DHTKD1 exon deletion associated with sporadic cerebellar ataxia

<title>Abstract</title> <p>Hereditary ataxia (HA) is a genetically heterogeneous category of progressive neurodegenerative diseases, typically manifesting with unsteady gait, incoordination of movement and speech. Recently, the discovery of numerous pathogenic genes, especially the most common repeat expansion mutations, has greatly enhanced our understanding of the genetic etiology of HA. However, our understanding of the pathogenic role and epidemiology of large deletion, particularly exon deletion, in HA remains limited. Its prevalence and associated gene spectrum require systematic elucidation. Here, we identified a heterozygous DHTKD1 exon deletion in a proband with HA through whole-exome sequencing combined with copy number variants (CNVs) analysis. And a systematic review of previously reported DHTKD1-related cases was performed to explore the potential genotype-phenotype correlations. Previous reports on DHTKD1 variants have primarily described association with 2-aminoadipic acid and 2-oxadipic aciduria (AMOXAD), amyotrophic lateral sclerosis (ALS), and Charcot-Marie-Tooth disease type 2 (CMT2). The phenotype of the patient in this study partially overlapped with previously reported cases, including ataxia and intellectual disability. The analysis of genotype-phenotype correlations revealed that DHTKD1 may lead to diverse neurodegenerative phenotypes through common dominant mechanisms in the nervous system. Our findings indicated that rare heterozygous DHTKD1 exon deletion may be a potential contributor to sporadic cerebellar ataxia.</p>