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

CGG repeat expansion screening for NOTCH2NLC and LRP12 by short-read WGS (ExpansionHunter) in 560 unsolved European CMT patients

CGG expansions in NOTCH2NLC and LRP12 were recently identified as a cause of Charcot-Marie-Tooth disease (CMT) in 1.2–10.6% of unsolved cases in East Asia. This study leveraged short-read WGS from 560 unsolved CMT patients in the 100,000 Genomes Project (mostly Northern European ancestry) and 32,509 non-neurological controls. Expansions in NOTCH2NLC, LRP12, RILPL1, NUTM2B-AS1, and ABCD3 were absent in CMT patients. Intermediate allele size distribution varied significantly by ancestry, with larger non-pathogenic alleles in East Asians, explaining their ancestry-specific propensity to expand into the pathogenic range.

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This negative result is clinically important: it confirms that NOTCH2NLC/LRP12 CGG expansions are not a significant cause of CMT in European-ancestry populations. The demonstration that intermediate allele distribution is ancestry-specific is useful for WGS report interpretation: an intermediate NOTCH2NLC allele in a European patient has different significance than in an Asian patient.

Clinical impact: 2/3 · Evidence quality: 3/3 · Novelty: 1/2 · Sample size: 1/1 · Journal quality: 0/1 → Total: 7/10