Ataxia and cerebellar anomalies - narrow panel

Gene: EXOSC5

Green List (high evidence)

Biallelic EXOSC5 variants have been associated with Cerebellar ataxia, brain abnormalities, and cardiac conduction defects (OMIM: 619576). At least five EXOSC5 variants have been found in five unrelated families with OMIM: 619576 (PMID: 30950035, 32504085, 34089229). The most common phenotypic features were: cerebella hypophasia / atrophy (5/5 families), ataxia (4/4 families reported), hypotonia ((5/5 families) and developmental delay (4/4 families reported), all of which were apparent from infancy (supplementary table S1 in PMID:34089229).

Created: 16 Dec 2024, 2:49 p.m. | Last Modified: 16 Dec 2024, 2:49 p.m.

Panel Version: 7.7

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Comment on list classification: Three unrelated families presenting ataxia in association with cerebellar hypoplasia/atrophy. However, all harbour the same p.Thr114Ile variant, and thus it is unclear whether other EXOSC5 variants result in cerebellar ataxia.

Therefore, rating Amber in anticipation of additional publications/clinical evidence.

Created: 7 Sep 2020, 10:36 a.m. | Last Modified: 7 Sep 2020, 10:36 a.m.

Panel Version: 2.10

- PMID: 32504085 (2020) - Five patients from four families with biallelic variants in EXOSC5. Clinical features included short stature (3/5), developmental delays that affect motor skills (3/5), hypotonia (4/5), ataxia (3/4), cerebellar hypoplasia/atrophy (4/5). Cognitive function was generally preserved, but included mild speech delays in one patient.
Cerebellar ataxia was described in two sibs and one singleton - all of whom were compound heterozygous for the p.Thr114Ile variant, inherited in trans with a frameshift variant (p.His30Thrfs*35) or deletion involving exons 5–6 of EXOSC5, respectively.

A LoF zebrafish model resulted in a variety of morphological defects including shortened and curved tails/bodies, reduced eye/head size and oedema. Functional studies of the variants in budding yeast and cultured cells showed some defects in RNA exosome function and interactions, that could not be explained by decrease in the steady-state level of EXOSC5.

- PMID: 29302074 (2019) - Three sibs with a homozygous EXOSC5 variant (p.Thr114Ile), associated with mild motor delays, cerebellar ataxia, nystagmus, dysarthria, and moderate ID. The family is also described in PMID: 30950035. No functional studies of the variant were undertaken.
Sources: Literature

Created: 7 Sep 2020, 10:27 a.m. | Last Modified: 7 Sep 2020, 10:38 a.m.

Panel Version: 2.10

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Short stature; Motor developmental delays; Cerebellar hypoplasia; Ataxia

Publications

• 32504085
• 29302074