Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders.

TitleParental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders.
Publication TypeJournal Article
Year of Publication2014
AuthorsCampbell, IM, Yuan, B, Robberecht, C, Pfundt, R, Szafranski, P, McEntagart, ME, Nagamani, SCS, Erez, A, Bartnik, M, Wiśniowiecka-Kowalnik, B, Plunkett, KS, Pursley, AN, Kang, S-HL, Bi, W, Lalani, SR, Bacino, CA, Vast, M, Marks, K, Patton, M, Olofsson, P, Patel, A, Veltman, JA, Cheung, SWai, Shaw, CA, Vissers, LELM, Vermeesch, JR, Lupski, JR, Stankiewicz, P
JournalAm J Hum Genet
Date Published2014 Aug 7
KeywordsCell Division, DNA Copy Number Variations, Female, Gametogenesis, Genetic Diseases, Inborn, Genomics, Germ Cells, Germ-Line Mutation, Humans, Male, Models, Genetic, Mosaicism, Mutation, Pedigree, Prospective Studies, Recurrence, Risk, Sex Characteristics, Smith-Magenis Syndrome

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.

Alternate JournalAm. J. Hum. Genet.
PubMed ID25087610
PubMed Central IDPMC4129404
Grant ListU54 HG006542 / HG / NHGRI NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States
R01 HL101975 / HL / NHLBI NIH HHS / United States
T32 GM007330-34 / GM / NIGMS NIH HHS / United States
U54 HD083092 / HD / NICHD NIH HHS / United States
R15 GM093957 / GM / NIGMS NIH HHS / United States
P30 HD024064 / HD / NICHD NIH HHS / United States
F31 NS083159 / NS / NINDS NIH HHS / United States
T32 GM007330 / GM / NIGMS NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States