Characterization of Leukodystrophy Penetrance Using Large-Scale Integration of Genomic Population Screening and Electronic Health Records

Genotype-first approach: genomic population screening (210,983 individuals) cross-referenced with longitudinal electronic health records (20+ years) to estimate penetrance and underdiagnosis

Leukodystrophies are rare central nervous system white-matter diseases whose penetrance and phenotypic spectrum remain poorly defined. The authors integrate genomic population screening (210,983 individuals from the HerediGene study, including 34,033 with genome sequencing) with longitudinal electronic health record data spanning over 20 years, across 19 genes covering 13 leukodystrophies. Pathogenic variants are identified in 4 genes (CSF1R, PLP1, POLR3A, SNORD118) in 9 individuals, several of whom were clinically undiagnosed. The linkage enables a first estimate of penetrance and phenotypic variability at this scale.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A powerful genotype-first approach to estimate penetrance and underdiagnosis — a critical issue in the era of early therapies, where presymptomatic diagnosis becomes central. The results remain preliminary (few positives, non-peer-reviewed preprint), but the methodology coupling population screening with longitudinal records is exemplary.

Analysis by Dr Thibaut Benquey