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EXOSC8 encodes the core exosome subunit RRP43, and biallelic pathogenic variants cause pontocerebellar hypoplasia type 1C (PCH1C), an autosomal recessive neurodegenerative disorder characterized by spinal motor neuron involvement and cerebellar‐pontine atrophy (Gene Symbol; Disease Name).
Genetic analyses across six unrelated families have identified homozygous and compound heterozygous EXOSC8 variants in PCH1C patients. A novel homozygous splice‐region missense variant c.238G>A (p.Val80Ile) was reported in one consanguineous family, confirmed to cause exon 5 skipping and early truncation of the transcript (PMID:38017281). A second case harbored compound heterozygous variants including a canonical splice donor deletion c.390+1delG (r.[345_390del]; p.Ser116LysfsTer27) and two cis‐acting missense changes c.628C>T (p.Pro210Ser) and c.815G>C (p.Ser272Thr) (PMID:34210538). Parental testing confirmed segregation of alleles in trans.
Functional assays demonstrate that c.238G>A results in skipping of exon 5, while c.390+1delG eliminates exon 7, each leading to premature protein truncation and loss of RRP43 expression. Quantitative analysis showed a 30% decrease in mRNA and 65% reduction in protein levels for the c.390+1delG allele, supporting a loss-of-function mechanism (PMID:34210538).
A complementary yeast model of Rrp43p variants revealed decreased exosome complex stability and altered exonuclease activity for core subunit mutants, consistent with impaired RNA processing in patients (PMID:24237138).
Together, biallelic EXOSC8 variants across six probands exhibit autosomal recessive inheritance with consistent phenotypes including psychomotor retardation, spasticity, spinal muscular atrophy, nystagmus, contractures, and diaphragmatic hernia. Experimental data confirm pathogenic loss of exosome function.
Key Take-home: EXOSC8 loss-of-function variants reliably underlie PCH1C and should be included in diagnostic panels for early cerebellar‐pontine hypoplasia with motor neuron involvement.
Gene–Disease AssociationStrongSix unrelated probands with biallelic EXOSC8 variants and concordant functional data Genetic EvidenceModerateSix probands in six families harbor homozygous or compound heterozygous splice and missense alleles Functional EvidenceModerateSplicing assays confirm exon skipping and truncation; yeast model shows impaired exosome stability |