WWOX

Chr 16AR

WW domain containing oxidoreductase

Also known as: D16S432E, DEE28, EIEE28, FOR, FRA16D, HHCMA56, PRO0128, SCAR12

NCBI Gene: 51741 ENSG00000186153 UniProt: Q9NZC7 OMIM: 605131

The WWOX protein is an oxidoreductase that functions as a tumor suppressor by inducing apoptosis and inhibiting Wnt signaling. Biallelic mutations cause autosomal recessive developmental and epileptic encephalopathy 28 and spinocerebellar ataxia 12. The gene shows very low constraint against loss-of-function variants, consistent with the recessive inheritance pattern where heterozygous carriers are typically unaffected.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the short-chain dehydrogenases/reductases (SDR) protein family. This gene spans the FRA16D common chromosomal fragile site and appears to function as a tumor suppressor gene. Expression of the encoded protein is able to induce apoptosis, while defects in this gene are associated with multiple types of cancer. Disruption of this gene is also associated with autosomal recessive spinocerebellar ataxia 12. Disruption of a similar gene in mouse results in impaired steroidogenesis, additionally suggesting a metabolic function for the protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 28MIM #616211

Esophageal squamous cell carcinoma, somaticMIM #133239

Spinocerebellar ataxia, autosomal recessive 12MIM #614322

UniProtEsophageal cancer

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · genetic developmental and epileptic encephalopathy · AR · ClinGen 2021
Strong · developmental and epileptic encephalopathy, 28 · AR · Labcorp Genetics (formerly Invitae)
Strong · autosomal recessive spinocerebellar ataxia 12 · AR · Labcorp Genetics (formerly Invitae)
Supportive · 46,XY partial gonadal dysgenesis · AD · Orphanet

Interpreting a novel variant

Loss of function is the established mechanism, though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.53

LOEUF

LOF

Mechanism· annotated

📖

GeneReview available — WWOX

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.53LOEUF

pLI 0.000

Z-score -0.31

OE 1.07 (0.77–1.53)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-4.44Z-score

OE missense 1.81 (1.67–1.94)

435 obs / 241.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.07 (0.77–1.53)

0≤0.351.4

Missense OE?1.81 (1.67–1.94)

0≤0.61.4

Synonymous OE?1.82

0≤1.21.6

LoF obs/exp: 22 / 20.5Missense obs/exp: 435 / 241.0Syn Z: -6.24

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 21

1,494 rare PASS variants

Rare truncating (LoF)

1 in 130

299 rare PASS variants

Rare synonymous (reference)

1 in 78

462 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for WWOX. 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 28	1 in 230
South Asian	~43k	1 in 28	1 in 150
Remaining (unassigned)	~30k	1 in 23	1 in 190
European (Finnish)	~27k	1 in 97	1 in 930
Admixed American	~22k	1 in 28	1 in 150
African / African American	~21k	1 in 20	1 in 200
East Asian	~20k	1 in 26	1 in 150
Ashkenazi Jewish	~13k	1 in 85	1 in 740
Middle Eastern	~2,884	1 in 29	1 in 180

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 9 coding exons well covered in gnomAD exomes and genomes.? see exons ↓