The following is a summary of “Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria,” published in the July 2023 issue of Neurology by Akula et al.
Polymicrogyria, a cortical malformation, causes cognitive deficits, motor abnormalities, and neurodevelopmental sequelae in syndromic brain disorders, often co-occurring with other brain malformations.
Researchers performed a retrospective study to evaluate the genetic causes of polymicrogyria in a large cohort. The study analyzed panel and exome sequencing of polymicrogyria families. Over 20 years (1994 to 2020) of sample collection in 2 stages, panel (June 2015 to January 2016) and whole-exome sequencing (September 2019 to March 2020), they included individuals with polymicrogyria in neurological complaints referred by clinicians. Next-gen sequencing & exome sequencing was done on probands (and available parents & siblings) from 284 families with isolated polymicrogyria or as part of a clinical syndrome & no genetic diagnosis at referral, with sequencing from 275 families passing quality control (QC). Genetic sequencing analyzed polymicrogyria in families, examining molecular diagnosis, frequency, and association with co-occurring head size changes.
The results showed that genetic variants were found in 32.7% (90 out of 275) of families affected by polymicrogyria. PIK3R2, TUBB2B, COL4A1, and SCN3A have commonly implicated genes. Investigators identified or confirmed six new candidate genes: PANX1, QRICH1, SCN2A, TMEM161B, KIF26A, and MAN2C1. These genes showed consistent genotype-phenotype relationships in multiple families.
They concluded that the higher genetic causes of channelopathies in polymicrogyria support exome sequencing’s value for affected families.