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Hereditary ataxia with onset in adulthood v8.15 PNPT1 Ida Ertmanska commented on gene: PNPT1: Comment on list classification: There are at least 4 unrelated families with adult-onset Spinocerebellar ataxia and heterozygous PNPT1 variants. While some carriers were very mildly affected or reported unaffected, there is good evidence of PNPT1 variants cosegregating with ataxia, supporting an autosomal dominant inheritance mode. Based on available evidence, this gene should be promoted to Green for Hereditary ataxia with onset in adulthood.
Hereditary ataxia with onset in adulthood v8.15 PNPT1 Ida Ertmanska changed review comment from: PMID: 35411967 Barbier et al., 2022
461–7 French index patient - congenital deafness, ataxia onset at 23yo with a Moderate (24/40) ataxia score - heterozygous for NM_033109.5:c.2091delA; p.Lys697AsnfsTer6 - inherited from an unaffected father.
Australian family A1 - 6 individuals with autosomal dominant progressive ataxia, 3 other individuals were heterozygous and mildly affected.
4 heterozygous candidate variants identified: MSH6 NM_000179.2:c.2633T>C; p.Val878Ala; STON1 NM_001198595.1:c.1231G>A; p.Glu411Lys; PSME4 NM_014614.2:c.3400G>A; p.Glu1134Lys, and PNPT1 NM_033109.5:c.2014-3C>G. Ataxia age of onset = 4 cases under 18 yrs old, 3 adult-onset cases (20-56yrs).

PMID: 39924761 Haddad et al., 2025
Reported two families with heterozygous PNPT1 variants with sensory ataxic neuropathy, including 3 adult-onset cases (20s-30s) - 2 of these cases had no neuropathy score, and 1 case (BII6) with CMT score of 15.
Affected members of Family 1 were heterozygous for NM_033109.5 PNPT1 c.2014‐3C>G; patients in Family 2 were heterozygous for PNPT1 NM_033109.5 c.2143C>T p.Arg715Ter - both variants segregated with disease.

PNPT1 is associated with AD Spinocerebellar ataxia 25 MIM:608703, AR Combined oxidative phosphorylation deficiency 13, MIM:614932, and AR Deafness, autosomal recessive 70, with or without adult-onset neurodegeneration, MIM:614934 in OMIM (accessed 12th Dec 2025).; to: PMID: 35411967 Barbier et al., 2022
461–7 French index patient - congenital deafness, ataxia onset at 23yo with a Moderate (24/40) ataxia score - heterozygous for NM_033109.5:c.2091delA; p.Lys697AsnfsTer6 - inherited from an unaffected father.
Australian family A1 - 6 individuals with autosomal dominant progressive ataxia, 3 other individuals were heterozygous and mildly affected.
4 heterozygous candidate variants identified: MSH6 NM_000179.2:c.2633T>C; p.Val878Ala; STON1 NM_001198595.1:c.1231G>A; p.Glu411Lys; PSME4 NM_014614.2:c.3400G>A; p.Glu1134Lys, and PNPT1 NM_033109.5:c.2014-3C>G. The PNPT1 splice variant introduces a premature stop codon (p.Gln672SerfsTer6) - confirmed by RT-PCR. OXPHOS enzyme activities were normal,
Ataxia age of onset = 4 cases under 18 yrs old, 3 adult-onset cases (20-56yrs).

PMID: 39924761 Haddad et al., 2025
Reported two families with heterozygous PNPT1 variants with sensory ataxic neuropathy, including 3 adult-onset cases (20s-30s) - 2 of these cases had no neuropathy score, and 1 case (BII6) with CMT score of 15.
Affected members of Family 1 were heterozygous for NM_033109.5 PNPT1 c.2014‐3C>G; patients in Family 2 were heterozygous for PNPT1 NM_033109.5 c.2143C>T p.Arg715Ter - both variants segregated with disease.

PNPT1 is associated with AD Spinocerebellar ataxia 25 MIM:608703, AR Combined oxidative phosphorylation deficiency 13, MIM:614932, and AR Deafness, autosomal recessive 70, with or without adult-onset neurodegeneration, MIM:614934 in OMIM (accessed 12th Dec 2025).
Hereditary ataxia with onset in adulthood v8.15 PNPT1 Ida Ertmanska changed review comment from: PMID: 35411967 Barbier et al., 2022
461–7 French index patient - congenital deafness, ataxia onset at 23yo with a Moderate (24/40) ataxia score - heterozygous for NM_033109.5:c.2091delA; p.Lys697AsnfsTer6 - inherited from an unaffected father.
Australian family A1 - 6 individuals with autosomal dominant progressive ataxia, 3 other individuals were heterozygous and mildly affected.
4 heterozygous candidate variants identified: MSH6 NM_000179.2:c.2633T>C; p.Val878Ala; STON1 NM_001198595.1:c.1231G>A; p.Glu411Lys; PSME4 NM_014614.2:c.3400G>A; p.Glu1134Lys, and PNPT1 NM_033109.5:c.2014-3C>G. Ataxia age of onset = 4 cases under 18 yrs old, 3 adult-onset cases (20-56yrs).
The authors pose that heterozygous variants cause lower penetrance and variable expressivity, which may explain later onset and milder phenotype than in homozygous cases.

PMID: 39924761 Haddad et al., 2025
Reported two families with heterozygous PNPT1 variants with sensory ataxic neuropathy, including 3 adult-onset cases (20s-30s).; to: PMID: 35411967 Barbier et al., 2022
461–7 French index patient - congenital deafness, ataxia onset at 23yo with a Moderate (24/40) ataxia score - heterozygous for NM_033109.5:c.2091delA; p.Lys697AsnfsTer6 - inherited from an unaffected father.
Australian family A1 - 6 individuals with autosomal dominant progressive ataxia, 3 other individuals were heterozygous and mildly affected.
4 heterozygous candidate variants identified: MSH6 NM_000179.2:c.2633T>C; p.Val878Ala; STON1 NM_001198595.1:c.1231G>A; p.Glu411Lys; PSME4 NM_014614.2:c.3400G>A; p.Glu1134Lys, and PNPT1 NM_033109.5:c.2014-3C>G. Ataxia age of onset = 4 cases under 18 yrs old, 3 adult-onset cases (20-56yrs).

PMID: 39924761 Haddad et al., 2025
Reported two families with heterozygous PNPT1 variants with sensory ataxic neuropathy, including 3 adult-onset cases (20s-30s) - 2 of these cases had no neuropathy score, and 1 case (BII6) with CMT score of 15.
Affected members of Family 1 were heterozygous for NM_033109.5 PNPT1 c.2014‐3C>G; patients in Family 2 were heterozygous for PNPT1 NM_033109.5 c.2143C>T p.Arg715Ter - both variants segregated with disease.

PNPT1 is associated with AD Spinocerebellar ataxia 25 MIM:608703, AR Combined oxidative phosphorylation deficiency 13, MIM:614932, and AR Deafness, autosomal recessive 70, with or without adult-onset neurodegeneration, MIM:614934 in OMIM (accessed 12th Dec 2025).
Hereditary ataxia with onset in adulthood v8.15 PNPT1 Ida Ertmanska Phenotypes for gene: PNPT1 were changed from to Spinocerebellar ataxia 25, OMIM:608703
Hereditary ataxia with onset in adulthood v8.14 PNPT1 Ida Ertmanska Publications for gene: PNPT1 were set to
Hereditary ataxia with onset in adulthood v8.13 PNPT1 Ida Ertmanska Classified gene: PNPT1 as Amber List (moderate evidence)
Hereditary ataxia with onset in adulthood v8.13 PNPT1 Ida Ertmanska Gene: pnpt1 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v8.12 PNPT1 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: PNPT1.
Tag Q4_25_NHS_review tag was added to gene: PNPT1.
Hereditary ataxia with onset in adulthood v8.12 PNPT1 Ida Ertmanska reviewed gene: PNPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35411967, 39924761; Phenotypes: Spinocerebellar ataxia 25, OMIM:608703; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary ataxia with onset in adulthood v8.12 PNPT1 Lucy Jackson gene: PNPT1 was added
gene: PNPT1 was added to Hereditary ataxia with onset in adulthood. Sources: NHS GMS
Mode of inheritance for gene: PNPT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Review for gene: PNPT1 was set to GREEN
Added comment: Already green on childhood ataxia panel, see https://panelapp.genomicsengland.co.uk/panels/477/gene/PNPT1/
The ataxia phenotype can manifest in adulthood, therefore suggest adding to this panel also.
Sources: NHS GMS