Pontocerebellar Hypoplasia via the VRK1 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).

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.

All pontocerebellar hypoplasias are transmitted with an autosomal recessive mode of inheritance. Only two homozygous VRK1 pathogenic variants were reported to date in PCH. The first is a nonsense variant (c.1072C>T; p.Arg358*) that was identified in a large PCH1 consanguineous family of Ashkenazi Jewish ancestry. In this family, the clinical features were mild and patients lived into their early teens (Renbaum et al. 2009. PubMed ID: 19646678). The second pathogenic variant is of the missense type (c.397C>T, p.Arg133Cys), and was reported in one single patient (Najmabadi et al. 2011. PubMed ID: 21937992). Detailed clinical features are unavailable for this patient.

No pathogenic large deletions or regulatory variants have been reported in the VRK1 gene.

The VRK1 gene encodes vaccinia-related kinase 1, a serine-threonine protein kinase, which is hypothesized to play a coordinator role in the process of cell division (Valbuena et al. 2008. PubMed ID: 18286197).

Pathogenic variants in the VRK1 gene appear to be a rare cause of PCH (Renbaum et al. 2009. PubMed ID: 19646678).

Thus far, no pathogenic gross deletions or duplications have been reported involving the VRK1 gene (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the VRK1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.