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March 16, 2026European Journal of Medical Genetics0 citationsOpen Access

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

ZRZahra RezaeiChildren's Medical Center FEFarnoosh EmamiChildren's Medical Center MHMorteza HeidariChildren's Medical Center

Key Points

The aim is to explore the clinical and genetic characteristics of Iranian patients with pontocerebellar hypoplasia.
Comprehensive clinical evaluations and brain imaging were conducted.
Laboratory tests and whole-exome sequencing (WES) were performed on the patients.
In silico structural analyses assessed the impact of novel mutations on protein function.
Ten unrelated patients were diagnosed with distinct PCH subtypes.
Eighty percent of cases exhibited microcephaly and spasticity, with all patients showing hypotonia and speech problems.
Eight pathogenic variants were identified, with four being novel mutations, including in SEPSECS and RARS2.

Abstract

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.395A>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.

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