title: Different X-linked KDM5C mutations in affected male siblings: is maternal reversion error involved?
abstract: Genetic reversion is the phenomenon of spontaneous gene correction by which gene function is partially or completely rescued. However, it is unknown whether this mechanism always correctly repairs mutations, or is prone to error. We investigated a family of three boys with intellectual disability, and among them we identified two different mutations in KDM5C, located at Xp11.22, using whole-exome sequencing. Two affected boys have c.633delG and the other has c.631delC. We also confirmed de novo germline (c.631delC) and low-prevalence somatic (c.633delG) mutations in their mother. The two mutations are present on the same maternal haplotype, suggesting that a postzygotic somatic mutation or a reversion error occurred at an early embryonic stage in the mother, leading to switched KDM5C mutations in the affected siblings. This event is extremely unlikely to arise spontaneously (with an estimated probability of 0.39-7.5 × 10(-28) ), thus a possible reversion error is proposed here to explain this event. This study provides evidence for reversion error as a novel mechanism for the generation of somatic mutations in human diseases.
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Fujita
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Waga
authors.affiliation: Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hachiya
authors.affiliation: Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Kurihara
authors.affiliation: Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kumada
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.|Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Takeshita
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.|Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Nakagawa
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Miyatake
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tsurusaki
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Saitsu
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.|Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Y-I
authors.initials: YI
authors.lastname: Goto
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Matsumoto
mesh_terms: D002675:Child, Preschool; D059472:Exome; D005260:Female; D050172:Genes, X-Linked; D006239:Haplotypes; D059014:High-Throughput Nucleotide Sequencing; D056466:Histone Demethylases / Q000235:genetics*; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D000072741:Maternal Inheritance / Q000235:genetics*; D009030:Mosaicism; D009035:Mothers; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype
chemical_list: D056466:Histone Demethylases; C086877:KDM5C protein, human
keywords: KDM5C; intellectual disability; mosaicism; reversion error; somatic mutation