A polymorphic AT-repeat causes frequent allele dropout for an MME mutational hotspot exon

Pathogenic variants in the MME gene cause dominant and recessive late-onset axonal hereditary neuropathy, that is, axonal Charcot-Marie-Tooth syndrome (LOCMT2). Here, we report next-generation sequencing (NGS) and Sanger sequencing (SS) results of 28 LOCMT2 patients carrying either the repeatedly reported c.467del p.(Pro156Leufs*14) or the c.440–2A>C variants. We demonstrate that an intronic AT-repeat in close proximity to these two mutations is frequently causing an allele dropout during SS that result in false genotyping in a considerable proportion of patients. This may result in an incorrect diagnosis, which has a considerable clinical impact for genetic counselling and prognosis. Recent studies have demonstrated that both heterozygous and biallelic variants in MME (encoding the metalloprotease neprilysin) are a frequent cause of LOCMT2 (MIM: 617017).1–3 The heterozygotes variants cause a milder phenotype with reduced penetrance. Besides the large spectrum of rare or even single pathogenic MME variants, the...
Source: Journal of Medical Genetics - Category: Genetics & Stem Cells Authors: Tags: Open access Diagnostics Source Type: research