genomic rearrangements in a 391 French bilateral periventricular nodular heterotopia cohort: prevalence and phenotypic correlations.

Background: loss of function manifests across a broad spectrum of phenotypes, ranging from severe prenatal onset to asymptomatic cases. Bilateral periventricular nodular heterotopia (BPNH) consistently occurs in affected individuals. This retrospective study involving French patients with BPNH evaluates the prevalence of gene dosage anomalies and investigates genotype-phenotype correlations in a large cohort of French patients with BPNH.

Methods: A retrospective observational study was conducted on 391 individuals diagnosed with BPNH confirmed by brain MRI. Sequencing analysis using Sanger or next-generation sequencing was complemented by targeted array-comparative genomic hybridisation to identify copy number variants (CNVs).

Results: variants were identified in 40% of females and 12% of males. Among these, 87% were single nucleotide variants (SNVs), while CNVs accounted for 13%, all of which were deletions. Half of the CNVs involved a recurrent deletion spanning exons 31-48, often accompanied by a duplication of the neighbouring gene. This del-dup was associated with a milder phenotype, whereas smaller de novo deletions correlated with severe outcomes. Mosaicism was also detected in three cases.

Conclusion: CNV analysis, particularly for recurrent deletions and mosaicism, is essential in the genetic evaluation of BPNH. Integrating CNV detection with SNV analysis improves diagnostic accuracy and enhances understanding of genotype-phenotype correlations.