Ataxia and cerebellar anomalies - narrow panel

Gene: TSEN34

I don't know

Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Ataxia and cerebellar anomalies - narrow panel, until more evidence emerges.

Created: 16 Dec 2025, 8:03 a.m. | Last Modified: 16 Dec 2025, 8:39 a.m.

Panel Version: 8.35

PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.
Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical.


PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).

Created: 15 Dec 2025, 1:25 p.m. | Last Modified: 16 Dec 2025, 8:18 a.m.

Panel Version: 8.33

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Pontocerebellar hypoplasia type 2C, OMIM:612390; pontocerebellar hypoplasia type 2C, MONDO:0012891

Publications

• 20952379
• 27370523
• 32476018
• 37544645