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Extending the clinical and mutational spectrum of TRIM32-related myopathies in a non-Hutterite population

Journal Contribution - Journal Article

Introduction TRIM32-related myopathies represent a phenotypic spectrum of a rare autosomal recessive muscle disorder. The disease is described as a mild and progressive myopathy without characteristic clinical features. Originally classified as limb-girdle muscular dystrophy (LGMD) 2H (OMIM #254110), the disorder was first identified in the Hutterite population and the homozygous TRIM32 founder mutation, p.Asp487Asn, was identified as the cause of this disease.1 Only seven patients with definite non-Hutterite TRIM32-related myopathy have been reported in the literature. Apart from two missense mutations residing in the NHL repeats of TRIM32, only deletions, frameshift and nonsense mutations have been reported.2 Having applied next generation sequencing technologies to over 1000 patients with suspected genetic muscle disorders, we present nine patients with TRIM32-related myopathies and three patients with a homozygous TRIM32 variant of unknown significance (VUS). Subjects and methods DNA samples from 1000 patients with unexplained limb-girdle muscle weakness and/or elevated serum creatine kinase (CK) levels were gathered through the MYO-SEQ project. Samples were processed and whole exome sequencing (WES) performed as described previously.3 Additional patients with TRIM32-related myopathy were diagnosed by the Northern Molecular Genetics Service (NMGS) diagnostic laboratory through panel sequencing of 32 LGMD genes. Variants were classified according to ACMG guidelines.4 MRI imaging was performed for eight patients on a 1.5T MRI platform. Muscle biopsies for all patients were analysed following standard histological techniques. Results Genetic findings Of the 1000 MYO-SEQ patients, we identified 36 with rare coding variants in TRIM32 (minor allele frequency <1%; numbered 136 in online supplementary table 1). Twenty-six patients had single heterozygous variants; these were discarded from our analysis as the variants were unlikely to be pathogenic in this autosomal recessive disease. Two further patients were excluded from our analysis: patient 18 was heterozygous for a pathogenic DES mutation and patient 10 was homozygous for a pathogenic CAPN3 mutation. This resulted in seven patients with suspected pathogenic TRIM32 variants and one patient with a homozygous VUS. We included four additional patients harbouring homozygous rare TRIM32 variants: three from NMGS and one for whom WES was performed in Tehran. Two patients harboured a pathogenic variant and two had a VUS. Pathogenic variants outside the NHL repeats were frameshift mutations (online supplementary figure 1); missense mutations in the coiled-coil region and intervening region were classified as a VUS.4
Journal: Journal of Neurology, Neurosurgery and Psychiatry
ISSN: 0022-3050
Volume: 90
Pages: 490 - +
Publication year:2019