title: A case report of two brothers with ATR-X syndrome due to low maternal frequency of somatic mosaicism for an intragenic deletion in the ATRX.
abstract: In clinical practice, it is important to diagnose the carrier state of female patients with X-linked diseases for genetic counseling to calculate the recurrent risk of offspring. Because some X-linked diseases show high rates of gonadal mosaicism, this diagnosis is sometimes difficult, when there are few offspring in a family and no mutation is detected in the maternal genomic DNA. Here, we report two male siblings with ATR-X syndrome carrying an intragenic deletion of 78.6 kb involving exons 2-5 out of the 35 exons in the ATRX, as revealed by PCR amplification of these exons. The mother was expected to be an obligate carrier, but we could not confirm her as a mutation carrier by quantitative PCR (qPCR) for the exons. However, we identified the breakpoint of ATRX, and qPCR with breakpoint-specific primers revealed gonosomal mosaicism, with a relative frequency of the mutation of <1% in genomic DNA of her peripheral blood. For these obligate carriers of X-linked disease, we should aggressively investigate the maternal genomic status, not only because her genetic condition is important for estimating the recurrent risk of her offspring but also because a diagnosis of her gonosomal mosaicism can render negligible the possibility that her female siblings are carriers. We should reconfirm that a female who has a risk of being a carrier has a gonosomal or somatic mutation, even if she is an obligate carrier or apparently harbors a mutation.
authors.affiliation: Department of Neurology, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shimbo
authors.affiliation: Department of Clinical Genetics, Kurashiki Central Hospital, Kurashiki, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ninomiya
authors.affiliation: Medical genetics, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kurosawa
authors.affiliation: 1] Department of Neurology, Kanagawa Children's Medical Center, Yokohama, Japan [2] Department of Medical Ethics and Medical Genetics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Wada
mesh_terms: D000483:Alleles; D002648:Child; D002675:Child, Preschool; D056905:Chromosome Breakpoints; D004265:DNA Helicases / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000175:diagnosis* / Q000235:genetics*; D009030:Mosaicism; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017384:Sequence Deletion; D035781:Siblings; D014178:Translocation, Genetic; D000075924:X-linked Nuclear Protein; D017085:alpha-Thalassemia / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D009687:Nuclear Proteins; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein