Pontocerebellar Hypoplasia via the VPS53 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).

PCH2E, also known as cerebello-cerebral atrophy type2, is distinguished by the degeneration of both the grey and white matter of the cerebellum. Clinical features include profound mental retardation, severe developmental delay, progressive spastic quadriplegia with painful joint contractures, clonus, epileptic seizures, mild hypotonia, sleep disorder, and marked irritability. Symptoms appear during early infancy (Ben-Zeev et al. 2003. PubMed ID: 12920088; Feinstein et al. 2014. PubMed ID: 24577744).

All pontocerebellar hypoplasias are transmitted with an autosomal recessive mode of inheritance. PCH2E is caused by pathogenic variants in the VPS53 gene. To date, only two pathogenic variants have been identified, via whole exome sequencing, in four non-consanguineous families of Jewish Moroccan ancestry. Compound heterozygosity was detected in all affected individuals. The pathogenic variants include one missense and one splice site variant and appear to be common in the Jewish Moroccan population with a carrier rate of ~ 1:37 (Feinstein et al. 2014. PubMed ID: 24577744).

No large pathogenic deletions or regulatory variants have been reported involving the VPS53 gene.

The VPS53 gene encodes one of the four subunits that constitute the Golgi-associated retrograde protein complex, which is involved in retrograde transport from early and late endosomes to the trans-Golgi network (Pérez-Victoria et al. 2008. PubMed ID: 18367545).

Pathogenic variants in the VPS53 gene appear to be rare. Such variants have been reported in four families of Jewish Moroccan ancestry. Available data suggest that this variant is common in this population with a carrier rate of ~ 1:37 (Feinstein et al. 2014. PubMed ID: 24577744). Thus far, no pathogenic gross deletions or duplications have been reported involving the VPS53 gene (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the VPS53 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.