Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria
Authors: Akula Shyam K. , Chen Allen Y. , Neil Jennifer E. , Shao Diane D. , Mo Alisa , Hylton Norma K. , DiTroia Stephanie , Ganesh Vijay S. , Smith Richard S. , O’Kane Katherine , Yeh Rebecca C. , Marciano Jack H. , Kirkham Samantha , Kenny Connor J. , Song Janet H. T. , Al Saffar Muna , Millan Francisca , Harris David J. , Murphy Andrea V. , Klemp Kara C. , Braddock Stephen R. , Brand Harrison , Wong Isaac , Talkowski Michael E. , O’Donnell-Luria Anne , Lai Abbe , Hill Robert Sean , Mochida Ganeshwaran H. , Doan Ryan N. , Barkovich A. James , Yang Edward , Amrom Dina , Andermann Eva , Poduri Annapurna , Walsh Christopher A. ,   Polymicrogyria Genetics Research Network, Abu-Libdeh Bassam , Al-Gazali Lihadh , Al Saffar Muna , Alva Moncayo Edith , Amrom Dina , Anderman Eva , Anttonen Anna-Kaisa , Barnes Saunder , Barnett Sara , Barron Todd , Barry Brenda J. , Basel-Vanagaite Lina , Bastaki Laila , Bello-Espinosa Luis , Ben-Omran Tawfeg , Bernard Matthew , Bonneman Carsten G. , Bourgeois Blaise , Brown Stephen , Caraballo Roberto H. , Cascino Gergory , Clarke Michael , Cohen Monika , Crow Yanick , Dan Bernard , Dies Kira A. , Dobyns William B. , Dubeau François , El Achkar Christelle , Enns Gregory M. , Faivre Laurence , Flores-Sarnat Laura , Gaitanis John , Giorgi Kuchukhidze , Green Andrew , Guberman Alan , Guerrini Renzo , Innes Micheil , Jacobsen Richard , Jacquemont Sebastian , Khalil Samir , Klepper Joerg , Kranic Dimitri , Krishnamoorthy Kalpathy , Lehesjoki Anna-Elina , Lev Dorit , Leventer Richard J. , Lisi Emily , Loik Ramey Valerie , Lynch Sally Ann , Mahmoud Laila , Manchester David , Mandelbaum David , Marom Daphna , Marsden Deborah , Martinez Ojeda Mayra , Masri Amira , Medne Livija , Melanson Denis , Miller David T. , Minster Anna , Neilan Edward , Nguyen Dang Khoa , Olson Heather E. , Pascual-Castroviejo Ignacio , Pearl Philip L. , Pilz Daniela , Quercia Nada , Raskin Salmo , Regev Miriam , Rodan Lance , Rooney Cynthia , Rutlin Michael , Sahin Mustafa , Salih Mustafa A. , Sarda Pierre , Sarnat Harvey B. , Scheffer Ingrid , Shieh Joseph , Smith Sharon E. , Soul Janet S. , Srivastava Siddharth , Sztriha Laszlo , Tampieri Donatella , Tolmie John , Topçu Meral , Trinka Eugen , Tsai John , Tsao Jack , Unger Sheila , Unterberger Iris , Uyanik Goekhan , Valente Kette , Voit Thomas , Wilson Louise , Yoon Grace 
Published: July 2023

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.