SETX

Chr 9ADAR

senataxin

Also known as: ALS4, AOA2, SCAN2, SCAR1, STEX, Sen1, bA479K20.2

NCBI Gene: 23064 ENSG00000107290 UniProt: Q7Z333 OMIM: 608465

This gene encodes a protein with DNA/RNA helicase activity that processes both DNA and RNA. Mutations cause either autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4) or autosomal recessive spinocerebellar ataxia with axonal neuropathy (ataxia-ocular apraxia-2). The pathogenic mechanism involves disrupted DNA and RNA processing due to loss of helicase function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAD/ARLOEUF 0.302 OMIM phenotypes

Clinical Summary— SETX

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Gene-Disease Validity (ClinGen)

distal hereditary motor neuropathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.95). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

36 unique Pathogenic / Likely Pathogenic· 43 VUS of 185 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SETX

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.30LOEUF

pLI 0.955

Z-score 7.45

OE 0.21 (0.14–0.30)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

-0.11Z-score

OE missense 1.01 (0.96–1.05)

1392 obs / 1380.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios

LoF OE0.21 (0.14–0.30)

0≤0.351.4

Missense OE1.01 (0.96–1.05)

0≤0.61.4

Synonymous OE1.11

0≤1.21.6

LoF obs/exp: 21 / 102.3Missense obs/exp: 1392 / 1380.3Syn Z: -1.95

0.4388th %ile

GOF

0.2497th %ile

LOF

0.60top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF31% of P/LP variants are LoF · LOEUF 0.30

DN1 literature citation

GOF1 literature citation

Literature Evidence

DNWorking synergistically, the N603D-Q653K mutations may confer a partial dominant negative effect, acting on the senataxin N-terminal, further expanding the phenotypic spectrum associated with Senataxin mutations.PMID:17096168

GOFA cellular assay for SETX function confirmed that like the Leu389Ser mutation, the Glu385Lys variant leads to a decrease in R loops, likely from a gain of function.INTERPRETATION: We identified clinical laboratory and radiological features of ALS4, and hence they should be monitored for disease progPMID:31957062

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.