Too rare to be random: genetic finding suggests previously unrecognized path of mutagenesis

Abstract

We report a previously undescribed genotypic configuration identified in twins with HNRNPU-related neurodevelopmental disorder. Both twins have two closely spaced mosaic variants on the same allele that never co-occur on any single DNA molecule, resulting in three distinct cell lineages within each individual. We define this genotypic configuration as clustered monoallelic mosaicism (cMoMa). Recognizing the extreme improbability of such a configuration, we systematically explore two potential mechanisms for its origin. We propose that this genotype arises from an asymmetric repair of a single mutational event in an early embryonic cell, yielding divergent outcomes on sister chromatids. Screening of datasets (COSMIC and MosaicBase) uncovered additional cMoMa-like cases, suggesting that the mechanism is not unique to our case, but rather represents a broader, previously unrecognized path of mutagenesis that extends our current definition of mosaicism.