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

Area of Science:

• Genetics
• Neurology
• Genomic Medicine

Background:

• Charcot-Marie-Tooth disease (CMT) is a group of inherited disorders affecting peripheral nerves.
• Recent studies identified CGG repeat expansions in NOTCH2NLC and LRP12 as causes of CMT in Asian populations.
• The prevalence of these expansions in non-Asian CMT patients remains largely unknown.

Purpose of the Study:

• To investigate the frequency and relevance of CGG repeat expansions in NOTCH2NLC, LRP12, and other oculopharyngodistal myopathy (OPDM)-associated genes in genetically unsolved CMT patients of diverse ancestry.
• To compare findings with a control cohort to assess the pathogenicity and ethnic variation of these repeat expansions.

Main Methods:

• Whole genome sequencing data from 560 genetically unsolved CMT patients and 32,509 controls were analyzed.
• The study focused on CGG repeat expansions in NOTCH2NLC, LRP12, RILPL1, NUTM2B-AS1, ABCD3, and GIPC1.
• Allele frequencies and repeat sizes were examined across different ethnic groups.

Main Results:

• No pathogenic CGG repeat expansions in NOTCH2NLC, LRP12, RILPL1, NUTM2B-AS1, or ABCD3 were found in UK-based CMT patients (mostly of Northern European ancestry).
• One patient of African ancestry had a GIPC1 expansion below the pathogenic threshold.
• Rare expansions were detected in controls, and repeat size distribution varied significantly by ethnicity, with larger intermediate alleles in East Asians for NOTCH2NLC and LRP12.

Conclusions:

• CGG expansions in NOTCH2NLC, LRP12, and other OPDM-related genes are unlikely to be a significant cause of CMT in the UK population.
• The larger non-pathogenic intermediate alleles observed in East Asians may confer an ancestry-specific risk for expansion into the pathogenic range.
• Further research is needed to understand the ethnic-specific mechanisms of repeat expansion in neurodegenerative diseases.