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.

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]

OMIM ResearchGenerating clinical summary…

AR/ADLOEUF 0.563 OMIM phenotypes

Clinical Summary— TWNK

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Gene-Disease Validity (ClinGen)

Perrault syndrome 5 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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ClinVar Variants

14 unique Pathogenic / Likely Pathogenic· 51 VUS of 98 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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

ClinVar Variant Classifications

98 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic8

VUS51

Likely Benign26

Benign1

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	2	0	0	6
Likely Pathogenic	2	6	0	0	8
VUS	1	49	1	0	51
Likely Benign	0	1	4	21	26
Benign	0	1	0	0	1
Conflicting	—				1
Total	7	59	5	21	93

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

2 pathogenic / likely-pathogenic (of 2) ClinVar copy-number / structural variants overlap TWNK — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →