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| Intellectual disability - microarray and sequencing v2.588 | TSEN15 |
Konstantinos Varvagiannis gene: TSEN15 was added gene: TSEN15 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: TSEN15 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TSEN15 were set to 27392077; 25558065 Phenotypes for gene: TSEN15 were set to Pontocerebellar hypoplasia, type 2F (MIM 617026) Penetrance for gene: TSEN15 were set to Complete Review for gene: TSEN15 was set to GREEN gene: TSEN15 was marked as current diagnostic Added comment: 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. ------ 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). ------ As a result, TSEN15 could be considered for inclusion in this panel as green (or amber). Sources: Literature, Radboud University Medical Center, Nijmegen |
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