Autosomal Recessive Spinocerebellar Ataxia Type 4 (SCAR4) via the VPS13D Gene

Spinocerebellar ataxia type 4 (SCAR4, also known as VPS13D movement disorder) is an extremely rare genetic movement disorder. The major features include ataxia, dystonia, chorea, and spasticity. Minor features can include developmental delay, mild intellectual disability, pyramidal signs, peripheral neuropathy, eye movement abnormalities, seizures, and abnormal brain MRI findings (Meijer. 2019. PubMed ID: 30789691).

Reported onset of symptoms is highly variable, ranging from infancy to adulthood. In general, features such as global developmental delay, hypotonia, chorea and mild intellectual disability were reported to have childhood onset, while development of progressive ataxia and dystonia were noted to have adult onset (Gauthier et al. 2018. PubMed ID: 29518281).

Advantages of testing include differential diagnosis from other ataxia-causing syndromes, molecular confirmation of diagnosis, and determining carrier status. In general, if the molecular cause of ataxia is not known (causative gene is not known), it is advisable to pursue larger panel testing or whole exome sequencing rather than a single gene test.

Many types of spinocerebellar ataxia have overlapping symptoms but differ in their genetic etiology. Autosomal recessive spinocerebellar ataxia 4 (SCAR4) is caused by biallelic pathogenic variants in the VPS13D gene.

The major pathogenic mechanism of VPS13D variants is loss of function variants, such as nonsense, frameshift, and splicing variants; however missense variants at highly conserved amino acid residues have also been reported (Gauthier et al. 2018. PubMed ID: 29518281; Seong et al. 2018. PubMed ID: 29604224; Koh et al. 2020. PubMed ID: 31876103). De novo variants have not been reported in SCAR4 patients to date nor have gross copy number variants (Meijer. 2019. PubMed ID: 30789691). Of note, partial duplication of VPS13D (exons 24-30) has been reported in the compound heterozygous state in one affected family (Gauthier et al. 2018. PubMed ID: 29518281).

Knockout of VPS13D homologs in flies and mice caused embryonic lethality in both organisms, indicating its importance in early development. In addition, both fly and human cells demonstrated abnormal mitochondrial structure and function with knockdown of Vps13D/VPS13D (Anding et al. 2018. PubMed ID: 29307555; Seong et al. 2018. PubMed ID: 29604224). Overall, VPS13D is considered an essential gene in human bone and soft tissue cell lines (Online Gene Essentiality, ogee.medgenius.info). VPS13D is ubiquitously expressed and is necessary for autophagy, mitochondrial size, and mitophagy (Anding et al. 2018. PubMed ID: 29307555; Seong et al. 2018. PubMed ID: 29604224).

The clinical sensitivity of this test is difficult to estimate based on the phenotypic overlap with other disorders featuring ataxia, dystonia, chorea, or spasticity. Out of 664 patients with spastic paraplegia phenotypes, Koh and colleagues identified four patients with biallelic causative variants in VPS13D (Koh et al. 2020. PubMed ID: 31876103). Other disorders that would be beneficial to consider in the differential diagnosis of SCAR4 include other types of spinocerebellar ataxia, spastic ataxias, Leigh syndrome, and hereditary spastic paraplegia (Meijer. 2019. PubMed ID: 30789691).

This test is performed using Next-Generation Sequencing with additional Sanger sequencing as necessary. 

This test provides full coverage of all coding exons of the VPS13D gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to 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).

This test is performed using Next-Generation sequencing on our exome backbone. There is the option to reflex to whole exome sequencing (PGxome).