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ABSTRACT Background: Fukuyama congenital muscular dystrophy (FCMD) is the most common form of a group of autosomal recessive disorders characterized by altered α-dystroglycan glycosylation and caused by FKTN gene mutations. However, mutations of this gene may cause a broad range of phenotypes, including Walker-Warburg syndrome, muscle-brain-eye disease, FCMD, limb-girdle muscular dystrophy without mental retardation, and cardiomyopathy with no or minimal skeletal muscle weakness. Objective: Our purpose was to describe two siblings who died at a young age with dilated cardiomyopathy (DCM), no muscle weakness, or atrophy, and were homozygous for a FKTN missense mutation. Methods: Site-directed next-generation sequencing (NGS) was performed. Pathogenicity of variants of interest was established according to the American College of Medical Genetics (ACMG) criteria, and all available first-degree relatives were screened for mutations by Sanger sequencing. Results: NGS revealed a homozygous FKTN variant in the index case (p.Gly424Ser, rs752358445), classified as likely pathogenic by ACMG criteria. Both parents and an unaffected brother were heterozygous carriers. Since the siblings had no apparent skeletal muscle weakness or central nervous system involvement, FKTN mutations were not initially suspected. Conclusions: This is the first report demonstrating that heterozygous individuals for the FKTN p.Gly424Ser mutation were healthy, while two homozygous brothers suffered severe DCM, strongly suggesting that this FKTN mutation is a rare cause of autosomal recessive DCM.
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Objective To summary the pathological and genetic features in nine Chinese limb girdle muscular dystrophy 2I (LGMD2I) patients.Methods Nine LGMD2I patients were recruited from Peking University First Hospital between 2011 and 2016, who came from nine unrelated and non-consanguineous families.The mean age of onset was (8.2±5.2) years (2 to 19 years), and the mean disease duration was (10.4±6.1) years (1 to 24 years).There were six males and three females, present with weakness in limb girdle muscles, four of whom accompanied with calf hypertrophy and three with scapular winging.Serum creatine kinase was 964-23 131 U/L (normal 25-190 U/L).Five of them who conducted electromyogram showed myogenic pattern.Muscle biopsy and next generation sequencing were performed in these patients, then sanger sequencing was performed to determine whether the variants co-segregated with the phenotype in these families.Results Muscle biopsy revealed myopathy features in six patients, dystrophic change in one, and only mild changes in two.Major histocompatibility complex-Ⅰ was positive in six cases, and rimmed vacuoles were found in two.There were seven mutations in fukutin-related protein (FKRP) gene.A reported mutation of c.545A>G (p.Y182C) appeared in eight cases, including three homozygotes and five compound heterozygotes.The mutation of c.1067T>C (p.Ile356Thr) was reported too.And c.1263C>A (p.Tyr421X), c.534G>T(p.Thr178Cys), c.1027G>C (p.Glu343Gln), c.1027G>T(p.Glu343X), c.1448A>G (p.Tyr483Cys) were found to be novel mutations.Conclusions LGMD2I showed large variation in myopathology.The missense mutation A545G(Y182C) is a hot spot of FKRP gene in our series.