title: A germline MTOR mutation in Aboriginal Australian siblings with intellectual disability, dysmorphism, macrocephaly, and small thoraces.
abstract: We report on three Aboriginal Australian siblings with a unique phenotype which overlaps with known megalencephaly syndromes and RASopathies, including Costello syndrome. A gain-of-function mutation in MTOR was identified and represents the first reported human condition due to a germline, familial MTOR mutation. We describe the findings in this family to highlight that (i) the path to determination of pathogenicity was confounded by the lack of genomic reference data for Australian Aboriginals and that (ii) the disease biology, functional analyses in this family, and studies on the tuberous sclerosis complex support consideration of an mTOR inhibitor as a therapeutic agent.
authors: Genetic Services of Western Australia, Princess Margaret and King Edward Memorial Hospitals, Perth, Western Australia, Australia.|School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia.|Office of Population Health Genomics, Department of Health, Public Health and Clinical Services Division, Government of Western Australia, Perth, Western Australia, Australia.|Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia.|Telethon Kids Institute, Perth, Western Australia, Australia.
authors: Gareth
authors: G
authors: Baynam
authors: Genetic Services of Western Australia, Princess Margaret and King Edward Memorial Hospitals, Perth, Western Australia, Australia.
authors: Angela
authors: A
authors: Overkov
authors: School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Western Australia, Australia.|Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Perth, Western Australia, Australia.
authors: Mark
authors: M
authors: Davis
authors: School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Western Australia, Australia.|Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Perth, Western Australia, Australia.
authors: Kym
authors: K
authors: Mina
authors: Genetic Services of Western Australia, Princess Margaret and King Edward Memorial Hospitals, Perth, Western Australia, Australia.|Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia.
authors: Lyn
authors: L
authors: Schofield
authors: School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Western Australia, Australia.|Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Perth, Western Australia, Australia.
authors: Richard
authors: R
authors: Allcock
authors: Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia.
authors: Nigel
authors: N
authors: Laing
authors: Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.|Australia and Translational Research Unit, Canberra Hospital, Canberra, Australian Capital Territory, Australia.
authors: Matthew
authors: M
authors: Cook
authors: School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia.|School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Western Australia, Australia.|Centre for Comparative Genomics, Murdoch University, Perth, Western Australia, Australia.|Centre for Population Health Research, Curtin Health Innovation Research Institute, Curtin University of Technology, Perth, Western Australia, Australia.
authors: Hugh
authors: H
authors: Dawkins
authors: Genetic Services of Western Australia, Princess Margaret and King Edward Memorial Hospitals, Perth, Western Australia, Australia.|School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia.|Office of Population Health Genomics, Department of Health, Public Health and Clinical Services Division, Government of Western Australia, Perth, Western Australia, Australia.
authors: Jack
authors: J
authors: Goldblatt
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology*; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000473:pathology; D008297:Male; D058627:Megalencephaly / Q000235:genetics / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D035781:Siblings; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D013909:Thorax / Q000473:pathology
chemical_list: C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Aboriginal; RASopathy; indigenous; mTOR; megalencephaly; rapamycin; repurposing