-related neurodevelopmental disorders: a systematic review on genotype-phenotype correlations.

Introduction: Genotype-phenotype correlations in -related neurodevelopmental disorders (-NDDs) remain unclear. This systematic review aimed to clarify these correlations.

Methods: Searches of PubMed and Embase were conducted on 8 August 2024 to identify studies that had investigated genetically diagnosed NDDs (5q31.3 deletion syndrome and PURA syndrome). All types and languages of studies were included. Study quality was assessed using a 20-item criterion checklist. Genetic and clinical data were extracted from each article and genotype-phenotype correlations were explored.

Results: Our analysis included 46 studies encompassing 230 patients with -NDDs (5q31.3 deletion syndrome 18 (8%) and PURA syndrome 212 (92%)). Patients with 5q31.3 deletion syndrome exhibited more congenital defects (50% vs 12%, p<0.0001), respiratory difficulties (94% vs 63%, p=0.013) and walking disability (94% vs 55%, p=0.0026) than patients with PURA syndrome. In PURA syndrome, protein-truncating (nonsense or frameshift) variants were associated with more speech deficits (93% vs 80%, p=0.014) than non-protein-truncating (missense or in-frame) variants. variant location had no effect on congenital defect occurrence or neurodevelopmental outcome. Overall, respiratory difficulties, walking disability and speech deficits were more commonly observed in the following order: 5q31.3 deletion (94%, 94% and 100%, respectively), multiple PUR-repeat deletions (68%, 60% and 95%, respectively), single PUR-repeat deletion or alteration (61%, 53% and 85%, respectively), and deletion or alteration located outside PUR repeats (38%, 33% and 43%, respectively).

Conclusion: The clinical severity of -NDDs appears to be associated with the deletion/alteration size including PUR repeats rather than the location of variants.