Hereditary neuropathy or pain disorder

Gene: EXOSC3

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 24 Feb 2025, 5:02 p.m. | Last Modified: 24 Feb 2025, 5:02 p.m.

Panel Version: 6.148

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Comment on list classification: Promoting this gene to amber with a proposal to promote to green following NHS GMS review. There are sufficient cases with a relevant phenotype and variants in this gene.

Created: 26 Oct 2024, 8:56 p.m. | Last Modified: 26 Oct 2024, 8:56 p.m.

Panel Version: 5.97

Associated with Pontocerebellar hypoplasia, type 1B in OMIM (OMIM:614678) and has a definitive association with EXOSC3-related PONTOCEREBELLAR HYPOPLASIA TYPE 1 on the Gene2Phenotype Developmental Disorders panel.

PMID: 22544365 - Wan et al 2012 - report 9 families with a variety of ethnicities with autosomal recessive pontocerebellar hypoplasia type 1B. Homozygous or compound heterozygous missing sense, frameshift or abberant splicing mutations in the EXOSC3 gene were identified. Knockdown of expression of exosc3 in zebrafish resulted in a phenotype with short curved spine and small brain with poor motility and even death.

PMID:23564332 - Biancheri et al 2013 - report 4 patients from 2 families with spinal anterior horn involvement associated with isolated cerebellar hypoplasia carrying a homozygous mutation [c.395A > C/p.D132A] in EXOSC3. Phenotypic features in common include strabismus, microcephaly, muscle hypotonia (diffuse or axial), MRI cerebellar hypoplasia, normal MRI brainstem, developmental delay with limited/no speech. Seizures were not observed. This is considered a 'mild' phenotype. Onset was in the first few months of life. Method for identifying the variants are not disclosed.

PMID:24524299 - Eggens et al 2014 - cohort of 99 PCH patients (90 families) tested negative for mutations in the TSEN genes, RARS2, VRK1 and CASK. 6 different variants were found through Sanger sequencing of the EXOSC3 gene, either in homozygous or compound heterozygous state, in 14 patients from twelve families with PCH subtype 1. 6 patients from 5 families had heterozygous c.92G > C, p.G31A were all of Roma decent suggesting a founder effect. The phenotypic spectrum ranged from mild to severe with death during infancy and hypoplasia of the pons. Seizures were reported in 2 patients.


PMID:25149867 - Halevy et al 2014 - describe 2 pairs of siblings from large consanguineous multiplex family of Arab origin, who showed a complicated HSP with progressive spastic paraplegia associated with signs of cerebellar dysfunction and variable cognitive impairment and strabismus, clinically consistent with the diagnosis of complicated HSP. They did not observe the hypotonia, respiratory dysfunction, or signs of anterior horn involvement, typical for PCH. They identified a novel variant c.571G>T; p.G191C (NM_016042.3) in EXOSC3 by WES which showed perfect segregation within the family.

PMID: 23975261 - Zanni et al 2013 - WES in a 2 generation family from Bangladesh with early onset spasticity, mild intellectual disability, distal amyotrophy, and cerebellar atrophy identified 2 missense mutations in the EXOSC3 gene: a novel p.V80F mutation and a known p.D132A change previously associated with mild variants of pontocerebellar hypoplasia type 1.

Created: 26 Oct 2024, 8:55 p.m. | Last Modified: 26 Oct 2024, 8:55 p.m.

Panel Version: 5.96

Phenotypes
Pontocerebellar hypoplasia, type 1B, OMIM:614678; pontocerebellar hypoplasia type 1B, MONDO:0013853

Publications

• 23564332
• 24524299
• 25149867
• 12548734

Green List (high evidence)

Sources: Expert list

Created: 19 Oct 2024, 10:32 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
pontocerebellar hypoplasia; motor neuropathy

Publications

• 23564332:24524299:25149867:12548734