title: Amplicon Resequencing Identified Parental Mosaicism for Approximately 10% of "de novo" SCN1A Mutations in Children with Dravet Syndrome.
abstract: The majority of children with Dravet syndrome (DS) are caused by de novo SCN1A mutations. To investigate the origin of the mutations, we developed and applied a new method that combined deep amplicon resequencing with a Bayesian model to detect and quantify allelic fractions with improved sensitivity. Of 174 SCN1A mutations in DS probands which were considered "de novo" by Sanger sequencing, we identified 15 cases (8.6%) of parental mosaicism. We identified another five cases of parental mosaicism that were also detectable by Sanger sequencing. Fraction of mutant alleles in the 20 cases of parental mosaicism ranged from 1.1% to 32.6%. Thirteen (65% of 20) mutations originated paternally and seven (35% of 20) maternally. Twelve (60% of 20) mosaic parents did not have any epileptic symptoms. Their mutant allelic fractions were significantly lower than those in mosaic parents with epileptic symptoms (P = 0.016). We identified mosaicism with varied allelic fractions in blood, saliva, urine, hair follicle, oral epithelium, and semen, demonstrating that postzygotic mutations could affect multiple somatic cells as well as germ cells. Our results suggest that more sensitive tools for detecting low-level mosaicism in parents of families with seemingly "de novo" mutations will allow for better informed genetic counseling.
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Xu
authors.affiliation: Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Yang
authors.affiliation: National Institute of Biological Sciences, Beijing, China.
authors.forename: Qixi
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, China.
authors.forename: Aijie
authors.initials: A
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Yang
authors.affiliation: Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.|Peking-Tsinghua Center for Life Sciences, Beijing, China.|Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
authors.forename: Adam Yongxin
authors.initials: AY
authors.lastname: Ye
authors.affiliation: National Institute of Biological Sciences, Beijing, China.
authors.forename: August Yue
authors.initials: AY
authors.lastname: Huang
authors.affiliation: Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
authors.forename: Jiarui
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.affiliation: National Institute of Biological Sciences, Beijing, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yu
authors.affiliation: National Institute of Biological Sciences, Beijing, China.|College of Biological Sciences, China Agricultural University, Beijing, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Andrology Center, Peking University First Hospital, Beijing, China.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, China.
authors.forename: Xiru
authors.initials: X
authors.lastname: Wu
authors.affiliation: Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.|National Institute of Biological Sciences, Beijing, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, China.
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000483:Alleles; D002648:Child; D004252:DNA Mutational Analysis; D004831:Epilepsies, Myoclonic / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D009030:Mosaicism; D009154:Mutation; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human
keywords: Dravet syndrome; SCN1A; de novo; mosaic; next-generation sequencing; somatic mutation