Parental Somatic Mosaicism Is Underrecognized and Influences Recurrence Risk of Genomic Disorders

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 som...

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Published in	American journal of human genetics Vol. 95; no. 2; pp. 173 - 182
Main Authors	Campbell, Ian M., Yuan, Bo, Robberecht, Caroline, Pfundt, Rolph, Szafranski, Przemyslaw, McEntagart, Meriel E., Nagamani, Sandesh C.S., Erez, Ayelet, Bartnik, Magdalena, Wiśniowiecka-Kowalnik, Barbara, Plunkett, Katie S., Pursley, Amber N., Kang, Sung-Hae L., Bi, Weimin, Lalani, Seema R., Bacino, Carlos A., Vast, Mala, Marks, Karen, Patton, Michael, Olofsson, Peter, Patel, Ankita, Veltman, Joris A., Cheung, Sau Wai, Shaw, Chad A., Vissers, Lisenka E.L.M., Vermeesch, Joris R., Lupski, James R., Stankiewicz, Paweł
Format	Journal Article
Language	English
Published	United States Elsevier Inc 07.08.2014 Cell Press Elsevier
Subjects	Cell Division Deoxyribonucleic acid DNA DNA Copy Number Variations - genetics Female Gametogenesis - genetics Gender differences Genetic Diseases, Inborn - genetics Genetic disorders Genomics Germ Cells - cytology Germ-Line Mutation - genetics Humans Male Models, Genetic Mosaicism Mutation Pedigree Prospective Studies Recurrence Risk Sex Characteristics Smith-Magenis Syndrome - genetics
Online Access	Get full text
ISSN	0002-9297 1537-6605 1537-6605
DOI	10.1016/j.ajhg.2014.07.003

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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.
AbstractList	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. 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.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.
Author	Campbell, Ian M. Marks, Karen Bacino, Carlos A. Plunkett, Katie S. Patton, Michael Cheung, Sau Wai Olofsson, Peter Vermeesch, Joris R. Wiśniowiecka-Kowalnik, Barbara Robberecht, Caroline Patel, Ankita Lalani, Seema R. Vast, Mala Lupski, James R. Shaw, Chad A. Yuan, Bo Bartnik, Magdalena Bi, Weimin Pfundt, Rolph Pursley, Amber N. Veltman, Joris A. Erez, Ayelet McEntagart, Meriel E. Vissers, Lisenka E.L.M. Szafranski, Przemyslaw Nagamani, Sandesh C.S. Stankiewicz, Paweł Kang, Sung-Hae L.
AuthorAffiliation	7 Mathematics Department, Trinity University, San Antonio, TX 78212, USA 2 Centre for Human Genetics, University Hospital, Katholieke Universiteit Leuven, Leuven 3000, Belgium 4 Department of Medical Genetics, St. George’s University of London, Cranmer Terrace SW17 0RE, UK 1 Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA 10 Institute of Mother and Child, Warsaw 01-211, Poland 8 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA 9 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA 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 5 Texas Children’s Hospital, Houston, TX 77030, USA 6 Department of Medical Genetics, Institute of Mother and Child, Warsaw 01-211, Poland
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BackLink	https://www.ncbi.nlm.nih.gov/pubmed/25087610$$D View this record in MEDLINE/PubMed
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ContentType	Journal Article
Copyright	2014 The American Society of Human Genetics Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. Copyright Cell Press Aug 7, 2014 2014 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved. 2014 The American Society of Human Genetics
Copyright_xml	– notice: 2014 The American Society of Human Genetics – notice: Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. – notice: Copyright Cell Press Aug 7, 2014 – notice: 2014 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved. 2014 The American Society of Human Genetics
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Snippet	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...
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SubjectTerms	Cell Division Deoxyribonucleic acid DNA DNA Copy Number Variations - genetics Female Gametogenesis - genetics Gender differences Genetic Diseases, Inborn - genetics Genetic disorders Genomics Germ Cells - cytology Germ-Line Mutation - genetics Humans Male Models, Genetic Mosaicism Mutation Pedigree Prospective Studies Recurrence Risk Sex Characteristics Smith-Magenis Syndrome - genetics
Title	Parental Somatic Mosaicism Is Underrecognized and Influences Recurrence Risk of Genomic Disorders
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