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. 2023 Sep 1;80(9):980-988.
doi: 10.1001/jamaneurol.2023.2363.

Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria

Shyam K Akula  1   2   3 , Allen Y Chen  1   4 , Jennifer E Neil  1   2 , Diane D Shao  1   5   2 , Alisa Mo  1   5   2 , Norma K Hylton  1   2   3 , Stephanie DiTroia  6 , Vijay S Ganesh  1   2 , Richard S Smith  7 , Katherine O'Kane  1   2 , Rebecca C Yeh  1   2 , Jack H Marciano  1   2 , Samantha Kirkham  1   2 , Connor J Kenny  1   2 , Janet H T Song  1   2 , Muna Al Saffar  1   2   8 , Francisca Millan  9 , David J Harris  1   2 , Andrea V Murphy  10 , Kara C Klemp  11 , Stephen R Braddock  11 , Harrison Brand  6   12 , Isaac Wong  6   12 , Michael E Talkowski  6   12 , Anne O'Donnell-Luria  1   6 , Abbe Lai  1   5 , Robert Sean Hill  1   2 , Ganeshwaran H Mochida  1   5   2 , Ryan N Doan  1 , A James Barkovich  13 , Edward Yang  14 , Dina Amrom  15   16   17   18 , Eva Andermann  16   18   19   20 , Annapurna Poduri  5 , Christopher A Walsh  1   2   3   6 ; Polymicrogyria Genetics Research Network
Collaborators, Affiliations

Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria

Shyam K Akula et al. JAMA Neurol. .

Abstract

Importance: Polymicrogyria is the most commonly diagnosed cortical malformation and is associated with neurodevelopmental sequelae including epilepsy, motor abnormalities, and cognitive deficits. Polymicrogyria frequently co-occurs with other brain malformations or as part of syndromic diseases. Past studies of polymicrogyria have defined heterogeneous genetic and nongenetic causes but have explained only a small fraction of cases.

Objective: To survey germline genetic causes of polymicrogyria in a large cohort and to consider novel polymicrogyria gene associations.

Design, setting, and participants: This genetic association study analyzed panel sequencing and exome sequencing of accrued DNA samples from a retrospective cohort of families with members with polymicrogyria. Samples were accrued over more than 20 years (1994 to 2020), and sequencing occurred in 2 stages: panel sequencing (June 2015 to January 2016) and whole-exome sequencing (September 2019 to March 2020). Individuals seen at multiple clinical sites for neurological complaints found to have polymicrogyria on neuroimaging, then referred to the research team by evaluating clinicians, were included in the study. Targeted next-generation sequencing and/or exome sequencing were performed on probands (and available parents and siblings) from 284 families with individuals who had isolated polymicrogyria or polymicrogyria as part of a clinical syndrome and no genetic diagnosis at time of referral from clinic, with sequencing from 275 families passing quality control.

Main outcomes and measures: The number of families in whom genetic sequencing yielded a molecular diagnosis that explained the polymicrogyria in the family. Secondarily, the relative frequency of different genetic causes of polymicrogyria and whether specific genetic causes were associated with co-occurring head size changes were also analyzed.

Results: In 32.7% (90 of 275) of polymicrogyria-affected families, genetic variants were identified that provided satisfactory molecular explanations. Known genes most frequently implicated by polymicrogyria-associated variants in this cohort were PIK3R2, TUBB2B, COL4A1, and SCN3A. Six candidate novel polymicrogyria genes were identified or confirmed: de novo missense variants in PANX1, QRICH1, and SCN2A and compound heterozygous variants in TMEM161B, KIF26A, and MAN2C1, each with consistent genotype-phenotype relationships in multiple families.

Conclusions and relevance: This study's findings reveal a higher than previously recognized rate of identifiable genetic causes, specifically of channelopathies, in individuals with polymicrogyria and support the utility of exome sequencing for families affected with polymicrogyria.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Song is a Howard Hughes Medical Institute Fellow of the Helen Hay Whitney Foundation. Dr Andermann reported grants from the Savoy Foundation for Epilepsy and Boston Children’s Hospital. Dr Walsh is an investigator of the Howard Hughes Medical Institute. No other relevant disclosures were reported.

Figures

Figure 1.
Figure 1.. Workflow and Diagnostic Yield
We performed panel sequencing, exome sequencing, or both on 275 families. After analysis for known genes associated with polymicrogyria (PMG), we also examined exomes for novel associations and used Matchmaker Exchange to build evidence for these associations. Our overall genetic explanation rate was 32.7% (90 of 275). tNGS indicates targeted next-generation sequencing.
Figure 2.
Figure 2.. Magnetic Resonance Images From Affected Individuals With PANX1 and QRICH1 Variants
A, PMG24901 has a de novo missense variant in PANX1 (p.Asn338Thr) and unilateral right severe polymicrogyria and agyria with an unremarkable left hemisphere. B, PMGSL101 has a de novo missense variant in PANX1 (p.Met37Arg) and has diffuse bilateral polymicrogyria with closed lip schizencephaly. C, PMG20601 has a de novo missense variant in PANX1 (p.Asp14His) as well as diffuse bilateral polymicrogyria, worse on the right than left, and poor myelination. D, PMG11701 has a de novo frameshift variant in QRICH1, p.Phe384GlnfsTer5. E, PS5201 has a de novo frameshift variant in QRICH1, p.Val102PhefsTer144. Example regions of polymicrogyria are marked with white arrowheads.
Figure 3.
Figure 3.. Summary of Genes Associated With Polymicrogyria by Category
Relative proportion in each category of polymicrogyria-associated genes identified in this study is summarized. The largest category includes genes encoding mTOR pathway proteins, followed by those encoding ion-conducting proteins. CoP indicates cortical plate; MZ, marginal zone; SP-IZ, subplate intermediate zone; SVZ, subventricular zone; VZ, ventricular zone.
Figure 4.
Figure 4.. Head Size Associations With Polymicrogyria Categories
Proportion of individuals affected with polymicrogyria that have macrocephaly, normocephaly, or microcephaly in each gene category, compared with that in all affected individuals. Shown are the Fisher exact test comparisons yielding the 4 smallest Benjamini-Hochberg–adjusted P values. Macrocephaly was associated with the mTOR category specifically, and microcephaly was absent in this category.
See this image and copyright information in PMC

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