Barth syndrome is characterized in affected males by cardiomyopathy, neutropenia, skeletal myopathy, prepubertal growth delay, and distinctive facial gestalt (most evident in infancy); not all features may be present in a given affected male. Cardiomyopathy, which is almost always present before age five years, is typically dilated cardiomyopathy with or without endocardial fibroelastosis or left ventricular noncompaction; hypertrophic cardiomyopathy can also occur. Heart failure is a significant cause of morbidity and mortality; risk of arrhythmia and sudden death is increased. Neutropenia is most often associated with mouth ulcers, pneumonia, and sepsis. The nonprogressive myopathy predominantly affects the proximal muscles, and results in early motor delays. Prepubertal growth delay is followed by a postpubertal growth spurt with remarkable "catch-up" growth. Heterozygous females who have a normal karyotype are asymptomatic and have normal biochemical studies.

Left 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.\n\nSome 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.

An autosomal dominant subtype of dilated cardiomyopathy caused by mutation(s) in the LDB3 gene, encoding LIM domain-binding protein 3.

Any familial isolated dilated cardiomyopathy in which the cause of the disease is a mutation in the CSRP3 gene.

Dilated cardiomyopathy, a disorder characterized by cardiac dilation and reduced systolic function, represents an outcome of a heterogeneous group of inherited and acquired disorders. For background and phenotypic information on dilated cardiomyopathy, see CMD1A (115200).

Any familial isolated dilated cardiomyopathy in which the cause of the disease is a mutation in the FKTN gene.

An genetic condition that is a subtype of dilated cardiomyopathy caused by mutation(s) in the VCL gene, encoding vinculin.

A dilated cardiomyopathy that has material basis in mutation in the TNNI3 gene on chromosome 19q13.

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).

A dilated cardiomyopathy that has material basis in mutation in the TNNI3 gene on chromosome 19q13.42.

Any familial isolated dilated cardiomyopathy in which the cause of the disease is a mutation in the MYH6 gene.

Any familial isolated dilated cardiomyopathy in which the cause of the disease is a mutation in the NEXN gene.

Dilated cardiomyopathy-1BB (CMD1BB) is a life-threatening, intractable disease characterized by ventricular dilation and thinning (Shiba et al., 2021). For a phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy, see CMD1A (115200).

Any familial isolated dilated cardiomyopathy in which the cause of the disease is a mutation in the ACTC1 gene.

Any familial isolated dilated cardiomyopathy in which the cause of the disease is a mutation in the PSEN2 gene.

An autosomal dominant subtype of dilated cardiomyopathy caused by mutation(s) in the BAG3 gene, encoding BAG family molecular chaperone regulator 3.

Any familial isolated dilated cardiomyopathy in which the cause of the disease is a mutation in the PSEN1 gene.

Any familial isolated dilated cardiomyopathy in which the cause of the disease is a mutation in the CRYAB gene.

The dystrophinopathies cover a spectrum of X-linked muscle disease ranging from mild to severe that includes Duchenne muscular dystrophy, Becker muscular dystrophy, and DMD-associated dilated cardiomyopathy (DCM). The mild end of the spectrum includes the phenotypes of asymptomatic increase in serum concentration of creatine phosphokinase (CK) and muscle cramps with myoglobinuria. The severe end of the spectrum includes progressive muscle diseases that are classified as Duchenne/Becker muscular dystrophy when skeletal muscle is primarily affected and as DMD-associated DCM when the heart is primarily affected. Duchenne muscular dystrophy (DMD) usually presents in early childhood with delayed motor milestones including delays in walking independently and standing up from a supine position. Proximal weakness causes a waddling gait and difficulty climbing stairs, running, jumping, and standing up from a squatting position. DMD is rapidly progressive, with affected children being wheelchair dependent by age 12 years. Cardiomyopathy occurs in almost all individuals with DMD after age 18 years. Few survive beyond the third decade, with respiratory complications and progressive cardiomyopathy being common causes of death. Becker muscular dystrophy (BMD) is characterized by later-onset skeletal muscle weakness. With improved diagnostic techniques, it has been recognized that the mild end of the spectrum includes men with onset of symptoms after age 30 years who remain ambulatory even into their 60s. Despite the milder skeletal muscle involvement, heart failure from DCM is a common cause of morbidity and the most common cause of death in BMD. Mean age of death is in the mid-40s. DMD-associated DCM is characterized by left ventricular dilation and congestive heart failure. Females heterozygous for a DMD pathogenic variant are at increased risk for DCM.

Any dilated cardiomyopathy in which the cause of the disease is a mutation in the MYPN gene.

Left 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.\n\nSome 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.

Any familial isolated dilated cardiomyopathy in which the cause of the disease is a mutation in the RAF1 gene.

Dilated cardiomyopathy-2F (CMD2F) is an autosomal recessive early-onset cardiomyopathy associated with refractory ventricular arrhythmias and severe heart failure requiring placement of a left ventricular assist device (Hakui et al., 2022). For a general phenotypic description and discussion of genetic heterogeneity of dilated cardiomyopathy, see 115200.

Cardiac valvular dysplasia-2 (CVDP2) is characterized primarily by congenital stenosis and insufficiency of the semilunar valves, although mild insufficiency of the atrioventricular valves has been observed as well. Other features include subaortic stenosis and dilation of the ascending aorta and/or pulmonary artery in some patients (Wunnemann et al., 2020; Massadeh et al., 2020). For a discussion of genetic heterogeneity of CVDP, see CVDP1 (212093).