title: Inherited germline ATRX mutation in two brothers with ATR-X syndrome and osteosarcoma.
abstract: We report a family in which two brothers had an undiagnosed genetic disorder comprised of dysmorphic features, microcephaly, severe intellectual disability (non-verbal), mild anemia, and cryptorchidism. Both developed osteosarcoma. Trio exome sequencing (using blood samples from the younger brother and both parents) was performed and a nonsense NM_000489.4:c.7156C>T (p.Arg2386*) mutation in the ATRX gene was identified in the proband (hemizygous) and in the mother's peripheral blood DNA (heterozygous). The mother is healthy, does not exhibit any clinical manifestations of ATR-X syndrome and there was no family history of cancer. The same hemizygous pathogenic variant was confirmed in the affected older brother's skin tissue by subsequent Sanger sequencing. Chromosomal microarray studies of both brothers' osteosarcomas revealed complex copy number alterations consistent with the clinical diagnosis of osteosarcoma. Recently, somatic mutations in the ATRX gene have been observed as recurrent alterations in both osteosarcoma and brain tumors. However, it is unclear if there is any association between osteosarcoma and germline ATRX mutations, specifically in patients with constitutional ATR-X syndrome. This is the first report of osteosarcoma diagnosed in two males with ATR-X syndrome, suggesting a potential increased risk for cancer in patients with this disorder.
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Personalized Medicine, Children's Hospital Los Angeles, Los Angeles, California.|Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Jianling
authors.identifier: http://orcid.org/0000-0003-4941-3538
authors.initials: J
authors.lastname: Ji
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Personalized Medicine, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Catherine
authors.initials: C
authors.lastname: Quindipan
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California.|Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: David
authors.initials: D
authors.lastname: Parham
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Personalized Medicine, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Lishuang
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Personalized Medicine, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: David
authors.initials: D
authors.lastname: Ruble
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Personalized Medicine, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Moiz
authors.initials: M
authors.lastname: Bootwalla
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Personalized Medicine, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Dennis T
authors.initials: DT
authors.lastname: Maglinte
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Personalized Medicine, Children's Hospital Los Angeles, Los Angeles, California.|Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Gai
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Personalized Medicine, Children's Hospital Los Angeles, Los Angeles, California.|Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Sulagna C
authors.initials: SC
authors.lastname: Saitta
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Personalized Medicine, Children's Hospital Los Angeles, Los Angeles, California.|Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Jaclyn A
authors.initials: JA
authors.lastname: Biegel
authors.affiliation: Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California.|Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Leo
authors.initials: L
authors.lastname: Mascarenhas
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D004265:DNA Helicases / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D038901:X-Linked Intellectual Disability / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D009687:Nuclear Proteins / Q000235:genetics*; D012516:Osteosarcoma / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D035781:Siblings; D000075924:X-linked Nuclear Protein; D017085:alpha-Thalassemia / Q000150:complications / Q000235:genetics* / Q000503:physiopathology
chemical_list: D009687:Nuclear Proteins; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
keywords: ATR-X syndrome; cancer predisposition syndrome; chromosomal microarray; intellectual disability; osteosarcoma; tumor; whole exome sequencing