Pontocerebellar Hypoplasia via the TSEN54 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.

PCH4 is characterized by severe features including hypertonia, clonus and cerebellar hypoplasia. Severe apnea usually results in early death (Namavar et al. 2011. PubMed ID: 20952379).

PCH5 was reported in one single non-consanguineous family of European ancestry with three affected children. In this family, symptoms included fetal-seizures-like activity starting as early as the 18th week of gestation, generalized symmetrical hypertonia, clonus, and absence of primitive reflexes. Death occurred during the first week of life as the result of severe apnea (Patel et al. 2006. PubMed ID: 16470708).

All pontocerebellar hypoplasias are transmitted with an autosomal recessive mode of inheritance. Pathogenic variants in the TSEN54 gene account for over 90% of patients with PCH2 and PCH4 (Budde et al. 2008. PubMed ID: 18711368; Namavar et al. 2011. PubMed ID: 21749694; Battini et al. 2014. PubMed ID: 23307886). To date 20 pathogenic variants have been reported. They include missense, nonsense and splicing variants, as well as small frameshift deletions and inframe insertions. No pathogenic large deletions or regulatory variants have been reported in the TSEN54 gene.

A splice site variant (c.468+2T>C) together with the common causative missense variant (c.919G>T, Ala307Ser) were shown to be the cause of the disease in the single PCH5 family that was previously reported (Namavar et al. 2011. PubMed ID: 21368912). See also Namvar et al. 2016 (PMID: 20301773).

The TSEN54 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, TSEN15, and TSEN34 (Paushkin et al. 2004. PubMed ID: 15109492).

Pathogenic variants in the TSEN54 gene account for over 90% of patients with PCH2 and PCH4 (Budde et al. 2008. PubMed ID: 18711368; Namvar et al. 2016. PubMed ID: 20301773). PCH5 appears to be rare. Only one family with PCH5 and pathogenic variants in TSEN54 has been reported to date (Namavar et al. 2011. PubMed ID: 21368912).

Thus far, no pathogenic gross deletions or duplications have been reported in the TSEN54 gene (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the TSEN54 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.