Somatic Mutations In Cerebral Cortical Malformations
Tarih
2014Yazar
Jamuar, Saumya S.
Lam, Anh-Thu N.
Kircher, Martin
D'Gama, Alissa M.
Wang, Jian
Barry, Brenda J.
Zhang, Xiaochang
Hill, Robert Sean
Partlow, Jennifer N.
Rozzo, Aldo
Servattalab, Sarah
Mehta, Bhaven K.
Topcu, Meral
Amrom, Dina
Andermann, Eva
Dan, Bernard
Parrini, Elena
Guerrini, Renzo
Scheffer, Ingrid E.
Berkovic, Samuel F.
Leventer, Richard J.
Shen, Yiping
Wu, Bai Lin
Barkovich, A. James
Sahin, Mustafa
Chang, Bernard S.
Bamshad, Michael
Nickerson, Deborah A.
Shendure, Jay
Poduri, Annapurna
Yu, Timothy W.
Walsh, Christopher A.
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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, = 200x) 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.)