Hereditary neuropathy or pain disorder

Gene: PNPT1

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.

Created: 24 Feb 2025, 5:02 p.m. | Last Modified: 24 Feb 2025, 5:02 p.m.

Panel Version: 6.148

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

I don't know

Caution, unaffected relatives with the same variant in three of the four families. Although non-penetrance is a possibility, it would be prudent to wait for more compelling segregation evidence.

Created: 11 Nov 2024, 6:02 a.m. | Last Modified: 11 Nov 2024, 6:02 a.m.

Panel Version: 6.131

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

Comment on phenotypes: OMIM phenotype last accessed on 27 October 2025.

Created: 27 Oct 2025, 5:21 p.m. | Last Modified: 27 Oct 2025, 5:21 p.m.

Panel Version: 7.27

Comment on list classification: There are three additional families reported with Spinocerebellar Ataxia 25 including polyneuropathy as part of the phenotype, and they are identified with monoallellic PNPT1 variants. Although there was incomplete penetrance observed in previously reported cases, the evidence from these recently reported families suggests that this gene can remain green on this panel.

Created: 27 Oct 2025, 4:27 p.m. | Last Modified: 27 Oct 2025, 4:36 p.m.

Panel Version: 7.25

There are additional cases reported recently:

PMID:39899068 (2025) reported a 1-year-8-month-old female proband of Brazilian descent with Spinocerebellar Ataxia 25 that presented with progressive ataxia, cerebellar atrophy, and sensory neuropathy. She was identified with a novel heterozygous truncating variant in PNPT1 (c.2068del), which she inherited from her father. Although the father was previously reported as asymptomatic, he was affected with axonal and demyelinating polyneuropathy but not ataxia upon detailed examination.

PMID:39924761 (2025) reported two unrelated families, where all individuals presented with sensory ataxic neuropathy (SAN), while some individuals developed cerebellar signs. Analysis of WGS variant data through the 100,000 Genomes Project identified two different heterozygous variants in these families. Family 1 underwent a 'quad' study and the previously reported c.2014‐3C>G variant segregated in all affected family members and was absent in all unaffected family members. Sanger sequencing confirmed segregation in two other individuals. c.2014‐3C>G is the same variant that was found in the 3-generation Australian family reported by PMID:35411967, where unaffected family members harboured the variant. A novel nonsense variant (c.2143C>T/ p.Arg715Ter) was found in both affected members of Family 2.

Created: 27 Oct 2025, 4:21 p.m. | Last Modified: 27 Oct 2025, 4:21 p.m.

Panel Version: 7.24

Comment on list classification: There are four unrelated cases reported with heterozygous PNPT1 variants and sensory neuropathy. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 4 Nov 2024, 2:49 p.m. | Last Modified: 4 Nov 2024, 3:17 p.m.

Panel Version: 6.64

PMID:14705117 reported a large family from Southeastern France with spinocerebellar ataxia with sensory involvement. Age at onset ranged from 17 months to 39 years, although most of those affected had onset in childhood. Cerebellar ataxia was always present and many patients had peripheral sensory neuropathy.

PMID:35411967 reported the identification of heterozygous splice site variants in PNPT1 in the above reported family from Southeastern France and from a 3-generation Australian family with spinocerebellar ataxia and sensory neuropathy reported in this study. All patients from the Australian family for whom information was available had an axonal sensory neuropathy with diminished or absent limb reflexes and decreased sensation. There was evidence of incomplete penetrance in the Australian family, as two carriers in this family had sensory neuropathy without ataxia or cerebellar atrophy in their thirties. A 40-year-old French patient was also reported with heterozygous frameshift PNPT1 variant, who had onset of deafness shortly after birth and onset of gait ataxia at 23 years of age. He also had sensory neuropathy. This patient inherited the variant from an asymptomatic 80+ years old father.

PMID:37935417 reported the identification of a novel PNPT1 variant in a 3-year-old child with spinocerebellar ataxia. The child had cerebellar atrophy and psychomotor delay. At a follow up at 6 years of age, the symptoms had worsened and also presented with axonal sensory neuropathy.

Monoallelic variants in this gene have been associated with relevant phenotype in OMIM (MIM #608703), which records sensory neuropathy/ axonal sensory neuropathy as clinical manifestations of the phenotype.

Created: 4 Nov 2024, 2:46 p.m. | Last Modified: 4 Nov 2024, 3:16 p.m.

Panel Version: 6.64

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Spinocerebellar ataxia 25, OMIM:608703; spinocerebellar ataxia type 25, MONDO:0012103

Publications

• 14705117
• 35411967
• 37935417
• 39899068
• 39924761

Green List (high evidence)

Sources: Expert list

Created: 19 Oct 2024, 11:15 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
ataxia; peripheral neuropathy

Publications

• 35411967: 14705117