Pontocerebellar Hypoplasia via the RARS2 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 (Rahman. 2012. PubMed ID: 22283595). 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 (Kastrissianakis. 2013. PubMed ID: 24047924; Ngoh. 2016. PubMed ID: 27061686).

PCH6 is distinguished by severe encephalopathy and elevated levels of lactate in the blood and cerebrospinal fluid. Additional features have been reported and include skeletal muscle respiratory chain defects, hypotonia, joint contractures, visual abnormalities, edema of the feet and hands, apnea, myoclonic seizures, and dysmorphic features. Symptoms are usually apparent at birth and death occurs in early infancy. PCH6 appears to be rare (Edvardson et al. 2007. PubMed ID: 17847012).

All pontocerebellar hypoplasias are transmitted with an autosomal recessive mode of inheritance. PCH6 is caused by pathogenic variants in the RARS2 gene (Edvardson et al. 2007). About 20 pathogenic variants, mostly of the missense type, have been reported. Truncating pathogenic variants include six splice site variants and one variant that affects the initiation codon. One small causative deletion that is predicted to result in an in-frame deletion of one single amino acid has also been reported (Edvardson. 2007. PubMed ID: 17847012; Li. 2015. PubMed ID: 25809939; Human Gene Mutation Database).

Of note, one RARS2 splice site variant (c.110+5A>G) was reported in one patient with PCH who had elevated levels of lactate in the cerebrospinal fluid, which is characteristic of PCH6, and loss of motor neurons in the anterior horn of the spinal cord, which is characteristic of PCH1 (Edvardson et al. 2007. PubMed ID: 17847012).

The RARS2 gene encodes mitochondrial arginyl-transfer RNA (tRNA) synthetase, which is involved in the synthesis of all mitochondrial proteins (Edvardson. 2007. PubMed ID: 17847012).

Pathogenic variants in the RARS2 gene appear to be a rare cause of pontocerebellar hypoplasia. To date, only 29 patients with such variants have been described worldwide (van Dijk et al. 2017. PubMed ID: 27683254).

Thus far, no gross deletions or duplications have been reported involving the RARS2 gene (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the RARS2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.