Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with a loss-of-function mutation in CDK5.

Lissencephaly comprises a heterogeneous group of developmental brain disorders of varying severity, involving abnormal cortical gyration. We studied a highly consanguineous Israeli Moslem family with a lethal form of autosomal recessive lissencephaly with cerebellar hypoplasia (LCH). Using microarray-based homozygosity mapping in the reported family, combined with whole exome sequencing in one affected infant, we identified a homozygous splice site mutation g.IVS8+1G>A in cyclin-dependent kinase 5 (CDK5), causing complete skipping of exon 8, and leading to a frame shift and premature stop codon (p.V162SfsX19). The mutation co-segregated with the disease phenotype in all 29 study participants (4 patients and 25 healthy relatives), and was not identified in 200 ethnically matched control chromosomes. The p.V162SfsX19 mutation causes lack of endogenous CDK5 expression in affected dermal fibroblasts and brain tissue at the mRNA and protein levels, consistent with nonsense-mediated mRNA decay. Functional analysis of the p.V162SfsX19 mutation, using a yeast complementation assay, showed loss-of-function of the mutant CDK5 gene product, thereby implicating its role in the pathogenesis of autosomal recessive LCH in the studied family.