Characterisation of the SMN1/SMN2 locus using a highly specific variant caller on whole-genome sequence data from 500,000 individuals.

SMN1 copy-number and deletion calling from short-read WGS via a dedicated caller (SMNCopyNumberCaller), overcoming high homology with the SMN2 paralog

Spinal muscular atrophy (SMA) is caused by bi-allelic loss of SMN1; ~95% of infantile cases result from homozygous exon 7-8 deletions that are hard to detect with short reads due to high similarity with the SMN2 paralog. The authors evaluate a dedicated caller (SMNCopyNumberCaller) on WGS from ~490,000 UK Biobank adults. Performance is excellent: 8,856 heterozygous carriers (1.8%) and only 2 individuals (0.0004%) with homozygous SMN1 deletions, one of whom had diagnosed SMA. A PheWAS confirms accuracy through associations with circulating proteins encoded or regulated at the locus.

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

Addresses a well-known technical bottleneck — short-read detection of SMN1 hampered by the SMN2 paralog. With SMA newborn screening and presymptomatic therapies now established, the value is direct: leveraging existing WGS data for carrier screening and diagnosis without a dedicated assay.

Analysis by Dr Thibaut Benquey