Pontocerebellar Hypoplasia via the EXOSC3 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). 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 (Rudnik-Schöneborn. 2013. PubMed ID: 23284067).

PCH1, previously known as Norman’s disease, is distinguished by a loss of motor neurons in the anterior horn of the spinal cord similar to that observed in spinal muscular atrophy (SMA), resulting in sensory and motor neuropathy. Additional features include severe hypotonia, fasciculation, ataxia, dysplasia, joint contractures, visual abnormalities and hyperventilation. Symptoms are usually apparent at birth, and death usually occurs within the first year of life. However, survival into childhood has been described. Based on the clinical features and electrophysiological and muscle biopsy findings, a number of patients with PCH1 were originally diagnosed with infantile SMA-PCH (Norman. 1961. PubMed ID: 13729575; Rudnik-Schöneborn et al. 2003. PubMed ID: 12548734; Renbaum et al. 2009. PubMed ID: 19646678). PCH1 appears to be rare.

PCH1 is further divided into PCH1A and PCH1B based on the causative gene.

All PCH types are transmitted with an autosomal recessive mode of inheritance. Pathogenic variants in the EXOSC3 gene result in PCH1B (Wan. 2012. PubMed ID: 22544365). About 15 pathogenic variants have been reported to date. Half of these are missense; the other half consist of truncating variants and include splicing, small frameshift deletions/insertions, and indels (Human Gene Mutation Database). To date, only one large pathogenic deletion that includes the first three exons of the gene has been reported (Eggens. 2014. PubMed ID: 24524299).

Defects in EXOSC3 were detected in patients of several ethnic and geographic origins such as American/European, Canadian/Cuban, German/Turkish, Spanish, Czech and Japanese (Wan. 2012. PubMed ID: 22544365; Ryan. 2000. PubMed ID: 11020648; Salman. 2003. PubMed ID: 12731647). They appear to be a significant cause of PCH1. The current data suggest that patients with PCH1 and pathogenic variants in EXOSC3 have a milder phenotype and variable life span, ranging from a few months of age to late teens, compared to that observed in patients with no EXOSC3 pathogenic variants (Wan. 2012. PubMed ID: 22544365).

The EXOSC3 gene encodes a core component of the human exosome complex, which is involved in RNA processing and degradation (Brouwer et al. 2001. PubMed ID: 11110791).

Pathogenic variants in the EXOSC3 gene were detected in 60% of patients with a clinical diagnosis of Pontocerebellar Hypoplasia 1 (Wan et al. 2012. PubMed ID: 22544365). To date, only one large pathogenic deletion that includes the first three exons of the EXOSC3 gene has been reported (Eggens. 2014. PubMed ID: 24524299).

This test provides full coverage of all coding exons of the EXOSC3 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.