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N Engl J Med DOI:10.1056/NEJMoa1314432

Somatic mutations in cerebral cortical malformations.

Publication TypeJournal Article
Year of Publication2014
AuthorsJamuar, SS, Lam, A-TN, Kircher, M, D'Gama, AM, Wang, J, Barry, BJ, Zhang, X, Hill, RSean, Partlow, JN, Rozzo, A, Servattalab, S, Mehta, BK, Topcu, M, Amrom, D, Andermann, E, Dan, B, Parrini, E, Guerrini, R, Scheffer, IE, Berkovic, SF, Leventer, RJ, Shen, Y, Wu, BLin, A Barkovich, J, Sahin, M, Chang, BS, Bamshad, M, Nickerson, DA, Shendure, J, Poduri, A, Yu, TW, Walsh, CA
JournalN Engl J Med
Date Published2014 Aug 21
KeywordsCerebral Cortex, Classical Lissencephalies and Subcortical Band Heterotopias, DNA Mutational Analysis, Humans, Lissencephaly, Magnetic Resonance Imaging, Malformations of Cortical Development, Mutation, Periventricular Nodular Heterotopia

BACKGROUND: Although there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the optimal techniques to detect somatic mosaicism have not been systematically evaluated.

METHODS: Using a customized panel of known and candidate genes associated with brain malformations, we applied targeted high-coverage sequencing (depth, ≥200×) to leukocyte-derived DNA samples from 158 persons with brain malformations, including the double-cortex syndrome (subcortical band heterotopia, 30 persons), polymicrogyria with megalencephaly (20), periventricular nodular heterotopia (61), and pachygyria (47). We validated candidate mutations with the use of Sanger sequencing and, for variants present at unequal read depths, subcloning followed by colony sequencing.

RESULTS: Validated, causal mutations were found in 27 persons (17%; range, 10 to 30% for each phenotype). Mutations were somatic in 8 of the 27 (30%), predominantly in persons with the double-cortex syndrome (in whom we found mutations in DCX and LIS1), persons with periventricular nodular heterotopia (FLNA), and persons with pachygyria (TUBB2B). Of the somatic mutations we detected, 5 (63%) were undetectable with the use of traditional Sanger sequencing but were validated through subcloning and subsequent sequencing of the subcloned DNA. We found potentially causal mutations in the candidate genes DYNC1H1, KIF5C, and other kinesin genes in persons with pachygyria.

CONCLUSIONS: Targeted sequencing was found to be useful for detecting somatic mutations in patients with brain malformations. High-coverage sequencing panels provide an important complement to whole-exome and whole-genome sequencing in the evaluation of somatic mutations in neuropsychiatric disease. (Funded by the National Institute of Neurological Disorders and Stroke and others.).


Alternate JournalN. Engl. J. Med.
PubMed ID25140959
PubMed Central IDPMC4274952
Grant ListU54 HG006493 / HG / NHGRI NIH HHS / United States
RC2 MH089952 / MH / NIMH NIH HHS / United States
R01NS079277 / NS / NINDS NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
T32GM07753 / GM / NIGMS NIH HHS / United States
HG006493 / HG / NHGRI NIH HHS / United States
R01NS035129 / NS / NINDS NIH HHS / United States
R01 NS079277 / NS / NINDS NIH HHS / United States
R01 NS073601 / NS / NINDS NIH HHS / United States
1RC2MH089952 / MH / NIMH NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R37 NS035129 / NS / NINDS NIH HHS / United States
R01 NS035129 / NS / NINDS NIH HHS / United States
K23NS069784 / NS / NINDS NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
K23 NS069784 / NS / NINDS NIH HHS / United States