Genes in panel

STRs in panel

Prev Next

Regions in panel

Prev Next

Xp21.2 region (includes NR0B1) Gain
ISCA-46302-Gain 2

Fetal anomalies
Gene: TK2

TK2 (thymidine kinase 2, mitochondrial)
EnsemblGeneIds (GRCh38): ENSG00000166548
EnsemblGeneIds (GRCh37): ENSG00000166548
OMIM: 188250, Gene2Phenotype
TK2 is in 15 panels

5 reviews

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Created: 10 Oct 2023, 3:39 p.m. | Last Modified: 10 Oct 2023, 3:39 p.m.

Panel Version: 3.111

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Created: 10 Oct 2023, 3:39 p.m.
Last Modified: 10 Oct 2023, 3:39 p.m.
Panel version: 3.111

Stephanie Allen (Birmingham Women's NHS Foundation Trust)

Green List (high evidence)

This gene and phenotype were reviewed during a meeting on 2nd March 2023 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, (North Thames GLH), and Stephanie Allen, Denise Williams, Anna de Burca and Megan Horton-Bell (Central & South GLH). Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.
Created: 5 May 2023, 3 p.m. | Last Modified: 5 May 2023, 3 p.m.

Panel Version: 3.8

On 14 panels, inc. IEM, severe paediatric disorders, DDG2P, fetal anomalies, arthrogryposis. Associated with ?Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 (AR); Mitochondrial DNA depletion syndrome 2 (myopathic type) (AR). PMID: 35094997: TK2-associated mitochondrial DNA depletion myopathy has a broad clinical spectrum ranging from severe, lethal, infantile onset to milder late-onset (mean 31 yrs). Treatment is available (deoxynucleoside monophosphates and deoxynucleosides), which would be an argument for inclusion. However most reported cases suggest that mtDNA depletion and myopathy develop after birth. Possible that reported case represents a severe phenotype. Existence of late-onset form is potentially problematic. Notes on R21: DDG2P rating in original PAGE list: Confirmed for MITOCHONDRIAL DNA DEPLETION SYNDROME, MYOPATHIC FORM. Outcome of review: Presentation of mitochondrial disorders can be variable, and most aren't obvious at birth. Therefore exclude unless the gene has been directly associated with a fetal presentation. Aug 2022. Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene. Details of review: Clinical case from USA presented at a fetal sequencing consortium call January 2021: consanguineous couple with 3 affected pregnancies, all presenting with normal anatomy at 18-20 weeks, followed by 3rd trimester onset of reduced fetal movements, polyhydramnios, cerebellar hypoplasia, talipes, clenched hands, extended neck and irregular 'jerky' movements. All three had no respiratory effort at birth, no spontaneous movements and died from respiratory distress shortly after birth. Homozygous TK2 variants found. Causes mitochondrial DNA depletion syndrome 2 - variable clinical presentation, including infantile-onset myopathy with neurologic involvement and rapid progression to early death. No reports of prenatal presentation in the literature so previously reviewed as red. Still not enough evidence to upgrade as this family not published yet but support Amber rating and watching for further evidence. Updated rating from Red to Amber inline with this recent Amber review by Rhiannon Mellis (GOSH), awaiting further evidence supporting that this gene can cause a fetal phenotype.
Created: 5 May 2023, 3 p.m. | Last Modified: 5 May 2023, 3 p.m.

Panel Version: 3.8

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560

Created: 5 May 2023, 3 p.m.
Last Modified: 5 May 2023, 3 p.m.
Panel version: 3.8

Arina Puzriakova (Genomics England Curator)

Comment on list classification: Updated rating from Red to Amber inline with this recent Amber review by Rhiannon Mellis (GOSH), awaiting further evidence supporting that this gene can cause a fetal phenotype.
Created: 22 Aug 2022, 4:18 p.m. | Last Modified: 22 Aug 2022, 4:18 p.m.

Panel Version: 1.960

Created: 22 Aug 2022, 4:18 p.m.
Last Modified: 22 Aug 2022, 4:18 p.m.
Panel version: 1.960

Rhiannon Mellis (Great Ormond Street Hospital)

I don't know

This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene.

Details of review:
Clinical case from USA presented at a fetal sequencing consortium call January 2021: consanguineous couple with 3 affected pregnancies, all presenting with normal anatomy at 18-20 weeks, followed by 3rd trimester onset of reduced fetal movements, polyhydramnios, cerebellar hypoplasia, talipes, clenched hands, extended neck and irregular 'jerky' movements. All three had no respiratory effort at birth, no spontaneous movements and died from respiratory distress shortly after birth. Homozygous TK2 variants found. Causes mitochondrial DNA depletion syndrome 2 - variable clinical presentation, including infantile-onset myopathy with neurologic involvement and rapid progression to early death. No reports of prenatal presentation in the literature so previously reviewed as red. Still not enough evidence to upgrade as this family not published yet but support Amber rating and watching for further evidence.
Created: 11 Aug 2022, 2 p.m. | Last Modified: 11 Aug 2022, 2 p.m.

Panel Version: 1.900

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mitochondrial DNA depletion syndrome 2

Created: 11 Aug 2022, 2 p.m.
Last Modified: 11 Aug 2022, 2 p.m.
Panel version: 1.900

Rebecca Foulger (Genomics England curator)

Red List (low evidence)

This gene was reviewed by Anna de Burca (Genomics England Clinical Team), and at a Fetal Working Group call on July 19th 2019 by Lyn Chitty, Anna de Burca, Richard Scott, Rhiannon Mellis, Rebecca Foulger and Ellen McDonagh. Outcome of review: Presentation of mitochondrial disorders can be variable, and most aren't obvious at birth. Therefore exclude unless the gene has been directly associated with a fetal presentation.
Created: 25 Jul 2019, 8:04 a.m. | Last Modified: 25 Jul 2019, 8:04 a.m.

Panel Version: 0.311

DDG2P rating in original PAGE list: Confirmed for MITOCHONDRIAL DNA DEPLETION SYNDROME, MYOPATHIC FORM
Created: 11 Dec 2018, 9:05 a.m.

In the original PAGE file, MOP listed as All missense/in frame.
Created: 8 Nov 2018, 4:45 p.m.

Mode of pathogenicity
Other - please provide details in the comments

Created: 8 Nov 2018, 4:45 p.m.

Panel version: 0.311

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

NHS GMS
Expert Review Green
PAGE DD-Gene2Phenotype

Phenotypes

Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560

OMIM

188250

Clinvar variants

Variants in TK2

Penetrance

None

Panels with this gene

History Filter Activity

10 Oct 2023, Gel status: 3

Removed Tag, Removed Tag

Sarah Leigh (Genomics England Curator)

Tag Q2_23_promote_green was removed from gene: TK2. Tag Q2_23_NHS_review was removed from gene: TK2.

10 Oct 2023, Gel status: 3

Added New Source, Added New Source, Status Update

Sarah Leigh (Genomics England Curator)

Source Expert Review Green was added to TK2. Source NHS GMS was added to TK2. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

5 May 2023, Gel status: 2