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

## TL;DR

This study explores the genetic and phenotypic complexity of lissencephaly, showing that whole exome sequencing improves prenatal and postnatal diagnosis and highlights new genetic links.

## Contribution

The study identifies novel genetic associations with lissencephaly and proposes a comprehensive classification framework for genetic aetiology.

## Key findings

- Whole exome sequencing achieved a 79.04% diagnostic yield across prenatal and postnatal cases.
- PAFAH1B1 mutations and 17p13.3 deletions were the most common genetic variants in both cohorts.
- DARS2 and NPRL3 were newly associated with lissencephaly in this study.

## 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 signalling 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 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 totalling 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 yields 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 aetiology 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 counselling.

Huang et al. report that by integrating prenatal and postnatal data, they identified significant genetic heterogeneity, phenotypic complexity and challenges in prenatal diagnosis for lissencephaly. They recommend whole exome sequencing as the first-line diagnostic method to improve genetic counselling and prognosis assessment.

Graphical Abstract