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Am J Med Genet A. 2015 Jul;167(7):1659-67. doi: 10.1002/ajmg.a.37070. Epub 2015 Apr 6.

A germline MTOR mutation in Aboriginal Australian siblings with intellectual disability, dysmorphism, macrocephaly, and small thoraces.

Baynam G1,2,3,4,5, Overkov A1, Davis M6,7, Mina K6,7, Schofield L1,4, Allcock R6,7, Laing N8, Cook M9,10, Dawkins H2,6,11,12, Goldblatt J1,2,3.

Author information

1
Genetic Services of Western Australia, Princess Margaret and King Edward Memorial Hospitals, Perth, Western Australia, Australia.
2
School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia.
3
Office of Population Health Genomics, Department of Health, Public Health and Clinical Services Division, Government of Western Australia, Perth, Western Australia, Australia.
4
Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia.
5
Telethon Kids Institute, Perth, Western Australia, Australia.
6
School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Western Australia, Australia.
7
Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Perth, Western Australia, Australia.
8
Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia.
9
Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.
10
Australia and Translational Research Unit, Canberra Hospital, Canberra, Australian Capital Territory, Australia.
11
Centre for Comparative Genomics, Murdoch University, Perth, Western Australia, Australia.
12
Centre for Population Health Research, Curtin Health Innovation Research Institute, Curtin University of Technology, Perth, Western Australia, Australia.

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.

KEYWORDS:

Aboriginal; RASopathy; indigenous; mTOR; megalencephaly; rapamycin; repurposing

PMID:
25851998
DOI:
10.1002/ajmg.a.37070
[Indexed for MEDLINE]

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