Pontocerebellar Hypoplasia via the TSEN15 Gene

Pontocerebellar hypoplasias (PCH) are a group of clinically and genetically heterogeneous neurodegenerative disorders characterized by abnormal development of the pons, cerebellum and cerebral cortex; progressive microcephaly; psychomotor developmental delay; and swallowing difficulties (Barth. 1993. PubMed ID: 8147499; Namavar et al. 2011. PubMed ID: 21368912). Several subtypes have been described based on the clinical presentation, progression, and pathological and molecular defects. However, clinical overlapping features among various subtypes have been reported, and some genes have been implicated in more than one subtype, suggesting that PCH constitute a spectrum (Burglen et al. 2012. PubMed ID: 22452838; Samanta and Willis. 2016. PubMed ID: 27570394).

PCH2 is the most common form of the syndrome (Barth et al. 1995. PubMed ID: 7854532; Namavar et al. 2011. PubMed ID: 20952379; Namavar et al. 2011. PubMed ID: 21749694). It is distinguished by dystonia, chorea and cerebral visual defects (Barth et al. 1990. PubMed ID: 2370559). Additional features include seizures, ataxia, hypotonia, muscle weakness and wasting, and nystagmus. Symptoms are usually apparent at birth and death occurs in early infancy or childhood.

All pontocerebellar hypoplasias are transmitted with an autosomal recessive mode of inheritance. Pathogenic variants in the TSEN15 gene were recently identified via whole-exome sequencing. A total of three missense variants were found in three unrelated consanguineous families from Pakistan, Saudi Arabia and Syria. Evidence for pathogenicity include co-segregation of the homozygous variants with the affected status, heterozygosity in parents, reduction of protein level, and almost complete loss of in-vitro enzyme activity (Breuss et al. 2016. PubMed ID: 27392077).

No pathogenic large deletions or regulatory variants have been reported in the TSEN15 gene.

The TSEN15 gene encodes one of four subunits of the tRNA splicing endonuclease complex, which catalyzes the removal of introns from precursor tRNAs. The other subunits are TSEN2, TSEN34, and TSEN54 (Paushkin et al. 2004. PubMed ID: 15109492).

Pathogenic variants in TSEN15 appear to be rare. Recently, three missense variants were found in three unrelated consanguineous families (Breuss et al. 2016. PubMed ID: 27392077).

This test provides full coverage of all coding exons of the TSEN15 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).