title: Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders.
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.
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Campbell
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Centre for Human Genetics, University Hospital, Katholieke Universiteit Leuven, Leuven 3000, Belgium.
authors.forename: Caroline
authors.initials: C
authors.lastname: Robberecht
authors.affiliation: 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.
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Szafranski
authors.affiliation: Department of Medical Genetics, St. George's University of London, Cranmer Terrace SW17 0RE, UK.
authors.forename: Meriel E
authors.initials: ME
authors.lastname: McEntagart
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Sandesh C S
authors.initials: SC
authors.lastname: Nagamani
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Erez
authors.affiliation: Department of Medical Genetics, Institute of Mother and Child, Warsaw 01-211, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Bartnik
authors.affiliation: Department of Medical Genetics, Institute of Mother and Child, Warsaw 01-211, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Wiśniowiecka-Kowalnik
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Katie S
authors.initials: KS
authors.lastname: Plunkett
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Amber N
authors.initials: AN
authors.lastname: Pursley
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Sung-Hae L
authors.initials: SH
authors.lastname: Kang
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Bi
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Seema R
authors.initials: SR
authors.lastname: Lalani
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Bacino
authors.affiliation: Department of Medical Genetics, St. George's University of London, Cranmer Terrace SW17 0RE, UK.
authors.forename: Mala
authors.initials: M
authors.lastname: Vast
authors.affiliation: Department of Medical Genetics, St. George's University of London, Cranmer Terrace SW17 0RE, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Marks
authors.affiliation: Department of Medical Genetics, St. George's University of London, Cranmer Terrace SW17 0RE, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Patton
authors.affiliation: Mathematics Department, Trinity University, San Antonio, TX 78212, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Olofsson
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.affiliation: 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.
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
authors.affiliation: 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.
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.affiliation: Centre for Human Genetics, University Hospital, Katholieke Universiteit Leuven, Leuven 3000, Belgium.
authors.forename: Joris R
authors.initials: JR
authors.lastname: Vermeesch
authors.affiliation: 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.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: 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.
authors.forename: Paweł
authors.initials: P
authors.lastname: Stankiewicz
mesh_terms: D002455:Cell Division; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D005718:Gametogenesis / Q000235:genetics*; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D023281:Genomics; D005854:Germ Cells / Q000166:cytology*; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009030:Mosaicism; D009154:Mutation; D010375:Pedigree; D011446:Prospective Studies; D012008:Recurrence; D012306:Risk; D012727:Sex Characteristics; D058496:Smith-Magenis Syndrome / Q000235:genetics
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