Pontocerebellar Hypoplasia via the CHMP1A 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).

PCH8 can be distinguished by relatively preserved cerebellar folds, in the presence of a small cerebellum. The symptoms are apparent at birth or during early infancy. Clinical features include variable degrees of motor and cognitive impairment, early motor and speech developmental delay, feeding and swallowing difficulties, clubfoot, multiple joint contractures, generalized hypotonia, ataxic gait, dystonic posturing, spasticity, choreiform movements, joint stiffness, mild scoliosis, repetitive vertical head movements, myopia, astigmatism, convergent strabismus and poor social interaction (Mochida et al. 2012. PubMed ID: 23023333).

All pontocerebellar hypoplasias are transmitted with an autosomal recessive mode of inheritance. PCH8 is caused by pathogenic variants in the CHMP1A gene. Only one nonsense and one splicing variant have been reported to date. They were identified in the homozygous state in three families from Peru and Puerto Rico. Evidence for pathogenicity included segregation of the variants with the disease phenotype according to a recessive mode of inheritance; absence of the variants from large population databases; and impaired proliferation of mutant cells via in vitro function studies (Mochida et al. 2012. PubMed ID: 23023333).

No large pathogenic deletions or regulatory variants have been reported involving the CHMP1A gene.

The CHMP1A gene encodes chromatin modifying protein 1A, which is involved in protein trafficking (Howard et al. 2001. PubMed ID: 11559748)

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

This test provides full coverage of all coding exons of the CHMP1A gene 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).