A number sign (#) is used with this entry because of evidence that familial restrictive cardiomyopathy-6 (RCM6) is caused by compound heterozygous mutation in the KIF20A gene (605664) on chromosome 5q31. One such family has been reported.

Familial restrictive cardiomyopathy-6 (RCM6) is characterized by prenatal onset of severe restrictive cardiomyopathy predominantly involving the right ventricle, resulting in irreversible heart failure and early death (Louw et al., 2018).

For a general phenotypic description and discussion of genetic heterogeneity of familial restrictive cardiomyopathy, see RCM1 (115210).

Louw et al. (2018) reported a brother and sister with restrictive cardiomyopathy of the right ventricle (RV) that was diagnosed prenatally. A small RV with severe pulmonary stenosis was observed in the brother at 35 weeks' gestation, as well as secondary hydrops fetalis, chylothorax, and ascites. Postnatal echocardiography showed a bipartite right ventricle with agenesis of the apex, functional pulmonary stenosis, moderate pulmonary insufficiency, and severe tricuspid insufficiency. He had persistent ascites and marked hepatomegaly with elevated transaminases; MRI and liver biopsy revealed cholestasis, hypoplasia of the portal vein, and hyperplasia of the hepatic artery. There was progressive biventricular decrease in cardiac function, and he died at 3 months of age. Autopsy showed a hypoplastic RV, with the cardiac apex formed solely by the left ventricle, and there was significant dilation of the right atrium and tricuspid annulus. Microscopic examination of the RV showed pronounced subendocardial to transmural ischemic fibrosis of the myocardium, and myocardial tissue was hypertrophic with hydropic swelling and myocytolysis. The endocardium showed fibrous thickening and there were prominent intramyocardial sinusoids. The myocardium of the left ventricle was grossly normal and not hypertrophic, except for endocardial fibrosis which was clearly less pronounced compared to the RV. In the next pregnancy, a diagnosis of restrictive right ventricular cardiomyopathy with RV dysfunction was made at 32 weeks' gestation in the female fetus. At birth she was cyanotic with cardiac decompensation and marked ascites. Postnatal echocardiography confirmed the diagnosis of restrictive cardiomyopathy. She had moderate tricuspid insufficiency. No hepatic abnormalities were observed. Heart function progressively decreased, and she died at age 2 months. No autopsy was performed.

The transmission pattern of restrictive cardiomyopathy in the family reported by Louw et al. (2018) was consistent with autosomal recessive inheritance.

By whole-exome sequencing in 2 affected sibs with restrictive cardiomyopathy of the right ventricle, who were negative for mutation in known cardiomyopathy-associated genes, Louw et al. (2018) identified compound heterozygosity for mutations in the KIF20A gene: a missense mutation (R182W; 605664.0001) and a 1-bp deletion (605664.0002). Sanger sequencing confirmed the mutations and revealed that the unaffected parents were each heterozygous for 1 of the variants; the unaffected sister of the sibs did not carry either variant. In the ExAC database, the missense mutation was present in 2 of 60,706 individuals of South Asian and European origin, respectively, and the frameshift variant was present in 32 individuals of African descent.