RNF170 mutation causes autosomal dominant sensory ataxia with variable pyramidal involvement

Abstract

Background Although hereditary ataxias are a group of clinically and genetically heterogeneous disorders, specific clinical clues can sometimes incriminate certain genes. This can trigger genetic testing in sporadic patients or prompt dissecting certain genes more thoroughly when initial genetic testing is negative. Also for the assembly of gene panels and interpretation of the results, genotype−phenotype correlations remain important to establish. Methods We clinically evaluated a Belgian family with autosomal dominant inherited sensory ataxia and variable pyramidal involvement and performed targeted clinical exome sequencing. Secondly, we retrospectively screened sequencing data of an in‐house cohort of 404 patients with neuromuscular disorders for variants in the identified gene RNF170. Results All affected family members showed sensory ataxia on examination. Pyramidal involvement, and sometimes slow‐pursuit abnormalities and/or a sensory neuropathy, were more variable findings. We identified the heterozygous variant p.Arg199Cys in RNF170 in all three affected siblings of our family. We did not find additional pathogenic variants in RNF170 in our in‐house neuromuscular cohort. Conclusions We confirm the heterozygous variant p.Arg199Cys in RNF170 in a Belgian family with autosomal dominant sensory ataxia and variable pyramidal involvement. This constitutes a rare but clinically recognizable phenotype that warrants testing of RNF170. Unlike the distinctive bi‐allelic loss of function variants in RNF170 associated with hereditary spastic paraplegia (HSP), the p.Arg199Cys variant is the only one reported in sensory ataxia. It is important for neurologists to be aware of this characteristic phenotype and to include this gene in gene panels for ataxia and HSP.

Novel stop‐gain RNF170 variation detected in a Chinese family with adolescent‐onset hereditary spastic paraplegia

“…The heterozygous mutation c.595C>T (p.R199C) within RNF170 was formerly shown to induce autosomal dominant sensory ataxia (ADSA) in four unrelated lines from Canada, Ecuador, and Belgium through toxic gain‐of‐function. Patients always present with late‐onset proprioceptive loss and progressive ataxia with ubiquitinated protein aggregates in brain tissue 9–11 . The first four RNF170 ‐related AR‐HSP families were reported in 2019, and cellular and zebrafish studies revealed LoF as the pathogenic mechanism of those homozygous variations 4 .…”

“…Patients always present with lateonset proprioceptive loss and progressive ataxia with ubiquitinated protein aggregates in brain tissue. [9][10][11] The first four RNF170-related AR-HSP families were reported in 2019, and cellular and zebrafish studies revealed LoF as the pathogenic mechanism of those homozygous variations. 4 Since then, two more mutations have been found.…”