Parental somatic mosaicism contributes an under-recognized source of potentially recurrent new mutations. I. M. Campbell1, B. Yuan1, C. Robberecht2, R. Pfundt3,4,5, P. Szafranski1, M. M. McEntagart6, S. C. S. Nagamani1,7, A. Erez1,7, M. Bartnik8, B. Wisniowiecka-Kowalnik8, K. S. Plunkett1, A. N. Pursley1, S. H. L. Kang1, W. Bi1, S. R. Lalani1,7, C. A. Bacino1, M. Vast6, K. Marks6, M. Patton6, P. Olofsson9, A. Patel1, J. A. Veltman3,4,5, S. W. Cheung1, C. A. Shaw1, L. E. L. M. Vissers3,4,5, J. R. Vermeesch2, J. R. Lupski1,7,10,11, P. Stankiewicz1,8 1) Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX; 2) Centre for Human Genetics, University Hospital, K.U. Leuven, Leuven, Belgium; 3) Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands; 4) Nijmegen Centre for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands; 5) Institute for Genetic and Metabolic Disorders, Radboud university medical center, Nijmegen, The Netherlands; 6) Centre for Human Genetics, St. George's University of London, Cranmer Terrace, United Kingdom; 7) Texas Childrens Hospital, Houston, TX; 8) Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland; 9) Mathematics Department, Trinity University, San Antonio, TX; 10) Department of Pediatrics, Baylor College of Medicine, Houston, TX; 11) Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX.

   New human mutations are thought to originate in germ cells, thus making a recurrence of the same mutation in a sibling exceedingly rare. However, increasing sensitivity of genomic technologies has anecdotally revealed mosaicism for mutations in somatic tissues of apparently healthy parents. Such somatically mosaic parents may also have germline mosaicim that can potentially cause unexpected intergenerational recurrences. Here we show that somatic mosaicism for transmitted mutations among parents of children with sporadic genetic disease is more common than currently appreciated. Using the sensitivity of patient-specific breakpoint PCR, we prospectively screened 100 families having children with genomic disorders due to rare variant deletion CNVs determined to be de novo by clinical analysis of parental DNA. Surprisingly, we identified four cases of low-level somatic mosaicism for the transmitted CNV in DNA isolated from parental blood. Integrated probabilistic modeling of gametogenesis developed in response to our observations predicts that identification of mutations in parental blood increases recurrence risk substantially compared to parents with mutations confined to the germline. Moreover, despite maternally transmitted mutations being the minority of alleles, our model suggests that sexual dimorphisms in gametogenesis result in a greater proportion of somatically mosaic transmitting mothers who are thus at increased risk of recurrence. Therefore, somatic mosaicism together with sexual differences in gametogenesis may explain a considerable fraction of unexpected recurrences of X-linked recessive disease. Overall, our results underscore an important role for somatic mosaicism and mitotic replicative mutational mechanisms in transmission genetics.

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