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Pontocerebellar hypoplasia type 1 (PCH1) is a rare, genetically heterogeneous neurodegenerative disorder characterized by early-onset cerebellar and pontine hypoplasia, spinal motor neuronopathy, and systemic neurological features. EXOSC9 encodes a core subunit of the RNA exosome complex essential for proper RNA processing and degradation. Biallelic pathogenic variants in EXOSC9 define PCH1D, expanding the spectrum of PCH1 subtypes and underscoring the critical role of RNA exosome integrity in neurodevelopment.
Genetically, PCH1D exhibits autosomal recessive inheritance with eight unrelated families identified to date harboring biallelic missense and truncating variants in EXOSC9 ([PMID:30690203]; [PMID:33040083]). A total of 8 probands have been reported across these cohorts ([PMID:30690203]; [PMID:33040083]). Segregation analysis in two multiplex pedigrees confirmed the recessive inheritance, with unaffected carrier parents and no additional affected relatives observed.
The variant spectrum includes recurrent missense alleles (e.g., c.41T>C (p.Leu14Pro)) and multiple loss-of-function mutations such as nonsense, frameshift, splice-site, and small indels. These variants disrupt exosome complex assembly or stability, leading to impaired RNA decay. Founder homozygous c.41T>C (p.Leu14Pro) has been observed in two unrelated patients with a milder phenotype but consistent neurodevelopmental impairment ([PMID:30690203]).
Functional studies in patient-derived cells and biochemical assays demonstrate that EXOSC9 variants lead to reduced exosome activity, accumulation of unprocessed RNA substrates, and perturbed ribonucleoprotein complex formation. In vitro complementation rescues RNA processing defects, supporting a loss-of-function mechanism consistent with haploinsufficiency of the RNA exosome in neuronal cells ([PMID:33040083]).
Clinically, PCH1D patients present with global developmental delay, hypotonia, feeding difficulties, respiratory insufficiency, lactic acidosis, cerebellar atrophy, and brachycephaly. Magnetic resonance imaging reveals cerebellar and pontine hypoplasia in severe cases or isolated cerebellar atrophy in milder alleles. The phenotypic spectrum ranges from lethal neonatal forms to survivors with restricted cognitive development and motor impairment.
Integration of genetic and functional data yields a Strong gene–disease association: eight probands across eight unrelated families with concordant cellular functional evidence. This knowledge enables precise molecular diagnostics, informs recurrence risk counseling, and guides future therapeutic targeting of RNA exosome dysfunction.
Key Take-home: Biallelic EXOSC9 variants cause autosomal recessive PCH1D via exosome loss-of-function, presenting with cerebellar hypoplasia and motor neuronopathy.
Gene–Disease AssociationStrong8 probands across 8 unrelated families; concordant functional data Genetic EvidenceStrong8 probands with biallelic missense and truncating variants; variant diversity demonstrated Functional EvidenceModerateCellular assays show EXOSC9 loss-of-function and impaired RNA exosome activity |