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

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.

Keywords: biparietal perisylvian polymicrogyria; de novo; exome sequencing; gene; optical genome mapping.

Graphical Abstract

Figure 1

Brain MR images of patients with pathogenic or likely pathogenic gene variants. The subject with an SCN3A variant shows BPP and thick grey matter over the frontal, parietal and perisylvian cortexes (A, B). The subject with a TUBB2B variant has bilateral fronto-parietal, perisylvian and insular polymicrogyria (C, D). The subject with an NUS1 variant has a similar pattern of distribution of polymicrogyria as seen with SCN3A and TUBB2B but additional white matter changes around the posterior horn of the lateral ventricles (E, F). The subject with a DDX23 variant has asymmetric patches of frontal, parietal and insular/perisylvian polymicrogyria (G, H). The polymicrogyric cortex of the subject with a TUBA1A variant is limited to the opercular and insular cortexes (I, J). SCN3A, the sodium voltage–gated channel alpha subunit 3; TUBB2B, tubulin 2B; NUS1, dehydrodolichyl diphosphate synthase subunit; DDX23, DEAD-box RNA helicase 23 gene; TUBA1A, tubulin alpha-1A.