Large distant deletion disrupts CDKN2A enhancer and predisposes to melanoma.

234-kb intergenic deletion disrupting a distant CDKN2A enhancer (loss of p16 expression)

Deleterious germline CDKN2A variants account for about 40% of familial melanoma. By sequencing 305 cases from 89 multi-case families negative for known genes, the authors identified in one family a rare DMRTA1 variant (p.Glu383Gln) located less than 480 kb upstream of CDKN2A. Whole-genome sequencing revealed a 234-kb intergenic deletion co-segregating with melanoma in 18 of 21 cases across four generations, found in a further 10 families. Tiled CRISPR inhibition of the predicted enhancer confirmed its interaction with CDKN2A, with near-complete loss of p16 mRNA expression from the affected chromosome. This distant non-coding deletion is one of the most common founder variants predisposing to melanoma.

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

This work illustrates how whole-genome sequencing can capture non-coding regulatory variants invisible to panels and targeted exome, with convincing CRISPR functional proof. Identifying a recurrent founder variant justifies, as the authors suggest, targeted screening in individuals at high melanoma risk without an identified cause. It is a reminder that the diagnostic challenge is shifting toward interpretation of regulatory regions.

Analysis by Dr Thibaut Benquey