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.

Keywords: case study; genotype−phenotype correlation; medical genetics; sensory ataxia; spastic paraparesis.

FIGURE 1

Pedigree and clinical characteristics of patients with the RNF170 p. Arg199Cys mutation. (a) Pedigree of the family with sensory ataxia described in this article. The proband is indicated with an arrow. A ‘+/−’‐sign indicates patients that are tested and found heterozygous for the p. Arg199Cys variant. (b) Clinical findings in this family as well as core features of the two Canadian families and the Ecuadorian family with the RNF170 p. Arg199Cys mutation [3, 4, 5, 6]. Abbreviations: LL, lower limbs; MRI, magnetic resonance imaging; NCS, nerve conduction studies; SNAP, sensory nerve action potential; SSEP, somatosensory evoked potential; UL, upper limbs

FIGURE 2

Mutational landscape of phenotypes related to RNF170. The figure shows a lolliplot of gene RNF170 locating the heterozygous variant described in sensory ataxia (orange) and the homozygous variants in HSP (blue) (including the large deletion in HSP shown as a blue line) in relation to gene structure and protein domains [9, 10]. Introns are scaled with a factor 1/100. Abbreviations: HSP, hereditary spastic paraplegia; UTR, untranslated region.