Danon disease is a multisystem condition with predominant involvement of the heart, skeletal muscles, and retina, with overlying cognitive dysfunction. Males are typically more severely affected than females. Males usually present with childhood onset concentric hypertrophic cardiomyopathy that is progressive and often requires heart transplantation. Rarely, hypertrophic cardiomyopathy can evolve to resemble dilated cardiomyopathy. Most affected males also have cardiac conduction abnormalities. Skeletal muscle weakness may lead to delayed acquisition of motor milestones. Learning disability and intellectual disability, most often in the mild range, are common. Additionally, affected males can develop retinopathy with subsequent visual impairment. The clinical features in females are broader and more variable. Females are more likely to have dilated cardiomyopathy, with a smaller proportion requiring heart transplantation compared to affected males. Cardiac conduction abnormalities, skeletal muscle weakness, mild cognitive impairment, and pigmentary retinopathy are variably seen in affected females.

LMNA-related dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and/or reduced systolic function preceded (sometimes by many years) by or accompanied by conduction system disease and/or arrhythmias. LMNA-related DCM usually presents in early to mid-adulthood with symptomatic conduction system disease or arrhythmias, or with symptomatic DCM including heart failure or embolus from a left ventricular mural thrombus. Sudden cardiac death can occur, and in some instances is the presenting manifestation; sudden cardiac death may occur with minimal or no systolic dysfunction.

Secundum atrial septal defect (ASD) is a common congenital heart malformation that occurs as an isolated anomaly in 10% of individuals with congenital heart disease. Uncorrected ASD can cause pulmonary overcirculation, right heart volume overload, and premature death (summary by Benson et al., 1998). Genetic Heterogeneity of Atrial Septal Defect The ASD1 locus has been mapped to chromosome 5p. Other forms of atrial septal defect that are associated with other congenital heart disease but no conduction defects or noncardiac abnormalities include ASD2 (607941), caused by mutation in the GATA4 gene (600576), and ASD4 (611363), caused by mutation in the TBX20 gene (606061). ASD3 (614089) and ASD5 (612794), in which atrial septal defect is not associated with other cardiac abnormalities, are caused by mutation in the MYH6 (160710) and ACTC1 (102540) genes, respectively. ASD6 (613087), in which atrial septal defect may be associated with aneurysm of the interatrial septum and cardiac arrhythmias, is caused by mutation in the TLL1 gene (606742). ASD7 (108900), in which ASD is often associated with atrioventricular conduction defects, is caused by mutation in the NKX2-5 gene (600584). ASD8 (614433), in which ASD may be associated with other cardiac anomalies, is caused by mutation in the CITED2 gene (602937). ASD9 (614475) is caused by mutation in the GATA6 gene (601656). Somatic mutations in the HAND1 gene (602406) have been identified in tissue samples from patients with ASDs.

A rare, genetic, neurologic disease characterized by primary hyperaldosteronism presenting with early-onset, severe hypertension, hypokalemia and neurological manifestations (including seizures, severe hypotonia, spasticity, cerebral palsy and profound developmental delay/intellectual disability).

Any Meier-Gorlin syndrome in which the cause of the disease is a mutation in the CDC45 gene.

Hydrops, lactic acidosis, and sideroblastic anemia (HLASA) is an autosomal recessive multisystem disorder characterized by the onset of hydrops in utero. The severity of the hydrops and the disorder in general is highly variable. At birth, affected infants usually show poor growth, lactic acidosis, pulmonary hypertension with hypoxic respiratory insufficiency, and sideroblastic anemia. More variable features may include hepatosplenomegaly or cholestasis, hypoglycemia, pancreatic insufficiency, and micropenis or hypospadias. Death in infancy may occur. Those who survive tend to have resolution of lactic acidosis and anemia, but may show developmental delay and sensorineural deafness (summary by Riley et al., 2020).

LQT16 Long QT syndrome-16 (LQT16) is characterized by a markedly prolonged corrected QT (QTc) interval and 2:1 atrioventricular (AV) block, with onset in the perinatal period. Patients experience bradycardia or ventricular tachyarrhythmias that may result in syncope, cardiac arrest, and/or sudden death (Reed et al., 2015; Wren et al., 2019). Patients with LQT14 (616247), LQT15 (616249), or LQT16, resulting from mutation in calmodulin genes CALM1 (114180), CALM2 (114182), or CALM3, respectively, typically have a more severe phenotype, with earlier onset, profound QT prolongation, and a high predilection for cardiac arrest and sudden death, than patients with mutations in other genes (Boczek et al., 2016). CPVT6 Catecholaminergic polymorphic ventricular tachycardia-6 (CPVT6) is characterized by childhood-onset syncopal episodes with exercise or stress. Electrocardiogram (ECG) shows a normal QT interval with a prominent U wave, and stress testing reveals premature ventricular contractions (PVCs) that may occur as bigeminy or couplets, and nonsustained ventricular tachycardia (Gomez-Hurtado et al., 2016).

Autosomal recessive limb-girdle muscular dystrophy-25 (LGMDR25) is characterized by slowly progressive onset of proximal lower limb weakness in adulthood. Affected individuals also develop cardiac arrhythmias resulting in syncopal episodes as young adults or later in life (summary by Schindler et al., 2016). For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy (LGMD), see LGMDR1 (253600).

Dilated cardiomyopathy-1OO (CMD1OO) is characterized by enlarged left ventricular end-diastolic diameter and reduced left ventricular ejection fraction, resulting in cardiac failure that may result in premature death. Some patients also exhibit second-degree atrioventricular block and premature ventricular beats (Shi et al., 2023). For a general phenotypic description and discussion of genetic heterogeneity of dilated cardiomyopathy, see CMD1A (115200).