Somatic mutations in cerebral cortical malformations
Open accessAbstract
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.).
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Somatic genetic changes during development and lifetime can affect the brain.
“Most recently, we have been discovering the extent to which genetic changes that occur somatically, during the development and lifetime of an individual, can affect the brain (Jamuar et al., 2014; Poduri et al., 2013).”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Jamuar et al., 2014
Somatic mutations were often missed by Sanger sequencing and by some whole exome sequencing with typical calling algorithms.
“This study revealed that such somatic mutations represented more than a quarter of all identified mutations, and were often missed both by Sanger sequencing and by some whole exome sequencing with typical calling algorithms.”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Jamuar et al., 2014
Analysis of leukocyte-derived DNA samples from 158 persons with brain malformations identified somatic mosaicism that had been difficult to detect previously.
“Analysis of leukocyte-derived DNA samples from 158 persons with brain malformations identified somatic mosaicism that had been difficult to detect previously.”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Jamuar et al., 2014
High-coverage sequencing panels provide an important complement to whole exome and genome sequencing in the evaluation of somatic mutations in the human brain.
“This report suggests that high-coverage sequencing panels provide an important complement to whole exome and genome sequencing in the evaluation of somatic mutations in the human brain (Jamuar et al., 2014).”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Jamuar et al., 2014
Substantial disability in the form of epilepsy and intellectual disability could be caused by mutations present in as few as 10% of brain cells.
“Substantial disability in the form of epilepsy and intellectual disability could be caused by mutations present in as few as 10% of brain cells.”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Jamuar et al., 2014
In the study of brain malformations, somatic mutations represented more than a quarter of all identified mutations.
“This study revealed that such somatic mutations represented more than a quarter of all identified mutations, and were often missed both by Sanger sequencing and by some whole exome sequencing with typical calling algorithms.”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Jamuar et al., 2014
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- Authors
- Jamuar, S. S., Lam, A.-T. N., Kircher, M., D’Gama, A. M., Wang, J., Barry, B. J., Zhang, X., Hill, R. S., Partlow, J. N., Rozzo, A., Servattalab, S., Mehta, B. K., Topcu, M., Amrom, D., Andermann, E., Dan, B., Parrini, E., Guerrini, R., Scheffer, I. E., Berkovic, S. F., Leventer, R. J., Shen, Y., Wu, B. L., Barkovich, A. J., Sahin, M., Chang, B. S., Bamshad, M., Nickerson, D. A., Shendure, J., Poduri, A., Yu, T. W., & Walsh, C. A.
- Affiliations
- Boston Children's Hospital (US)
- University of Washington (US)
- Shanghai Children's Medical Center (CN)
- Montreal Neurological Institute and Hospital (CA)
- Université Libre de Bruxelles (BE)
- Meyer Children's Hospital (IT)
- Royal Children's Hospital (AU)
- The University of Melbourne (AU)
- Claritas Genomics (United States) (US)
- University of California, San Francisco (US)
- Beth Israel Deaconess Medical Center (US)
- Neurology, Inc (US)
- Broad Institute (US)
- ORCID
- Jamuar, Saumya S.
- Kircher, Martin
- D’Gama, Alissa M.
- Wang, Jian
- Barry, Brenda J.
- Zhang, Xiaochang
- Servattalab, Sarah
- Mehta, Bhaven K.
- Amrom, Dina
- Dan, Bernard
- Parrini, Elena
- Guerrini, Renzo
- Scheffer, Ingrid E.
- Berkovic, Samuel F.
- Leventer, Richard J.
- Shen, Yiping
- Barkovich, A. James
- Bamshad, Michael
- Nickerson, Deborah A.
- Shendure, Jay
- Poduri, Annapurna
- Yu, Timothy W.
- Walsh, Christopher A.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2014-08-21
- Volume
- 371
- Issue
- 8
- Pages
- 733-743
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4274952
- OpenAlex
- W2120282622
- Cited by
- 392
- References
- 28
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 26 · 2023: 20 · 2022: 27 · 2021: 42 · 2020: 63 · 2019: 33 · 2018: 32 · 2017: 39 · 2016: 33 · 2015: 44 · 2014: 9
- FWCI
- 39.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, cc-by)
- Hacettepe University Institutional Repository (hacettepe.edu.tr) (submittedVersion, other-oa)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5rc2mh089952-02)
- Manton Center for Orphan Disease Research, Boston Children's Hospital (R01NS035129, R01NS079277, 1RC2MH089952)
- National Institute of Mental Health (1RC2MH089952, RC2-MH089952)
- National Human Genome Research Institute (HG006493, U54HG006493, UM1HG006493)
- National Institute of General Medical Sciences (T32 GM07753, T32GM007753)
- National Institute of Neurological Disorders and Stroke (R01NS073601, K23NS069784, R01NS035129, R01NS079277)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- somatic mutations, somatic mosaicism, double cortex syndrome, subcortical band heterotopia, periventricular nodular heterotopia, pachygyria, doublecortin, LIS1, filamin A, TUBB2B, DYNC1H1, KIF5C, subcloning
- MeSH terms
- Cerebral Cortex, DNA Mutational Analysis, Humans, Magnetic Resonance Imaging, Mutation, Lissencephaly, Periventricular Nodular Heterotopia, Malformations of Cortical Development, Classical Lissencephalies and Subcortical Band Heterotopias
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