Cystic kidney disease

Gene: NEK8

Green List (high evidence)

NEK8 (NIMA related kinase 8)
EnsemblGeneIds (GRCh38): ENSG00000160602
EnsemblGeneIds (GRCh37): ENSG00000160602
OMIM: 609799, Gene2Phenotype
NEK8 is in 15 panels

5 reviews

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.
Created: 3 May 2024, 10:02 a.m. | Last Modified: 3 May 2024, 10:02 a.m.
Panel Version: 5.3

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Achchuthan Shanmugasundram (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There is sufficient evidence available in support of the association of monoallelic NEK8 variants with polycystic kidney disease. Hence, this gene can be promoted to green rating in the next GMS review.
Created: 2 Jan 2024, 1:34 p.m. | Last Modified: 2 Jan 2024, 1:34 p.m.
Panel Version: 4.24
PMID:37598857 reported the identification of monoallelic NEK8 variants in 12 different families reported with autosomal dominant polycystic kidney disease (ADPKD). Of these, de novo missense variant p.Arg45Trp was found in 10 families and missense variants p.Ile150Met and p.Lys157Gln were found in one family each. Patient fibroblasts show normal ciliogenesis and normal localisation and expression of NEK8. Carriers of AR-NEK8 disease do not show renal manifestations, as variants are LOF and these variants are suspected of dominant negative effect.

PMID:18199800 reported one patient with biallelic NEK8 variant (p.His425Tyr) and with nephronophthisis. Nephronophthisis is an autosomal recessive kidney disease that leads to kidney cyst formation and progressive renal failure.

Although nephronophthisis 9 (MIM #613824) caused by biallelic variants is reported in both OMIM and Gene2Phenotype, cystic kidney disease caused by monoallelic variants are not yet reported in these resources.
Created: 2 Jan 2024, 1:20 p.m. | Last Modified: 2 Jan 2024, 1:31 p.m.
Panel Version: 4.22

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
polycystic kidney disease, MONDO:0020642; ?Nephronophthisis 9, OMIM:613824

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

Dmitrijs Rots (Children's Clinical University Hospital)

Green List (high evidence)

The authors describe: "Here we identify NEK8 as a disease gene for ADPKD in 12 families. Clinical evaluation was combined with functional studies using fibroblasts and tubuloids from affected individuals. Nek8 knockout mouse kidney epithelial (IMCD3) cells transfected with wild type or variant NEK8 were further used to study ciliogenesis, ciliary trafficking, kinase function, and DNA damage responses. Twenty-one affected monoallelic individuals uniformly exhibited cystic kidney disease (mostly neonatal) without consistent extra-kidney manifestations. Recurrent de novo mutations of the NEK8 missense variant p.Arg45Trp, including mosaicism, were seen in ten families. Missense variants elsewhere within the kinase domain (p.Ile150Met and p.Lys157Gln) were also identified. Functional studies demonstrated normal localization of the NEK8 protein to the proximal cilium and no consistent cilia formation defects in patient-derived cells. NEK8-wild type protein and all variant forms of the protein expressed in Nek8 knockout IMCD3 cells were localized to cilia and supported ciliogenesis. However, Nek8 knockout IMCD3 cells expressing NEK8-p.Arg45Trp and NEK8-p.Lys157Gln showed significantly decreased polycystin-2 but normal ANKS6 localization in cilia. Moreover, p.Arg45Trp NEK8 exhibited reduced kinase activity in vitro. In patient derived tubuloids and IMCD3 cells expressing NEK8-p.Arg45Trp, DNA damage signaling was increased compared to healthy passage-matched controls. Thus, we propose a dominant-negative effect for specific heterozygous missense variants in the NEK8 kinase domain as a new cause of PKD."

so enough evidence for green rating as monoallelic
Created: 18 Oct 2023, 5:10 p.m. | Last Modified: 18 Oct 2023, 5:10 p.m.
Panel Version: 4.17

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
polycystic kidney disease

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

Ellen Thomas (Genomics England Curator)

Comment on list classification: Only 1 family. Await further evidence.
Created: 10 May 2016, 10:48 a.m.

Miranda Durkie (Genetics)

Green List (high evidence)

No current test experience but this gene is on the list for an extended panel.
Created: 22 Oct 2015, 12:02 p.m.

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • NHS GMS
  • Expert Review Green
  • Expert
Phenotypes
  • polycystic kidney disease, MONDO:0020642
  • ?Nephronophthisis 9, OMIM:613824
OMIM
609799
Clinvar variants
Variants in NEK8
Penetrance
Complete
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
Panels with this gene

History Filter Activity

3 May 2024, Gel status: 3

Removed Tag

Achchuthan Shanmugasundram (Genomics England Curator)

Tag Q4_23_promote_green was removed from gene: NEK8.

3 May 2024, Gel status: 3

Added New Source, Added New Source, Status Update

Achchuthan Shanmugasundram (Genomics England Curator)

Source Expert Review Green was added to NEK8. Source NHS GMS was added to NEK8. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

2 Jan 2024, Gel status: 2

Added Tag

Achchuthan Shanmugasundram (Genomics England Curator)

Tag Q4_23_promote_green tag was added to gene: NEK8.

2 Jan 2024, Gel status: 2

Entity classified by Genomics England curator

Achchuthan Shanmugasundram (Genomics England Curator)

Gene: nek8 has been classified as Amber List (Moderate Evidence).

2 Jan 2024, Gel status: 1

Set mode of inheritance

Achchuthan Shanmugasundram (Genomics England Curator)

Mode of inheritance for gene: NEK8 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

2 Jan 2024, Gel status: 1

Set mode of pathogenicity

Achchuthan Shanmugasundram (Genomics England Curator)

Mode of pathogenicity for gene: NEK8 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

2 Jan 2024, Gel status: 1

Set publications

Achchuthan Shanmugasundram (Genomics England Curator)

Publications for gene: NEK8 were set to

2 Jan 2024, Gel status: 1

Set Phenotypes

Achchuthan Shanmugasundram (Genomics England Curator)

Phenotypes for gene: NEK8 were changed from Ciliopathy genes associated with cystic kidney disease to polycystic kidney disease, MONDO:0020642; ?Nephronophthisis 9, OMIM:613824

10 May 2016, Gel status: 1

Gene classified by Genomics England curator

Ellen Thomas (Genomics England Curator)

This gene has been classified as Red List (Low Evidence).

10 May 2016, Gel status: 1

Gene classified by Genomics England curator

Ellen Thomas (Genomics England Curator)

This gene has been classified as Red List (Low Evidence).

15 Jul 2015, Gel status: 0

Added New Source

Ellen McDonagh (Genomics England Curator)

NEK8 was added to Cystic kidney diseasepanel. Sources: Expert