Biallelic DAB1 Variants Are Associated With Mild Lissencephaly and Cerebellar Hypoplasia
Daphne J Smits1, Rachel Schot1, Martina Wilke1
1Department of Clinical Genetics (D.J.S., R.S., M.W., M.S., G.M.S.M.), ErasmusMC University Medical Center Rotterdam; Department of Child Neurology (M.C.Y.W.) and Department of Radiology (M.H.G.D.), Sophia Children's Hospital, ErasmusMC University Medical Center Rotterdam, the Netherlands; Department of Pediatrics (W.B.D.), University of Washington; Department of Neurology (W.B.D.), University of Washington, Seattle; Center for Integrative Brain Research (W.B.D.), Seattle Children's Research Institute, WA; Department of Human Genetics (W.B.D.), University of Minnesota, Minneapolis; Department of Radiology and Biomedical Imaging (A.J.B.), University of California, San Francisco; and ENCORE Expertise Center for Neurodevelopmental Disorders (M.C.Y.W., M.H.G.D., G.M.S.M.), ErasmusMC University Medical Center, Rotterdam, the Netherlands.
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.
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