Characterization of activating mutations in FGRF3 and their expansion in the male germline

Description

FGFR3, is a well-known oncogene that is highly expressed in the male gonad. Here we investigated how a series of missense mutations in FGFR3, associated with different dysplasias, expand in the male germline. Specifically, we investigated the functional activation, as well as the occurrence in human testis and sperm of ten different FGFR3 variants categorized by ClinVar as deleterious, benign, or not reported. We found that FGFR3 promiscuous (ligand-independent) activation likely leads to the accumulation of mutations in the male germline. We also observed that variants forming larger clonal expansions in the testis also increase in frequency with age in sperm. This has important implications of a higher transmission with paternal age, adding to the list of canonical paternal-age disorders. However, some variants were already enriched in sperm of younger donors, and did not result in large sub-clonal expansion events in the aging testis. This suggests that some mutation clusters might stay constant throughout the gonad’s lifetime, a novel finding for this type of mutagenesis. Finally, we describe three variants not reported in ClinVar that have an activating effect at the cellular level that also could have early- or late-onset consequences in offspring. These results provide important data for the evaluation and interpretation of variants with relevant clinical implications and the likelihood of these variants to form micro-mosaics in the male gonad.

Period	29 Sept 2023
Event title	Österreichische Gesselschaft für Humangenetik
Event type	Conference
Location	AustriaShow on map