Heterozygous PNPT1 Variants Cause a Sensory Ataxic Neuropathy

Abstract

Background: Biallelic variants in polyribonucleotide-nucleotidyltransferase-1 (PNPT1) have been associated with a range of phenotypes from syndromic hearing loss to Leigh's syndrome. More recently, heterozygous variants in PNPT1, have been reported in three families with cerebellar ataxia and prominent sensory neuropathy.

Methods: Whole genome sequencing was performed in two families with autosomal dominant sensory ataxic neuropathy (SAN).

Results: Segregating heterozygous splice site (c.2014-3C>G) and nonsense (p.Arg715Ter) variants were detected in both families. All patients initially presented with an isolated SAN clinically and neurophysiologically with subsequent variable cerebellar involvement.

Conclusion: We report two heterozygous PNPT1 variants in two families with a predominant SAN, including the novel p.Arg715Ter. This strengthens the argument of PNPT1 causing dominant disease and highlights a new cause for dominantly inherited SAN.

Keywords: CMT; ataxia; neurogenetics; sensory ataxic neuropathy; spinocerebellar ataxia.

FIGURE 1

Genetic features of dominant PNPT1 families A. Pedigrees, Sanger confirmation of heterozygous variants and MRI brain showing cerebellar atrophy (AIII6 and BIII9) of Families 1 and 2. The black arrows represent the probands. B. Schematic of the PNPT1 protein domains and lollipop plot displaying pathogenic variants reported in PNPT1. Heterozygous variants are displayed in the above protein schematic, including variants in Families 1 (c.2014–3 C>f the recessive variants, only variants associated with predominant or isolated cerebellar features and/or sensory neuropathy are annotated. Blue/green variants are those found in trans in individuals. RNase‐PH = 3′exoribonuclease family, domain 1;RNase_PH‐C = 3′exoribonuclease family, domain 2:PNPase = polynucleotide nucleotidyltransferase, RNA binding domain; KH_1 = KH domain: S1 = S1 RNA binding domain.