# Identification of a Novel CLPX Variant in a Mixed-Breed Dog with Anemia and Spinocerebellar Ataxia

## TL;DR

A new CLPX gene variant was found in a dog with ataxia, anemia, and retinal degeneration, offering insights into a rare neurological disorder.

## Contribution

The first report linking a CLPX variant to spinocerebellar ataxia in any species.

## Key findings

- The dog showed atypical SCA features including retinal degeneration and non-regenerative anemia.
- A novel homozygous frameshift deletion in CLPX was identified through whole-genome sequencing.
- The CLPX variant is predicted to truncate the protein and may contribute to neurodegeneration and anemia.

## Abstract

Background/Objectives: Spinocerebellar ataxia (SCA), or hereditary ataxia, is a progressive neurodegenerative disorder primarily affecting motor control and voluntary muscle coordination due to cerebellar or spinocerebellar dysfunction. While numerous genetic variants have been linked to SCA in both humans and dogs, some cases remain genetically unexplained. This study aimed to describe the clinical and pathological phenotype, and to identify the genetic basis, of an atypical form of SCA observed in a mixed-breed dog presenting with additional clinical signs beyond classic SCA. Methods: Clinical and postmortem examinations were performed to document neurological and systemic pathology. Whole-genome sequencing (WGS) was conducted on the affected dog, and variant filtering was carried out using a control cohort of over 700 unaffected dog genomes to identify candidate variants. Results: In addition to classical SCA features, the affected dog exhibited retinal and optic nerve degeneration and severe, non-regenerative anemia. WGS did not reveal any known SCA-associated variants. Variant filtering identified a novel homozygous 4-base-pair frameshift deletion in CLPX (caseinolytic mitochondrial matrix peptidase chaperone subunit X) [XM_038580726.1:c.1723_1726del; chr30:g.29943285_29943288del]. This variant is predicted to cause a frameshift and premature stop codon within 17 amino acids, truncating approximately 6.64% of the protein. Conclusions: This is the first report associating a CLPX variant with SCA in any species. Given the gene’s high evolutionary conservation and known role in mitochondrial protein homeostasis, this finding may have implications for understanding CLPX-related neurodegeneration and anemia in both veterinary and human medicine.