Electroclinical and genetic profiling of Tunisian families with malformations of cortical development: report of novel DENND5A mutation, functional DYNC1H/DCX variants and structural correlates

Abstract

Malformations of cortical development (MCD) are neurodevelopmental disorders arising from disrupted neuronal proliferation and migration during embryogenesis and represent a major cause of epilepsy and developmental impairment. Although numerous genes have been implicated, variant-specific mechanisms and population-specific mutational spectra remain incompletely defined, particularly in underrepresented regions. Here we investigated the genetic basis of MCD in three Tunisian families using whole-exome sequencing, segregation analysis, and high-resolution structural modelling. We identified a novel loss of function DENND5A mutation (p.Glu423LysfsTer13) in a patient with developmental and epileptic encephalopathy with severe global delay, cortical malformations and additional structural brain defects. We also report the first Tunisian case of a de novo DYNC1H1 linker-domain variant (p.Arg1623Gln) in a child with severe polymicrogyria, microcephaly and congenital cataracts, and show that this substitution disrupts conserved electrostatic interactions required for dynein linker stability. A de novo DCX mutation (p.Arg186Leu) was identified in a patient with lissencephaly-subcortical band heterotopia and support convergent destabilization of the doublecortin microtubule-binding interface across Arg186 substitutions, indicating residue-specific vulnerability in neuronal migration disorders. In addition, a truncating SEZ6L variant (p.Trp858Ter) a putative candidate autism linked gene, suggesting a potential modifying contribution to phenotypic variability. Collectively, our study expands the mutational spectrum of malformations of cortical development in North Africa and adds incremental evidence of the molecular underpinnings of MCD and contribute valuable data to genotype-phenotype correlations in neurodevelopmental disorders.