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Am J Hum Genet. 2014 Aug 7;95(2):173-82. doi: 10.1016/j.ajhg.2014.07.003. Epub 2014 Jul 31.

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

Author information

1
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
2
Centre for Human Genetics, University Hospital, Katholieke Universiteit Leuven, Leuven 3000, Belgium.
3
Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands.
4
Department of Medical Genetics, St. George's University of London, Cranmer Terrace SW17 0RE, UK.
5
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
6
Department of Medical Genetics, Institute of Mother and Child, Warsaw 01-211, Poland.
7
Mathematics Department, Trinity University, San Antonio, TX 78212, USA.
8
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: jlupski@bcm.edu.
9
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Institute of Mother and Child, Warsaw 01-211, Poland. Electronic address: pawels@bcm.edu.

Abstract

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.

PMID:
25087610
PMCID:
PMC4129404
DOI:
10.1016/j.ajhg.2014.07.003
[Indexed for MEDLINE]
Free PMC Article

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