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This summary reviews the evidence linking variants in EXOSC9 (HGNC:9137) to pontocerebellar hypoplasia (MONDO_0020135). Multiple independent studies have revealed that biallelic variants in EXOSC9 are causative for a subtype of pontocerebellar hypoplasia characterized by early‐onset severe developmental delay, progressive motor neuronopathy, and cerebellar as well as pontine atrophy (PMID:33040083) (PMID:35893425).
Clinical case reports and multi‐patient studies document at least four unrelated probands identified with pathogenic EXOSC9 variants in one study and nine additional cases reported in a separate cohort. These findings, encompassing distinct families with evidence of biallelic inheritance, support autosomal recessive transmission. No significant contradictory clinical reports have been identified to date.
The genetic evidence is bolstered by a diverse spectrum of variants including missense and frameshift changes. For example, the variant c.41T>C (p.Leu14Pro) has been observed in multiple patients and is consistent with the pattern of inheritance. Additional variants such as frameshift mutations further underscore the gene’s sensitivity to dosage alterations. Segregation analysis in affected families has provided further support as the identified variants co‐segregate with the disease phenotype.
Functional studies have elucidated the mechanism underlying EXOSC9‐related pontocerebellar hypoplasia. Experimental assays have demonstrated that these variants disrupt the normal function of the RNA exosome, a complex integral to RNA processing and degradation. Cellular and animal models have recapitulated aspects of the human phenotype, thereby supporting a pathogenic role for these mutations (PMID:33040083).
While the current literature does not present substantial conflicting evidence, differences in the severity of clinical presentations among patients may reflect genetic or environmental modifiers. Overall, however, the convergence of genetic and functional data reinforces the strength of the association.
In conclusion, the integration of robust clinical, genetic, and experimental evidence confirms that biallelic variants in EXOSC9 are strongly associated with pontocerebellar hypoplasia. This association informs clinical diagnostic decision‑making and supports the development of targeted molecular diagnostics.
Key Take‑home Message: The strong correlation between EXOSC9 variants and pontocerebellar hypoplasia provides a reliable molecular basis for diagnosis and underscores the potential for future therapeutic intervention.
Gene–Disease AssociationStrongAt least four unrelated probands identified (PMID:33040083) and nine additional patients reported (PMID:35893425) with consistent biallelic segregation and clinical presentation. Genetic EvidenceStrongMultiple variant types, including missense and frameshift variants (e.g., c.41T>C (p.Leu14Pro)), observed across independent studies with autosomal recessive inheritance. Functional EvidenceModerateFunctional assays demonstrate that EXOSC9 variants impair RNA exosome activity, consistent with the neurodegenerative phenotype, as evidenced in cell and animal models (PMID:33040083). |