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 07
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
2013095 / DDCF_ / Doris Duke Charitable Foundation / United States
F31 NS083159 / NS / NINDS 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
T32 GM007330 / GM / NIGMS NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States

Similar Publications

Chen F, Zhang Y, Chandrashekar DS, Varambally S, Creighton CJ. Global impact of somatic structural variation on the cancer proteome. Nat Commun. 2023;14(1):5637.
Rhie A, Nurk S, Cechova M, Hoyt SJ, Taylor DJ, Altemose N, et al.. The complete sequence of a human Y chromosome. Nature. 2023;621(7978):344-354.
Saengboonmee C, Sorin S, Sangkhamanon S, Chomphoo S, Indramanee S, Seubwai W, et al.. γ-aminobutyric acid B2 receptor: A potential therapeutic target for cholangiocarcinoma in patients with diabetes mellitus. World J Gastroenterol. 2023;29(28):4416-4432.
Wojcik MH, Reuter CM, Marwaha S, Mahmoud M, Duyzend MH, Barseghyan H, et al.. Beyond the exome: What's next in diagnostic testing for Mendelian conditions. Am J Hum Genet. 2023;110(8):1229-1248.
Chin C-S, Behera S, Khalak A, Sedlazeck FJ, Sudmant PH, Wagner J, et al.. Multiscale analysis of pangenomes enables improved representation of genomic diversity for repetitive and clinically relevant genes. Nat Methods. 2023;20(8):1213-1221.
Calame DG, Guo T, Wang C, Garrett L, Jolly A, Dawood M, et al.. Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease. Am J Hum Genet. 2023;110(8):1394-1413.
Walker KA, Chen J, Shi L, Yang Y, Fornage M, Zhou L, et al.. Proteomics analysis of plasma from middle-aged adults identifies protein markers of dementia risk in later life. Sci Transl Med. 2023;15(705):eadf5681.
Zhao N, Teles F, Lu J, Koestler DC, Beck J, Boerwinkle E, et al.. Epigenome-wide association study using peripheral blood leukocytes identifies genomic regions associated with periodontal disease and edentulism in the Atherosclerosis Risk in Communities study. J Clin Periodontol. 2023;50(9):1140-1153.
Harris RA, McAllister JM, Strauss JF. Single-Cell RNA-Seq Identifies Pathways and Genes Contributing to the Hyperandrogenemia Associated with Polycystic Ovary Syndrome. Int J Mol Sci. 2023;24(13).
Qian X, Srinivasan T, He J, Chen R. The Role of Ceramide in Inherited Retinal Disease Pathology. Adv Exp Med Biol. 2023;1415:303-307.