Somatic mutations in cerebral cortical malformations

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

Research output: Contribution to journalArticlepeer-review


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 leukocytederived 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.

Original languageEnglish
Pages (from-to)733-743
Number of pages11
JournalNew England Journal of Medicine
Issue number8
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Medicine(all)


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