An Unexpected Case of Somatic Mosaicism of the Dutch p16-Leiden Founder Variant in the CDKN2A Gene.

Abstract

CDKN2A is the primary high-risk predisposition gene for familial cutaneous melanoma. In the Netherlands, most carriers of pathogenic germline variants in CDKN2A harbor a unique, population-specific founder variant, c.225_243del, commonly referred to as p16-Leiden. For decades, this distinctive 19 base-pair deletion in CDKN2A had been identified exclusively as a germline variant. Here, we report an exceptional case of somatic mosaicism for the p16-Leiden variant in an Irish male with a concurrent diagnosis of Kartagener's syndrome but no history of malignancy. The variant was first identified through targeted next-generation sequencing (NGS) of a fundic gland polyp in the distal esophagus, showing a variant allele frequency (VAF) of 40%. Subsequent analysis also detected the variant in the patient's buccal swab DNA (VAF 0.3%), while it was notably absent in multiple other tissue samples, including blood, urine, skin, and several additional samples from the proximal gastrointestinal tract. We explore several hypotheses that could explain these intriguing findings.