Pontocerebellar Hypoplasia via the CLP1 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).

A new form of PCH, proposed to be designated PCH10, is characterized by delayed or absent developmental milestones, intellectual disability, seizures, spasticity, hypertonia, and increased deep tendon reflexes. Additional features include irritability, jitteriness, hypotonia, and visual impairment in the form of primary optic atrophy or strabismus. Facial features include high arched eyebrows, prominent eyes, long palpebral fissures and eyelashes. Electromyography findings include age-dependent muscle fibrillations and high amplitude motor unit potentials, indicating progressive loss of spinal motor neurons. Electrophysiological studies indicate axonal sensorimotor neuropathies (Schaffer et al. 2014. PubMed ID: 24766810; Karaca et al. 2014. PubMed ID: 24766809).

All pontocerebellar hypoplasias are transmitted with an autosomal recessive mode of inheritance. A homozygous missense variant, Arg140His, in the CLP1 gene has been reported to be the cause of PCH10 in all affected members of 9 consanguineous families with history of the disease. Evidence for pathogenicity of the missense variant include in vitro functional studies, which revealed a defective kinase activity of the CLP1 mutant enzyme and destabilization of the tRNA endonuclease complex (TSEN). Animal model studies confirmed the pathogenicity of this variant (Schaffer et al. 2014. PubMed ID: 24766810; Karaca et al. 2014. PubMed ID: 24766809).

CLP1 encodes an RNA kinase. It is involved in tRNA splicing via its interaction with the TSEN complex (Weitzer and Martinez. 2007. PubMed ID: 17786051). The R140H variant is postulated to cause impaired splicing, as the result of decreased interactions between mutant CLP1 and the TSEN complex (Hanada et al. 2013. PubMed ID: 23474986; Karaca et al. 2014. PubMed ID: 24766809).

To date, one pathogenic missense variant has been reported to be the cause of PCH10 in 9, apparently unrelated, consanguineous families from the Middle East (Schaffer et al. 2014. PubMed ID: 24766810; Karaca et al. 2014. PubMed ID: 24766809).

This test provides full coverage of all coding exons of the CLP1 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 full 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).