Detection of mosaic chromosomal alterations in children with severe developmental disorders recruited to the DDD study

ABSTRACT Purpose Structural mosaicism has been previously implicated in developmental disorders. We aim to identify rare mosaic chromosomal alterations (MCAs) in probands with severe undiagnosed developmental disorders. Methods We identified MCAs in SNP array data from 12,530 probands in the Deciphering Developmental Disorders (DDD) study using MoChA. Results We found 61 MCAs in 57 probands, many of these were tissue specific. In 23/26 (88.5%) cases for which the MCA was detected in saliva where blood was also available for analysis, the MCA could not be detected in blood. The MCAs included 20 polysomies, comprising either one arm of a chromosome or a whole chromosome, for which we were able to show the timing of the error (25% mitosis, 40% meiosis I, 35% meiosis II). Only 2/57 (3.5%) of the probands in whom we found MCAs had another likely genetic diagnosis identified by whole exome sequencing, despite an overall diagnostic yield of ∼40% across the cohort. Conclusion Our results show that identification of MCAs provides candidate diagnoses for previously undiagnosed patients with developmental disorders, potentially explaining ∼0.45% of cases in the DDD study. Nearly 90% of these MCAs would have remained undetected by analysing DNA from blood and no other tissue.