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

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

Gareth Baynam ¹ ² ³ ⁴ ⁵, Angela Overkov ¹, Mark Davis ⁶ ⁷, Kym Mina ⁶ ⁷, Lyn Schofield ¹ ⁴, Richard Allcock ⁶ ⁷, Nigel Laing ⁸, Matthew Cook ⁹ ¹⁰, Hugh Dawkins ² ⁶ ¹¹ ¹², Jack Goldblatt ¹ ² ³

Affiliations

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.

PMID: 25851998 DOI: 10.1002/ajmg.a.37070

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.

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