CGG repeat expansions in Charcot-Marie-Tooth disease: insights from the 100 000 Genomes Project.

Abstract

CGG expansions in <i>NOTCH2NLC</i> and <i>LRP12</i> were recently identified as a cause of Charcot-Marie-Tooth disease (CMT) in 1.2%-10.6% of genetically undiagnosed patients in China, Taiwan and Japan. However, their relevance in CMT patients of different ethnic origin is still unknown. Here, we leveraged short-read whole genome sequencing data from the 100 000 Genomes Project to investigate the presence and frequency of CGG expansions in <i>NOTCH2NLC</i>, <i>LRP12</i> and additional genes associated with oculopharyngodistal myopathy (OPDM), in 560 genetically unsolved patients diagnosed with CMT and 32 509 non-neurological controls. Repeat expansions in <i>NOTCH2NLC</i>, <i>LRP12</i>, <i>RILPL1</i>, <i>NUTM2B-AS1</i> and <i>ABCD3</i> were absent from 560 genetically unsolved patients with CMT, mostly of Northern European ancestry. One patient of African ancestry carried an expanded allele in <i>GIPC1</i>, below the reported pathogenic threshold. However, rare expansions in this gene, as well as in <i>NOTCH2NLC</i>, <i>NUTM2B-AS1</i> and <i>ABCD3</i>, were also detected in controls (≤0.05%). The distribution of repeat size at these loci varied significantly across different ethnicities, with larger non-pathogenic intermediate alleles of <i>NOTCH2NLC</i> and <i>LRP12</i> typically observed in East Asians. CGG expansions in <i>NOTCH2NLC</i>, <i>LRP12</i> and other OPDM-associated genes do not appear to be a relevant cause of CMT in the UK. The larger size of non-pathogenic intermediate alleles of <i>NOTCH2NLC</i> and <i>LRP12</i> in East Asians could explain their ancestry-specific propensity to further expand into the full pathogenic range.