Childhood onset hereditary spastic paraplegia
Gene: KPNA3The mode of inheritance of this gene has been updated to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.Created: 1 Feb 2023, 2:55 p.m. | Last Modified: 1 Feb 2023, 2:55 p.m.
Panel Version: 3.9
Comment on list classification: Promoting this gene from grey to amber with a recommendation of GREEN rating following GMS review.Created: 5 Aug 2022, 9:44 p.m. | Last Modified: 5 Aug 2022, 9:44 p.m.
Panel Version: 2.144
As the reviewer state, Shob et al 2021 (PMID: 34564892) report 8 individuals from 5 families affected by an early-onset (first year of life) pure HSP and bearing heterozygous variants in KPNA3 identified by trio WES. 5 different missense variants were detected, which could be identified as either de novo or inherited and segregating with HSP within the family. In Individual 8, 2 independent de novo KPNA3 variants (ie, p.Leu328Met and p.Pro415Leu) were identified, and it couldn't be determined whether 1 variant alone or both variants were causing the disease. 1 patient showed also presented with a delay in speech development and intellectual disability, but was found to carry an additional maternally inherited PURA variant (p.Arg169Cys), classified as likely pathogenic. Functional characterization of the protein variants showed that the proteins exhibited a variable pattern of altered expression level, subcellular distribution, and protein interaction.Created: 5 Aug 2022, 9:42 p.m. | Last Modified: 5 Aug 2022, 9:42 p.m.
Panel Version: 2.140
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
autosomal dominant pure spastic paraplegia, MONDO:0015088
Publications
8 reported families with de novo missense variants, that segregates with pure HSP with infantile onset and some functional data PMID: 34564892
Sources: LiteratureCreated: 25 Oct 2021, 5:56 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Infantile onset spastic paraplegia; developmental delay
Publications
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Tag Q3_22_rating was removed from gene: KPNA3.
Source Expert Review Green was added to KPNA3. Source NHS GMS was added to KPNA3. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Gene: kpna3 has been classified as Amber List (Moderate Evidence).
Tag Q3_21_rating was removed from gene: KPNA3. Tag Q3_22_rating tag was added to gene: KPNA3.
Tag Q3_21_rating tag was added to gene: KPNA3.
Phenotypes for gene: KPNA3 were changed from Infantile onset spastic paraplegia; developmental delay to autosomal dominant pure spastic paraplegia, MONDO:0015088
Publications for gene: KPNA3 were set to PMID: 34564892
Mode of inheritance for gene: KPNA3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
gene: KPNA3 was added gene: KPNA3 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature Mode of inheritance for gene: KPNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KPNA3 were set to PMID: 34564892 Phenotypes for gene: KPNA3 were set to Infantile onset spastic paraplegia; developmental delay Penetrance for gene: KPNA3 were set to unknown Mode of pathogenicity for gene: KPNA3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: KPNA3 was set to GREEN