Genetic and clinical insights into pontocerebellar hypoplasia: Identification of novel variants in an Iranian cohort

Pontocerebellar hypoplasia (PCH) comprises a group of rare neurodevelopmental disorders characterized by prenatal-onset cerebellar and pontine atrophy, often leading to severe motor and cognitive impairments. While advances in genetic diagnostics have improved our understanding, the full spectrum of causative mutations remains unclear, particularly in underrepresented populations. This study aims to delineate the clinical and genetic characteristics of Iranian patients with PCH. We conducted comprehensive clinical evaluations, brain imaging, and laboratory tests, followed by whole-exome sequencing (WES) in Iranian patients with PCH to establish genotype-phenotype correlations. In silico structural and modeling analyses were performed to assess the impact of novel variants on protein function. Ten unrelated patients were diagnosed with different PCH subtypes. Microcephaly and spasticity were observed in 80% of cases, while hypotonia, psychomotor retardation, and speech problems were present in all patients. Additional features included nystagmus (40%), ataxia (20%), decreased deep tendon reflexes (50%), respiratory insufficiency (10%), feeding difficulties (30%), scoliosis (10%), cognitive deficits (20%), seizures (40%), and vision problems (10%). Genetic analysis identified eight pathogenic variants, including four reported mutations in RARS2, EXOSC3, and TSEN54, and four novel mutations in SEPSECS, and RARS2. A recurrent missense variant (EXOSC3: c.395 A > C) was detected in 40% of cases. This study expands the mutational spectrum of PCH by identifying novel variants and underscores the disorder's genetic heterogeneity. The clinical manifestations ranged from mild developmental delay to severe neurodevelopmental decline with respiratory insufficiency and seizures. Our findings provide valuable insights into genotype-phenotype correlations, facilitating early diagnosis and personalized management strategies. Additionally, these results contribute to genetic counseling and future functional studies to elucidate disease mechanisms.