Baynam Gareth, Overkov Angela, Davis Mark, Mina Kym, Schofield Lyn, Allcock Richard, Laing Nigel, Cook Matthew, Dawkins Hugh, Goldblatt Jack
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.
Am J Med Genet A. 2015 Jul;167(7):1659-67. doi: 10.1002/ajmg.a.37070. Epub 2015 Apr 6.
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.
我们报告了三名澳大利亚原住民兄弟姐妹，他们具有独特的表型，与已知的巨脑综合征和RAS病（包括科斯特洛综合征）有重叠。在MTOR基因中鉴定出一个功能获得性突变，这是首次报道的因种系、家族性MTOR突变导致的人类病症。我们描述了这个家族中的发现，以强调：（i）由于缺乏澳大利亚原住民的基因组参考数据，致病性的确定路径受到了干扰；（ii）该家族的疾病生物学、功能分析以及结节性硬化症复合体的研究支持将mTOR抑制剂作为一种治疗药物。
