Cerebellar hypoplasia

Gene: EXOSC8

Green List (high evidence)

Comment on list classification: Upgraded from Red to Green on the basis that cerebellar hypoplasia is a significant feature of the disorder associated with biallelic variant in this gene - at least 5 families have been reported.

Created: 8 Sep 2025, 12:26 p.m. | Last Modified: 8 Sep 2025, 12:26 p.m.

Panel Version: 1.78

- PMID: 38017281 (2024) - Homozygous missense variant c.238G>A;p.Val80Ile causing exon skipping in a patient with psychomotor retardation, spasticity, spinal muscle atrophy, respiratory problems, diaphragmatic hernia, severe hypoplasia of cerebellum, dilated lateral ventricles, hypoplastic temporal lobes, thinning of the brain stem, dysmorphic facies, nystagmus, congenital esotropia and contractures.

- PMID: 34210538 (2021) - 16-year-old Spanish boy with cerebellar and spinal muscular atrophy, spasticity, psychomotor retardation, nystagmus, ophthalmoparesis, epilepsy, and mitochondrial respiratory chain (MRC) deficiency. The phenotype was described as milder compared to previous cases. WES revealed three variants in the EXOSC8 gene (c.[390+1delG];[628C>T;815G>C]) which lead to reduced mRNA expression and protein levels.

- PMID: 24989451 (2014) - 22 infants, belonging to two Roma and one Palestinian families, with a complex infantile neurological disorder characterised by psychomotor deficit, cerebellar and corpus callosum hypoplasia, hypomyelination and spinal motor neuron disease. A homozygous missense variant (p.Ser272Thr) segregated with disease in the two Roma families from the same region. The change was found at a frequency of 3% in the general Roma population, consistent with a founder effect. In the Palestinian family, a second homozygous missense variant (p.Ala2Val) was determined as the disease-causing change. Supporting functional data, as well as zebrafish model. Both variants affect a highly conserved residue and result in significantly decreased EXOSC8 protein in patient cells.

Created: 8 Sep 2025, 12:25 p.m. | Last Modified: 8 Sep 2025, 12:25 p.m.

Panel Version: 1.75

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Pontocerebellar hypoplasia, type 1C, OMIM:616081

Publications

• 24989451
• 38017281
• 34210538

Red List (low evidence)

Only one report -mutations found in three families. Not listed on G2P. Not offered as diagnostic test on UKGTN

Created: 3 Nov 2016, 10:58 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
pontocerebellar hypoplasia type 1C 616081

Publications

• 24989451