Homozygous Fukutin Missense Mutation in Two Mexican Siblings with Dilated Cardiomyopathy

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, limbgirdle 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.

Is Cardiac Transplantation Still a Contraindication in Patients with Muscular Dystrophy-Related End-Stage Dilated Cardiomyopathy? A Systematic Review

“…LGMDR9 manifests with a wide clinical variability and evidence suggests that this, in part, reflects the genotype: subjects homozygous for c.826C>A gene variant express a milder phenotype compared to compound heterozygous subjects, but can develop severe cardiomyopathy [71,74]. Cardiomyopathy has also been observed in patients affected by sarcoglycanopathies (LGMDR3-R6) [77][78][79][80][81][82][83][84][85][86][87] and LGMDR13 [88][89][90] in percentages ranging from 12.9 to 50; the tendency to evolution towards dilated cardiomyopathy and heart failure is more frequently observed in patients with EDMD2, LGMDR6, R9, R11, and R13 . Isolated cases of cardiac involvement have also been described in patients with LGMDR7 (defects in telethonin), R10 (defects in titin) [91], and R23 (defects in LAMA 2 gene) [92].…”

Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review

“…Cardiac symptoms have been more often reported during the second decade of life, especially in patients with subtypes caused by p.Q358P and p.R179T mutations, who experience DCM with minimal muscle weakness [14]. Our systematic search results in 77 patients with FKTN deficiency and cardiac manifestations, encompassing DCM, VD, DI, SI, AF, PFO, double subaortic ventricular defect, HoLV, PPS, MF and infundibular TGA (with no innominate vein) [14,185,[330][331][332][333][334][335][336][337][338][339][340][341][342][343] (Table 5, Supplementary Tables S2 and S3).…”

Dilated cardiomyopathy and mild limb girdle muscular dystrophy caused by the p.Gly424Ser genetic variant in the fukutin gene

“…3 The clinical symptoms of DCM become apparent from the second decade of life and an infrequent form of DCM with limited or absent muscle involvement has been described. 1,4,5 It seems that there is a dissociation between the muscle and cardiac involvement; fukutin has been reported to have other functions and to be essential in the heart to maintain contractility, calcium homeostasis, Golgi apparatus integrity, and mitochondrial stress resistance. 6 The p.Gly424Ser variant is localized to a region involved in the phosphorylation of the C-terminal end of FKTN.…”

“…It appears with low frequency (< 0.01%) in the control population in gnomAD, without homozygotic carriers; the affected residue is highly conserved and replacement of glycine with serine is classified as pathogenic in bioinformatic predictions. It has recently been reported, also in homozygosis, in 2 Mexican siblings with DCM who died at 20 and 21 years of age, with no apparent neuromuscular involvement 4 ; however, no information was provided on CK status or the histological results.…”