# Heterogeneous genetic patterns in bilateral perisylvian polymicrogyria: insights from a Finnish family cohort

## TL;DR

This study identifies new genetic causes of a brain development disorder called bilateral perisylvian polymicrogyria in a Finnish family group.

## Contribution

The study reports the first association of NUS1 and DDX23 with bilateral perisylvian polymicrogyria.

## Key findings

- Pathogenic or likely pathogenic variants were found in 24% of families.
- Variants were identified in five genes, including two (NUS1 and DDX23) previously unlinked to the condition.
- The findings confirm the genetic heterogeneity of bilateral perisylvian polymicrogyria.

## Abstract

Bilateral perisylvian polymicrogyria is the most common form of regional polymicrogyria within malformations of cortical development, constituting 20% of all malformations of cortical development. Bilateral perisylvian polymicrogyria is characterized by an excessive folding of the cerebral cortex and abnormal cortical layering. Notable clinical features include upper motoneuron dysfunction, dysarthria and asymmetric quadriparesis. Cognitive impairment and epilepsy are frequently observed. To identify genetic variants underlying bilateral perisylvian polymicrogyria in Finland, we examined 21 families using standard exome sequencing, complemented by optical genome mapping and/or deep exome sequencing. Pathogenic or likely pathogenic variants were identified in 5/21 (24%) of families, of which all were confirmed as de novo. These variants were identified in five genes, i.e. DDX23, NUS1, SCN3A, TUBA1A and TUBB2B, with NUS1 and DDX23 being associated with bilateral perisylvian polymicrogyria for the first time. In conclusion, our results confirm the previously reported genetic heterogeneity of bilateral perisylvian polymicrogyria and underscore the necessity of more advanced methods to elucidate the genetic background of bilateral perisylvian polymicrogyria.

Järvelä et al. report de novo pathogenic or likely pathogenic variants in five genes underlying bilateral perisylvian polymicrogyria in a Finnish cohort using exome sequencing, optical genome mapping and deep sequencing. The outcome identified variants in 24% of families, expanding the genetic heterogeneity of bilateral perisylvian polymicrogyria.

Graphical Abstract