A number sign (#) is used with this entry because of evidence that hypertrophic cardiomyopathy-29 (CMH29) is caused by homozygous mutation in the KLHL24 gene (611295) on chromosome 3q27.

Hypertrophic cardiomyopathy-29 (CMH29) is characterized by recurrent syncope, dyspnea on exertion, and palpitations. The clinical phenotype is associated with a poor prognosis due to lethal arrhythmias and cardiac failure. Cardiac muscle biopsies show intermyofibrillar accumulation of glycogen and polyglucosan bodies within cardiomyocytes, and skeletal muscle accumulation of glycogen has also been observed (Hedberg-Oldfors et al., 2019).

For a general phenotypic description and discussion of genetic heterogeneity of hypertrophic cardiomyopathy, see CMH1 (192600).

Hedberg-Oldfors et al. (2019) reported 2 unrelated consanguineous families, of Iraqi (family A) and Iranian (family B) origin, segregating autosomal recessive hypertrophic cardiomyopathy (CMH) and mutation in the KLHL24 gene. Of 11 affected young adults in the 2 families, 3 died suddenly and 1 underwent cardiac transplantation due to heart failure. Onset of symptoms was in the second or third decade of life, and the initial symptoms included palpitations, syncope, shortness of breath, and dyspnea on exertion. Echocardiographic findings were reported for 8 patients and showed increased septal and posterior wall thickness, with asymmetric septal hypertrophy in 3 patients. Most had a small left ventricular cavity with reduced left ventricular end-diastolic volumes, and left ventricular outflow obstruction was documented in 3 patients. Cardiac biopsies from an affected sister and brother in family A showed cardiomyocyte hypertrophy, accumulation of glycogen, and scattered cardiomyocytes with polyglucosan bodies. Electron microscopy showed intermyofibrillar accumulation of glycogen, tubular structures, and irregularly arranged intermediate filaments. Skeletal muscle biopsies from patients in both families showed focal subsarcolemmal and intermyofibrillar accumulation of glycogen, as well as intermediate filaments with desmin (DES; 125660) immunostaining, together causing a jagged appearance at the edges of both type 1 and type 2 muscle fibers that the authors designated as 'cogwheel-like.' No signs of muscular atrophy or weakness were found in the patients, and nerve conduction studies were normal. No skin abnormalities were found.

The transmission pattern of CMH29 in the families reported by Hedberg-Oldfors et al. (2019) was consistent with autosomal recessive inheritance.

In a large multigenerational Iranian family (family B) segregating autosomal recessive CMH, Hedberg-Oldfors et al. (2019) performed linkage analysis and identified an approximately 3.4-Mb region of homozygosity on chromosome 3 with an estimated lod score of 3.6. The interval was defined by rs9877496 and rs73175592.

By exome sequencing in 2 unrelated families segregating autosomal recessive hypertrophic cardiomyopathy, Hedberg-Oldfors et al. (2019) identified homozygosity for mutations in the KLHL24 gene: in family A, of Iraqi origin, an affected brother and sister were homozygous for a nonsense mutation (E350X; 611295.0005); and in family B, of Iranian origin, 4 sibs and an affected cousin with CMH mapping to chromosome 3 were homozygous for a missense mutation (R306H; 611295.0006). The unaffected parents in both pedigrees were heterozygous for the respective mutations, neither of which was found in the Greater Middle Eastern Variome database. Western blot analysis of cardiac tissue from the sibs in family A showed marked upregulation of desmin.

Hedberg-Oldfors et al. (2019) knocked down the cardiac-specific zebrafish homolog of KLHL24, klhl24a, and observed defects in heart function at 48 hours postfertilization (hpf). The defects initially manifested as pericardial edema, alterations in heart rate, and reduced blood circulation; ventricular failure and blocked blood circulation were observed at 72 hpf. Site-specific mutagenesis corresponding to the human mutations E350X and R306H (see MOLECULAR GENETICS) gave rise to heart defects in more than 70% of embryos, and the mutant mRNA could not rescue the knockdown of endogenous klhl24a.