The landscape of Lissencephaly among Egyptian Patients

Background: Lissencephaly (LIS) encompasses a spectrum of malformations of cortical development due to defective neuronal migration with diverse genetic contextual. LIS spectrum includes agyria, pachygyria, and subcortical band heterotopia. Whereas, microlissencephaly (MILS) is associated with severe congenital microcephaly and signifies a distinct subgroup. Brain magnetic resonance allows the characterization of various anatomic and morphological abnormalities and further radiological-genotype correlations. Objective: We studied a cohort of 92 Egyptian patients derived from 70 families with LIS spectrum and microlissencephaly. Based on the radiological classification, target gene sequencing was done for LIS1, DCX, RELN, VLDLR, and LAMB1 genes. For patients with nonspecific neuroradiological patterns, whole-exome sequencing (WES) was performed. Results: The causative mutations were identified in 60 families. LIS1 gene constitute 11.7 % of families followed by RELN and VLDLR, both 11.4% (8F), DCX (7.6%-5F) DYNC1H1(7.6%-5F), KATNB1 (7.6%- 5F), TUBA1A (5.7%-4F), APC2 (5.7%-4F), PIDD1 (4.2%-3F), LAMB1(2.8%-2F), TMTC3 (2.8% 2F), CDK5 (1.4%-1F), ACTG1(1.4%-1F) and MACF1 (1.4%-1F). Ten families (14.2%) remained unsolved. Because of the high consanguinity rate in our community, autosomal recessive linked LIS was prevalent. Novel mutations were also dominant in our study and significantly present in all families with RLN and VLDLR genes. Interestingly, the novel mutation identified in the MACF1 gene was homozygous. Conclusion: Herein, we present the phenotype and radiological findings of a large series of lissencephaly from the same ethnic group. We expand the mutational spectrum of lissencephaly and point to the predominance of autosomal recessive.
Keywords: Lissencephaly -Microclissencephaly - Cortical malformations – Egyptian - RLN -VLDLR