Diverse genetic causes of polymicrogyria with epilepsy

Epilepsy Phenome/Genome Project, Epi4K Consortium

Research output: Contribution to journalArticlepeer-review


Objective: We sought to identify novel genes and to establish the contribution of known genes in a large cohort of patients with nonsyndromic sporadic polymicrogyria and epilepsy. Methods: We enrolled participants with polymicrogyria and their parents through the Epilepsy Phenome/Genome Project. We performed phenotyping and whole exome sequencing (WES), trio analysis, and gene-level collapsing analysis to identify de novo or inherited variants, including germline or mosaic (postzygotic) single nucleotide variants, small insertion-deletion (indel) variants, and copy number variants present in leukocyte-derived DNA. Results: Across the cohort of 86 individuals with polymicrogyria and epilepsy, we identified seven with pathogenic or likely pathogenic variants in PIK3R2, including four germline and three mosaic variants. PIK3R2 was the only gene harboring more than expected de novo variants across the entire cohort, and likewise the only gene that passed the genome-wide threshold of significance in the gene-level rare variant collapsing analysis. Consistent with previous reports, the PIK3R2 phenotype consisted of bilateral polymicrogyria concentrated in the perisylvian region with macrocephaly. Beyond PIK3R2, we also identified one case each with likely causal de novo variants in CCND2 and DYNC1H1 and biallelic variants in WDR62, all genes previously associated with polymicrogyria. Candidate genetic explanations in this cohort included single nucleotide de novo variants in other epilepsy-associated and neurodevelopmental disease-associated genes (SCN2A in two individuals, GRIA3, CACNA1C) and a 597-kb deletion at 15q25, a neurodevelopmental disease susceptibility locus. Significance: This study confirms germline and postzygotically acquired de novo variants in PIK3R2 as an important cause of bilateral perisylvian polymicrogyria, notably with macrocephaly. In total, trio-based WES identified a genetic diagnosis in 12% and a candidate diagnosis in 6% of our polymicrogyria cohort. Our results suggest possible roles for SCN2A, GRIA3, CACNA1C, and 15q25 deletion in polymicrogyria, each already associated with epilepsy or other neurodevelopmental conditions without brain malformations. The role of these genes in polymicrogyria will be further understood as more patients with polymicrogyria undergo genetic evaluation.

Original languageEnglish (US)
Pages (from-to)973-983
Number of pages11
Issue number4
StatePublished - Apr 2021

Bibliographical note

Funding Information:
We thank the patients and families who enrolled in the Epilepsy Phenotype/Genotype Project as well as the Community Referral Network of physicians who referred patients to the study. This study was supported by the National Institute of Neurological Disorders and Stroke (Epilepsy Phenome/Genome Project NS053998; Epi4K—Administrative Core NS077274; Epi4K—Sequencing, Biostatistics, and Bioinformatics Core NS077303; Epi4K—Project 1–Epileptic Encephalopathies NS077364, Epi4K—Phenotyping and Clinical Informatics Core NS077276).

Funding Information:
D.B.G. is a founder of and holds equity in Q State Biosciences and Praxis Therapeutics; holds equity in Apostle, and serves as a consultant to AstraZeneca and Gilead. S.Petrov. has equity in and is employed by AstraZeneca. O.D. receives grant support from NINDS, NIMH, MURI, CDC, and NSF. He has equity and/or compensation from the following companies: Privateer Holdings, Tilray, Receptor Life Sciences, Qstate Biosciences, Tevard, Empatica, Egg Rock/Papa & Barkley, Rettco, SilverSpike, and California Cannabis Enterprises. He has received consulting fees from GW Pharma, Cavion, Zogenix, and Eisai. R.A.S. receives research funding from PCORI, NIH, the Pediatric Epilepsy Research Foundation, and the University of Michigan. She serves as a consultant for the Epilepsy Study Consortium, receives royalties from UpToDate for authorship of topics related to neonatal seizures, and serves as an Associate Editor for . L.S. is funded by the Health Research Council of New Zealand and Cure Kids New Zealand. She is a consultant for the Epilepsy Consortium and has received travel grants from Seqirus and Nutricia. She has received research grants and consulting fees from Zynerba and consulting fees from Eisai. None of the other authors has any conflict of interest to disclose. Neurology

Funding Information:
Data collection and sharing with the Washington Heights‐Inwood Columbia Aging Project (WHICAP; used for controls in this analysis) was supported by WHICAP (PO1AG07232, R01AG037212, RF1AG054023), funded by the National Institute on Aging and National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1TR001873. The manuscript was reviewed by WHICAP investigators for scientific content and consistency of data interpretation with previous WHICAP study publications. We acknowledge the WHICAP study participants and the WHICAP research and support staff for their contributions to this study.

Funding Information:
The collection of control samples and data was funded in part by Biogen; Gilead Sciences; UCB; Bryan Alzheimer's Disease Research Center, National Institute on Aging (P30AG028377); B57 SAIC‐Fredrick (M11‐074); National Institute of Neurological Disorders and Stroke (RC2NS070344, RC2MH089915, U01NS077303, U01NS053998, U54NS078059, P01HD080642); National Human Genome Research Institute (Yale Mendelian Genomics Center, UM1HG006504, U01HG007672); National Institute of Mental Health (K01MH098126, R01MH097971, R01MH099216, RC2MH089915); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK080099); National Institute of Allergy and Infectious Diseases (Division of Intramural Research, 1R56AI098588‐01A1); National Institute of Allergy and Infectious Diseases Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (UM1AI100645, U19AI067854); National Center for Advancing Translational Sciences (UL1TR000040); Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD048805); Ellison Medical Foundation New Scholar Award (AG‐NS‐0441‐08); Duke Chancellor’s Discovery Program Research Fund 2014; Neil Molberger Brain Research Fund; Endocrine Fellows Foundation Grant; Bill and Melinda Gates Foundation; Murdock Study Community Registry and Biorepository; Stanley Institute for Cognitive Genomics at Cold Spring Harbor Laboratory; Duke Genome Sequencing Clinic; New York‐Presbyterian Hospital; Columbia University College Physicians and Surgeons; Columbia University Medical Center; J. Willard and Alice S. Marriott Foundation; Muscular Dystrophy Association; Nicholas Nunno Foundation; JDM Fund for Mitochondrial Research; Arturo Estopinan TK2 Research Fund; Endocrine Fellows Foundation; and Helaine B. Allen and Emily Allen Wolff.

Publisher Copyright:
© 2021 International League Against Epilepsy


  • de novo variant
  • epilepsy
  • exome sequencing
  • polymicrogyria
  • trio

PubMed: MeSH publication types

  • Journal Article
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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