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Pontocerebellar hypoplasia type 1 (PCH1) is an autosomal recessive neurodegenerative disorder characterized by early-onset cerebellar atrophy, spinal motor neuron degeneration, and progressive microcephaly. Affected infants typically present with central and peripheral motor dysfunction, hypotonia, feeding difficulties, and respiratory insufficiency leading to high mortality in infancy. Pathogenic variants in EXOSC3, encoding the RNA exosome component 3, define PCH1B (MONDO:0016396) and phenotypically overlap with spinal muscular atrophy (PMID:22544365). EXOSC3 is one of nine core subunits of the RNA exosome complex essential for 3′–5′ RNA degradation and processing. Disruption of EXOSC3 function impairs pre-rRNA maturation and neuronal development. Since the initial discovery in 2012, multiple independent cohorts have confirmed its role in PCH1B.
In 2012, exome sequencing of a consanguineous kindred uncovered biallelic EXOSC3 variants in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, microcephaly, and profound developmental delay, establishing the first genetic link for PCH1B (PMID:22544365). The initial cohort included homozygous frameshift and nonsense mutations as well as splice-site variants. Subsequent analysis of 12 SMN1-negative families identified pathogenic EXOSC3 variants in eight additional kindreds across diverse ethnic backgrounds, confirming an autosomal recessive inheritance pattern and complete segregation in affected relatives. No EXOSC3 variants were observed in ethnically matched controls, indicating variant specificity. Penetrance in homozygous carriers was complete with early lethality typical of PCH1B. These observations satisfy strong genetic evidence under ClinGen guidelines.
Across reported cases, eight loss-of-function alleles (including four frameshift and splice-site variants) and four missense substitutions have been identified (PMID:22544365). One missense variant, c.92G>C (p.Gly31Ala), represents a founder allele in Roma populations. This variant was homozygous in three Slovak siblings and in multiple Czech Roma patients, with haplotype analysis demonstrating a shared ancestral origin (PMID:35852507; PMID:23883322; PMID:29656927). Additional missense variants p.Asp132Ala and p.Trp238Arg display variable phenotypic severity when in homozygous or compound heterozygous states. Disease-associated alleles are absent or extremely rare in population databases, underscoring pathogenicity.
Functional validation in zebrafish revealed that morpholino-mediated knockdown of exosc3 led to small brain size, cerebellar hypoplasia, and impaired motility, phenocopying human PCH1 features. These developmental defects were largely rescued by co-injection of wild-type human EXOSC3 mRNA but not by mRNAs carrying patient-derived mutations (PMID:22544365). In Saccharomyces cerevisiae, orthologous substitutions corresponding to p.Gly31Ala and p.Asp132Ala maintained viability but exhibited altered exosome assembly and reduced exoribonuclease activity (PMID:27777260; PMID:28053271). A more severe allele corresponding to p.Trp238Arg resulted in protein instability and growth defects, aligning with the severe human phenotype. These complementary in vivo and in vitro assays support a loss-of-function mechanism for EXOSC3-associated PCH1B.
Population screening in Bulgarian SMN1-negative cohorts identified homozygous c.92G>C (p.Gly31Ala) in 14 Roma patients, constituting three-quarters of Roma PCH1 cases and supporting ethnic-specific recurrence (PMID:29656927). The variant was absent in non-Roma controls, consistent with a high carrier frequency within Roma communities. Clinical presentation in p.Gly31Ala homozygotes is uniformly severe, with early-onset hypotonia, respiratory insufficiency, and infantile mortality. Milder phenotypes have been observed in p.Asp132Ala homozygotes, indicating genotype-phenotype correlation and phenotypic spectrum extension (PMID:23564332). Clinical imaging reveals variable cerebellar and pontine hypoplasia, sometimes absent early in infancy, mandating serial neuroimaging.
The cumulative evidence from multi-family segregation, diverse biallelic variant spectrum, founder allele recurrence, and concordant functional assays achieves a definitive ClinGen classification for the EXOSC3–PCH1B association. Autosomal recessive inheritance, complete penetrance, and strong genotype-phenotype correlations support robust diagnostic utility. Variants such as c.92G>C (p.Gly31Ala) should be prioritized in Roma patients presenting with SMA-like phenotype and cerebellar hypoplasia. Further studies may expand the variant and phenotypic spectrum beyond current cohorts. Key take-home: EXOSC3 genetic testing should be integrated into diagnostic workflows for infants with motor neuron degeneration and cerebellar hypoplasia, enabling early intervention and genetic counseling.
Gene–Disease AssociationDefinitiveEvidence from 12 unrelated families with 7 affected relatives segregating biallelic EXOSC3 variants and consistent functional concordance across model systems Genetic EvidenceStrongFour siblings and eight additional families with autosomal recessive biallelic variants, including LoF and missense, segregating with disease (total 12 families) ([PMID:22544365]; [PMID:35852507]) Functional EvidenceModerateZebrafish morpholino knockdown and mRNA rescue assays plus yeast ortholog modeling demonstrate loss-of-function mechanism ([PMID:22544365]; [PMID:27777260]; [PMID:28053271]) |