Intellectual disability
Gene: TSEN15

TSEN15 (tRNA splicing endonuclease subunit 15)
EnsemblGeneIds (GRCh38): ENSG00000198860
EnsemblGeneIds (GRCh37): ENSG00000198860
OMIM: 608756, Gene2Phenotype
TSEN15 is in 8 panels

3 reviews

Catherine Snow (Genomics England)

Comment on list classification: Gene identified in literature PMID:30914295 as missing in PanelApp compared to other curated gene list for ID genes. No further evidence to gene since Rebecca reviewed and I concur therefore TSEN15 will stay as Amber.
Created: 22 May 2019, 2:11 p.m.

Created: 22 May 2019, 2:11 p.m.

Panel version: Imported from Intellectual disability update May 2019 panel version 0.57

Rebecca Foulger (Genomics England curator)

Comment on publications: One of the individuals in family II reported by Breuss et al. (PMID:27392077) was previously included in a study by Alazami et al (PMID:25558065).
Created: 16 May 2019, 9:12 a.m.

Comment on list classification: TSEN15 was added to the ID panel and rated Green by Konstantinos Varvagiannis based on PMID:27392077 (Breuss et al., 2016) who report three homozygous TSEN15 variants in four individuals from three families. Affected individuals showed progressive microcephaly, delayed developmental milestones, variable intellectual disability (and in 2 of 4 cases, epilepsy). Although there are three unrelated cases, on balance I have rated TSEN15 as Amber (borderline) for now based on the following: The His116Tyr variant found in the two individuals from Family III had no effect on the level of expression of TSEN15 (but may instead result in destabilization of the complex), TSEN15 has a Disease confidence rating of 'probable' in DD-G2P for 'Pontocerebellar Hypoplasia and Progressive Microcephaly' as MRI was not performed/not available for Family III, and the ID is only mild-moderate in Family III. Added a 'watchlist' tag awaiting further cases.
Created: 14 May 2019, 2:58 p.m.

Created: 14 May 2019, 2:58 p.m.

Panel version: 2.828

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Biallelic pathogenic variants in TSEN15 cause Pontocerebellar hypoplasia, type 2F (MIM 617026).

Four individuals with molecular confirmation of the diagnosis, from 3 unrelated consanguineous families have been reported by Breuss et al. (PMID: 27392077). One of these individuals was previously included in a study of neurogenetic disorders in consanguineous families (Alazami et al. - PMID: 25558065). A similarly affected sib (possibly not tested) was reported for one patient.

DD with variable degrees of ID (mild to severe), progressive microcephaly were common to all. Seizures were noted in 2 individuals. MRI images (for the feature of pontocerebellar hypoplasia - PCH) were only available for 2 families.

Affected subjects were homozygous for missense variants private to each family, namely:
- NM_052965.3:c.226T>G (p.Trp76Gly)
- NM_052965.3:c.346C>T (p.His116Tyr)
- NM_052965.3:c.455A>G (p.Tyr152Cys)

Trp76Gly and Tyr152Cys resulted in reduced protein abundance while His116Tyr did not have an effect on TSEN15 expression levels.

TSEN15 is part of the tRNA splicing endonuclease complex, the 3 other components of which (TSEN2, TSEN34, TSEN54) have already been associated with PCH. The complex interacts with an RNA kinase encoded by CLP1.

All 3 variants resulted in altered stoichiometry (/relative abundance) of the 3 other subunits of the complex as well as the relative levels of CLP1.

Almost complete loss of in vitro tRNA cleavage activity was the case for purified complexes from all 3 mutants.
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TSEN15 is included in the DD panel of G2P associated with Pontocerebellar Hypoplasia and Progressive Microcephaly (Disease confidence: probable). ID is among the assigned phenotypes.

This gene is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc).
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As a result, TSEN15 could be considered for inclusion in this panel as green (or amber).
Sources: Literature, Radboud University Medical Center, Nijmegen
Created: 26 Dec 2018, 12:18 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Pontocerebellar hypoplasia, type 2F (MIM 617026)

Publications

Variants in this GENE are reported as part of current diagnostic practice

Created: 26 Dec 2018, 12:18 p.m.

Panel version: 2.588

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Amber
Literature
Expert Review Amber

Phenotypes

Pontocerebellar hypoplasia, type 2F, OMIM:617026

Tags

watchlist

OMIM

608756

Clinvar variants

Variants in TSEN15

Penetrance

Complete

Publications

Panels with this gene

History Filter Activity

18 May 2021, Gel status: 2

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: TSEN15 were changed from delayed developmental milestones; Pontocerebellar hypoplasia, type 2F, 617026; Intellectual disability to Pontocerebellar hypoplasia, type 2F, OMIM:617026

25 Jul 2019, Gel status: 2

Set Phenotypes, Set publications

Catherine Snow (Genomics England)

Added phenotypes Pontocerebellar hypoplasia, type 2F, 617026 for gene: TSEN15 Publications for gene TSEN15 were changed from 27392077; 25558065 to 27392077; 30914295; 25558065

16 May 2019, Gel status: 2