TWNK

Chr 10ARAD

twinkle mtDNA helicase

Also known as: ATXN8, C10orf2, IOSCA, MTDPS7, PEO, PEO1, PEOA3, PRLTS5

NCBI Gene: 56652 ENSG00000107815 UniProt: Q96RR1 OMIM: 606075

The protein is a mitochondrial DNA helicase that unwinds double-stranded DNA during mitochondrial DNA replication in the mitochondrial matrix. Mutations cause mitochondrial DNA depletion syndrome 7 (hepatocerebral type), Perrault syndrome 5, and progressive external ophthalmoplegia with mitochondrial DNA deletions through both autosomal recessive and autosomal dominant inheritance patterns. The pathogenic mechanism involves impaired mitochondrial DNA replication leading to mitochondrial dysfunction and energy deficiency in affected tissues.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a hexameric DNA helicase which unwinds short stretches of double-stranded DNA in the 5' to 3' direction and, along with mitochondrial single-stranded DNA binding protein and mtDNA polymerase gamma, is thought to play a key role in mtDNA replication. The protein localizes to the mitochondrial matrix and mitochondrial nucleoids. Mutations in this gene cause infantile onset spinocerebellar ataxia (IOSCA) and progressive external ophthalmoplegia (PEO) and are also associated with several mitochondrial depletion syndromes. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Aug 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Mitochondrial DNA depletion syndrome 7 (hepatocerebral type)MIM #271245

Perrault syndrome 5MIM #616138

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3MIM #609286

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · Perrault syndrome 5 · AR · ClinGen 2026
Strong · mitochondrial DNA depletion syndrome 7 (hepatocerebral type) · AR · Labcorp Genetics (formerly Invitae)
Strong · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 · AD · Labcorp Genetics (formerly Invitae)
Supportive · autosomal dominant progressive external ophthalmoplegia · AD · Orphanet

+1 more curated pair

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.56

LOEUF

—

Mechanism

📖

GeneReview available — TWNK

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.56LOEUF

pLI 0.003

Z-score 3.42

OE 0.33 (0.20–0.56)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.61Z-score

OE missense 0.77 (0.70–0.85)

301 obs / 390.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.33 (0.20–0.56)

0≤0.351.4

Missense OE?0.77 (0.70–0.85)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 10 / 30.3Missense obs/exp: 301 / 390.4Syn Z: -0.62

Background carrier burden — how many people carry a rare variant somewhere in TWNK?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 91

757 rare PASS variants

Rare truncating (LoF)

1 in 3,200

90 rare PASS variants

Rare synonymous (reference)

1 in 200

377 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TWNK. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 100	1 in 3,500
South Asian	~43k	1 in 120	1 in 5,400
Remaining (unassigned)	~30k	1 in 74	1 in 2,300
European (Finnish)	~27k	1 in 570	1 in 1,600
Admixed American	~22k	1 in 120	≈ 1 in 11,000
African / African American	~21k	1 in 81	1 in 1,900
East Asian	~20k	1 in 120	1 in 1,600
Ashkenazi Jewish	~13k	1 in 280	≈ 1 in 3,300
Middle Eastern	~2,884	1 in 110	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 5 coding exons well covered in gnomAD exomes and genomes.? see exons ↓