Biallelic DAB1 Variants Are Associated With Mild Lissencephaly and Cerebellar Hypoplasia

Marie Claire de Wit, GS Verheijen-Mancini*, Marjolein Dremmen, R (Rachel) Schot, Martina Wilke

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Scopus)
13 Downloads (Pure)

Abstract

Objective: We aimed to identify pathogenic variants in a girl with epilepsy, developmental delay, cerebellar ataxia, oral motor difficulty, and structural brain abnormalities with the use of whole-exome sequencing.

Methods: Whole-exome trio analysis and molecular functional studies were performed in addition to the clinical findings and neuroimaging studies.

Results: Brain MRI showed mild pachygyria, hypoplasia of the cerebellar vermis, and abnormal foliation of the cerebellar vermis, suspected for a variant in one of the genes of the Reelin pathway. Trio whole-exome sequencing and additional functional studies were performed to identify the pathogenic variants. Trio whole-exome sequencing revealed compound heterozygous splice variants in DAB1, both affecting the highly conserved functional phosphotyrosine-binding domain. Expression studies in patient-derived cells showed loss of normal transcripts, confirming pathogenicity.

Conclusions: We conclude that these variants are very likely causally related to the cerebral phenotype and propose to consider loss-of-function DAB1 variants in patients with RELN-like cortical malformations.
Original languageEnglish
Pages (from-to)e558
Number of pages5
JournalNeurology: Genetics
Volume7
Issue number2
DOIs
Publication statusPublished - Apr 2021

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