncompaction experience no symptoms at all; others have heart problems that can include sudden cardiac death. Additional signs and symptoms include abnormal blood clots, irregular heart rhythm (arrhythmia), a sensation of fluttering or pounding in the chest (palpitations), extreme fatigue during exercise (exercise intolerance), shortness of breath (dyspnea), fainting (syncope), swelling of the legs (lymphedema), and trouble laying down flat. Some affected individuals have features of other heart defects. Left ventricular noncompaction can be diagnosed at any age, from birth to late adulthood. Approximately two-thirds of individuals with left ventricular noncompaction develop heart failure.\n\nLeft ventricular noncompaction is a heart (cardiac) muscle disorder that occurs when the lower left chamber of the heart (left ventricle), which helps the heart pump blood, does not develop correctly. Instead of the muscle being smooth and firm, the cardiac muscle in the left ventricle is thick and appears spongy. The abnormal cardiac muscle is weak and has an impaired ability to pump blood because it either cannot completely contract or it cannot completely relax. For the heart to pump blood normally, cardiac muscle must contract and relax fully.

X-linked syndromic intellectual developmental disorder-34 (MRXS34) is an X-linked recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability with poor speech, dysmorphic facial features, and mild structural brain abnormalities, including thickening of the corpus callosum (summary by Mircsof et al., 2015).

Congenital megabladder (MGBL) is characterized by a massively dilated bladder with disrupted smooth muscle in the bladder wall. MGBL is a sex-limited trait with 95% male predominance, likely the result of differences in urethra and bladder development and length differences in urethra between males and females (Houweling et al., 2019).

Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (VACRDS) is characterized by syncope, cardiac arrest, and/or sudden unexpected death. Polymorphic ventricular tachycardia and ventricular fibrillation have been documented in these patients. Symptoms generally occur with physical activity or emotional stress, but unlike typical catecholaminergic ventricular tachycardia (CPVT), arrhythmias are not reproducible on exercise stress testing or adrenaline challenge (Sun et al., 2021). Mutation in the RYR2 gene also causes catecholaminergic polymorphic ventricular tachycardia-1 (CPVT1; 604772).

Infantile-onset myofibrillar myopathy-12 with cardiomyopathy (MFM12) is a severe autosomal recessive disorder affecting both skeletal and cardiac muscle tissue that is apparent in the first weeks of life. Affected infants show tremor or clonus at birth, followed by onset of rapidly progressive generalized muscle weakness and dilated cardiomyopathy and cardiac failure, usually resulting in death by 6 months of age. Skeletal and cardiac muscle tissues show hypotrophy of type I muscle fibers and evidence of myofibrillar disorganization (summary by Weterman et al., 2013). For a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419).

Combined oxidative phosphorylation deficiency-57 (COXPD57) is an autosomal recessive multisystem mitochondrial disease with varying degrees of severity from premature death in infancy to permanent disability in young adulthood (Lee et al., 2022). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).