Pontocerebellar Hypoplasia Panel

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). Distinguishing features for the various subtypes are listed in the individual gene Test Descriptions.

All pontocerebellar hypoplasias are transmitted with an autosomal recessive mode of inheritance. Defects in the following genes have been documented as causative for the disorder: AMPD2, CHMP1A, CLP1, EXOSC3, RARS2, SEPSECS, TSEN2, TSEN15, TSEN34, TSEN54, VPS53, and VRK1. To date, about 80 causative variants have been reported. About half the variants are missense; the other half comprise variants that are predicted to result in truncated proteins and include substitutions leading to premature stop codons, small deletions/insertions, splicing variants and two large deletions (Human Gene Mutation Database). Information on molecular biology of gene products is provided in individual gene test descriptions.

Pathogenic variants in the EXOSC3 gene were detected in 60% of patients with a clinical diagnosis of PCH1 (Wan et al. 2012. PubMed ID: 22544365).

Pathogenic variants in the AMPD2 gene have been reported in 16% of patients with a clinical diagnosis of Pontocerebellar Hypoplasia (PCH) (Akizu et al. 2013. PubMed ID: 23911318).

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. 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).

Pathogenic variants in the TSEN34 gene account for less than 2% of patients with PCH2 (Namavar et al. 2011. PubMed ID: 20952379). To date, only one homozygous missense variant was reported in a patient of Turkish origin (Budde et al. 2008. PubMed ID: 18711368).

Pathogenic variants in the TSEN2 gene account for less than 2% of patients with PCH2 (Namavar et al. 2011. PubMed ID: 20952379).

A total of 29 patients with pathogenic variants in the RARS2 gene have been described worldwide (van Dijk et al. 2017. PubMed ID: 27683254).

Pathogenic variants in the SEPSECS gene have been reported in a total of 13 unrelated patients with PCH (Iwama et al. 2016. PubMed ID: 26888482; Human Gene Mutation Database).

Three missense variants in the TSEN15 gene were found in three unrelated consanguineous families with a history of the PCH (Breuss et al. 2016. PubMed ID: 27392077).

Two pathogenic variants in the VPS53 gene have been implicated in PCH. They appear to be common in the Jewish Moroccan population with a carrier rate of ~ 1:37 (Feinstein et al. 2014. PubMed ID: 24577744).

Only two truncating variants in the CHMP1A gene have been reported to be causative of PCH in 3 families from Peru and Puerto Rico (Mochida et al. 2012. PubMed ID: 23023333).

Two variants in the VRK1 gene have been implicated in PCH. They appear to be rare (Renbaum et al. 2009. PubMed ID: 19646678; Najmabadi et al. 2011. PubMed ID: 21937992).

One pathogenic missense variant in the CPL1 gene has been reported to be the cause of PCH10 in nine, apparently unrelated, consanguineous families from the Middle East (Schaffer et al. 2014. PubMed ID: 24766810; Karaca et al. 2014. PubMed ID: 24766809).

Pathogenic copy number variants have been reported only in the EXOSC3 and SEPSECS genes (Eggens. 2014. PubMed ID: 24524299; Iwama et al. 2016. PubMed ID: 26888482).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 98.0% coverage of all coding exons of the genes 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 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).