Am J Hum Genet. 2014 Aug 7;95(2):173-182. doi: 10.1016/j.ajhg.2014.07.003. Epub 2014 Jul 31.
Parental Somatic Mosaicism Is Underrecognized and Influences Recurrence Risk of Genomic Disorders.
Campbell IM1, Yuan B1, Robberecht C2, Pfundt R3, Szafranski P1, McEntagart ME4, Nagamani SC5, Erez A5, Bartnik M6, Wiśniowiecka-Kowalnik B6, Plunkett KS1, Pursley AN1, Kang SH1, Bi W1, Lalani SR5, Bacino CA5, Vast M4, Marks K4, Patton M4, Olofsson P7, Patel A1, Veltman JA3, Cheung SW1, Shaw CA1,Vissers LE3, Vermeesch JR2, Lupski JR8, Stankiewicz P9.
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 might also have germline mosaicism that can potentially cause unexpected intergenerational recurrences. Here, we show that somatic mosaicism for transmitted mutations among parents of children with simplex genetic disease is more common than currently appreciated. Using the sensitivity of individual-specific breakpoint PCR, we prospectively screened 100 families with children affected by genomic disorders due to rare deletion copy-number variants (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 mutations in parental blood increase recurrence risk substantially more than parental mutations confined to the germline. Moreover, despite the fact that maternally transmitted mutations are 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 might 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.
Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
- [PubMed - as supplied by publisher]