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Title: Hemispheric cortical dysplasia secondary to a mosaic somatic mutation in MTOR.
Austin Authors: Leventer, Richard J;Scerri, Thomas;Marsh, Ashley P L;Pope, Kate;Gillies, Greta;Maixner, Wirginia;MacGregor, Duncan;Harvey, A Simon;Delatycki, Martin B ;Amor, David John;Crino, Peter B;Bahlo, Melanie;Lockhart, Paul J
Affiliation: and Shriners Hospital Pediatric Research Center (P.C.), Temple University, Philadelphia, PA.
From the Departments of Neurology (R.J.L., A.S.H.), Neurosurgery (W.M.), and Anatomical Pathology (D.M.), The Royal Children's Hospital, Melbourne; Department of Pediatrics (R.J.L., A.S.H., M.B.D., D.J.A., P.J.L.), The University of Melbourne; Bioinformatics Division (T.S., M.B.), The Walter and Eliza Hall Institute of Medical Research, Melbourne; Bruce Lefroy Centre for Genetic Health Research (A.P.L.M., K.P., G.G., M.B.D., D.J.A., P.J.L.), Murdoch Childrens Research Institute (R.J.L., A.S.H.), Melbourne; Clinical Genetics (M.B.D.), Austin Health, Melbourne, Australia
Issue Date: 15-Apr-2015
Publication information: Neurology 2015; 84(20): 2029-32
Abstract: To define causative somatic mutations in resected brain tissue from an infant with intractable epilepsy secondary to hemispheric cortical dysplasia.Whole-exome sequencing was conducted on genomic DNA derived from both resected brain tissue and peripheral blood leukocytes. Comparison of the brain vs blood sequencing results was performed using bioinformatic methods designed to detect low-frequency genetic variation between tissue pairs.Histopathology of the resected tissue showed dyslamination and dysmorphic neurons, but no balloon cells, consistent with focal cortical dysplasia type IIa. mTOR activation was observed by immunohistochemistry in the dysplasia. A missense mutation (c.4487T>G; p.W1456G) was detected in the FAT domain of MTOR in DNA from the dysplasia but not in lymphocytes. The mutation is predicted damaging (i.e., leading to mTOR activation) and was observed as a low-level mosaic with 8% of cells being heterozygous for the variant.We report the novel finding of an MTOR mutation associated with nonsyndromic cortical dysplasia. Somatic-specific mutations in MTOR and related genes should be considered in a broader spectrum of patients with hemispheric malformations and more restricted forms of cortical dysplasia.
Gov't Doc #: 25878179
DOI: 10.1212/WNL.0000000000001594
Type: Journal Article
Appears in Collections:Journal articles

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