Hereditary neuropathy or pain disorder

Gene: PNKP

Green List (high evidence)

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 3 Mar 2022, 6:31 p.m. | Last Modified: 3 Mar 2022, 6:31 p.m.

Panel Version: 1.83

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Created: 25 Jan 2021, 2:49 p.m. | Last Modified: 25 Jan 2021, 2:49 p.m.

Panel Version: 1.21

Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen, although variants PNKP have been given a confirmed classification in Gen2Phen for Ataxia-oculomotor apraxia 4 (OMIM:616267). At least 2 variants were reported: rs774995635, was homozygous in 5 affected members of a large Costa Rican family (18 affected members, but only 5 were sequenced) and heterozygous in the mother of one of the affected subjects who was sequenced (PMID 30039206). Compound heterozygous rs774995635 and rs770849181 were reported in five unrelated Costa Rican cases, although it was reported that there appeared to be a ancestral founder haplotype for the rs770849181 (PMID 30039206). A further case was reported where a 17year old with axonal Charcot-Marie-Tooth disease was homozygous and his parents were heterozygous for rs770849181 (PMID 27066567).

Created: 25 Jan 2021, 2:48 p.m. | Last Modified: 25 Jan 2021, 2:48 p.m.

Panel Version: 1.19

Green List (high evidence)

In PMID: 30039206 reported a homozygous nonsense variant in a large Costa Rican family segregating with CMT2 phenotype. Additional 5 cases with compound heterozygous nonsense variants and CMT2 phenotype also reported. Some patients have Ataxia, but not oculomotor apraxia or Microcephaly, seizures, and developmental delay.

Created: 13 Jan 2021, 6:41 a.m. | Last Modified: 13 Jan 2021, 6:41 a.m.

Panel Version: 1.19

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Polyneuropathy; ataxia

Publications

• PMID: 30039206

Variants in this GENE are reported as part of current diagnostic practice

I don't know

Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope but limited evidence / Broader phenotype: good evidence for ataxia/oculomotor apraxia, less for more severe phenotype

Created: 7 Dec 2019, 12:03 a.m. | Last Modified: 7 Dec 2019, 12:03 a.m.

Panel Version: 0.86

This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.

Created: 6 Dec 2019, 10:25 p.m. | Last Modified: 6 Dec 2019, 10:25 p.m.

Panel Version: 0.84

Review and rating uploaded from file (Curation_Template_GMS_Neuro_AR_20190521.xlsx) submitted by Alex Rossor (UCL Institute of Neurology) on behalf of London North GLH for GMS Neurology specialist test group.

Created: 11 Jun 2019, 1:40 p.m.

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Microcephaly, global developmental delay, progressive cerebellar ataxia and atrophy, sensory-motor axonal neuropathy

Publications

• 30039206