Genetic landscape and phenotypic correlations of lissencephaly: prenatal and postnatal insights

Abstract Lissencephaly (LIS) is a spectrum of cortical malformations including agyria, pachygyria, and subcortical band heterotopia, which arises from aberrant neuronal migration and is associated with severe neurodevelopmental impairments. Despite advancements in prenatal imaging, diagnosing LIS remains challenging. Genetic factors play a crucial role in LIS, involving multiple genes and signaling pathways, yet research on prenatal diagnosis and the genetic basis is still limited. This study aimed to assess the diagnostic yield of whole exome sequencing (WES) in LIS and to examine genotype-phenotype correlations, addressing the challenge of “phenotype lag” in prenatal LIS diagnosis. This study included 20 fetuses with LIS suggested by prenatal imaging and 20 children with LIS diagnosed after birth; all cases were diagnosed by magnetic resonance imaging (MRI) and underwent genetic testing. In addition, a literature review was conducted and 80 studies were included, of which 1 was used to compare detection efficacy and 79 studies totaling 210 cases were used to assess genotype-phenotype correlation. In the prenatal cohort, 85.0% (17/20) of cases exhibited concurrent anomalies, predominantly ventriculomegaly (50.0%) and microcephaly (25.0%). In the postnatal cohort, the most common phenotypes were epilepsy (80.0%, 16/20) and global developmental delay (65.0%, 13/20), with half of the cases (10/20) showing no abnormalities in the prenatal period. The diagnostic yield were 55.0% (11/20) and 65.0% (13/20), respectively, with PAFAH1B1 point mutations or 17p13.3 microdeletions being the predominant genetic variant in both cohorts, accounting for 31.3% (prenatal) and 25.5% (postnatal) of cases, respectively. DARS2 and NPRL3 were reported to be associated with LIS for the first time in this study. Literature synthesis revealed an overall diagnostic yield of 79.04%, dominated by PAFAH1B1 (26.3%), DYNC1H1 (11.9%), and DCX (10.2%). By reviewing the prenatal images, up to 48.05% (74/154) of the cases had no specific findings in the prenatal period, and the most common presentations were ventriculomegaly/hydrocephalus (52.63%) and head circumference anomalies (29.82%). This study highlights the significant genetic heterogeneity, phenotypic complexity, and diagnostic challenges of LIS by integrating data from our cohort and the published literature. We developed a comprehensive genetic etiology classification framework for LIS and identified novel associations with non-canonical genes such as NPRL3 and DARS2. With a high molecular diagnostic yield of 79.04%, we recommend WES as the first-line genetic test. Furthermore, the establishment of an integrated prenatal imaging-molecular diagnostic system, along with a postnatal multidisciplinary model, is crucial for improving prognosis assessment, clinical decision-making, and genetic counseling.