Diverse Genetic Etiologies of Unilateral Polymicrogyria

TL;DR

This study explores the genetic causes of unilateral polymicrogyria, finding that some genes are unique to this condition and suggesting the value of genetic testing.

Contribution

The study is the first to report variants in DYNC1H1, TMEM216, and ACVRL1 associated with unilateral polymicrogyria.

Findings

A likely genetic cause was identified in 26.7% of unrelated individuals with uPMG.

Recessive and dominant genetic causes, including ASPM, WDR62, and DYNC1H1, were found in the cohort.

Some genetic causes of uPMG overlap with bilateral PMG, but others are unique.

Abstract

Polymicrogyria (PMG) is one of the most common human malformations of cortical development and is often classified by its radiographic pattern of distribution. Unilateral polymicrogyria (uPMG) is a subtype of PMG affecting a portion or all of one cerebral hemisphere. As most PMGs occur bilaterally, there has been no specific investigation as to whether the genetic underpinnings of uPMG comprise a subset of or a distinct entity from bilateral PMG. In this study, our goal was to assess both the genetic etiology of uPMG and the value of diagnostic genetic testing in this setting.

We conducted a retrospective analysis of clinical data from individuals with uPMG seen in the Brain Development and Genetics Clinic and/or research participants of the Walsh Laboratory at Boston Children's Hospital. The final study cohort included 35 individuals from 30 families who were diagnosed with uPMG on brain magnetic resonance imaging (MRI) and also underwent genetic testing.

A likely genetic cause was identified in 26.7% (8/30) of unrelated individuals with uPMG in this cohort and segregated within one family (10/35 total subjects). Recessive genetic causes included ASPM, WDR62, and TMEM216. Dominant causes included 22q deletion syndrome, DYNC1H1, SCN3A, and hereditary hemorrhagic telangiectasia (HHT) genes, ACVRL1 and ENG. This is the first report of variants in DYNC1H1, TMEM216, and ACVRL1 in association with uPMG.

The genetic causes of bilateral PMG and uPMG can overlap, but some are unique to certain distributions of the malformation. Genetic explanations for uPMG are found at comparable rates to bilateral PMG, suggesting that germline testing for this unique presentation is warranted. ANN NEUROL 2026;99:1277–1286

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