Clustered monoallelic mosaicism in twins suggests previously unrecognized path of mutagenesis.

We report monozygotic twins with HNRNPU-related neurodevelopmental disorder who harbor two closely spaced mosaic single-nucleotide deletions on the same allele (c.1463del [p.Pro488Glnfs∗13] and c.1466del [p.Lys489Argfs∗12]). The variants are mutually exclusive on individual DNA molecules and result in three distinct cellular lineages within each individual. We term this rare genotypic configuration clustered monoallelic mosaicism (cMoMa). Recognizing the extreme improbability of such a configuration, we systematically explore potential mechanisms for its origin. Based on our analysis, we propose that this genotype arises from a single mutational event in an early embryonic cell, yielding divergent outcomes on sister chromatids. Screening of large datasets (COSMIC and MosaicBase) identified additional cMoMa-like cases, suggesting that the mechanism is not unique to our case but may represent a broader, previously unrecognized path of mutagenesis that extends our current definition of mosaicism.