DMRT2

Chr 9AR

doublesex and mab-3 related transcription factor 2

Also known as: DSXL-2, SCDO7

NCBI Gene: 10655 ENSG00000173253 UniProt: Q9Y5R5 OMIM: 604935

The protein is a transcriptional activator that directly regulates the myogenic determination gene MYF5 and is essential for somitogenesis during embryogenesis, controlling somite development and differentiation into sclerotome and dermomyotome. Mutations cause spondylocostal dysostosis 7, a skeletal disorder affecting vertebral and rib development, with autosomal recessive inheritance. The gene shows low constraint to loss-of-function variation, consistent with its recessive disease association.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to the DMRT gene family, sharing a DM DNA-binding domain with Drosophila 'doublesex' (dsx) and C. elegans mab3, genes involved in sex determination in these organisms. Also, this gene is located in a region of the human genome (chromosome 9p24.3) associated with gonadal dysgenesis and XY sex reversal. Hence this gene is one of the candidates for sex-determining gene(s) on chr 9. [provided by RefSeq, Apr 2010]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Spondylocostal dysostosis 7, autosomal recessiveMIM #621523

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Spondylocostal dysostosis 7, autosomal recessive; no ClinGen or GenCC tier

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.76

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.76LOEUF

pLI 0.010

Z-score 2.26

OE 0.38 (0.21–0.76)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-2.06Z-score

OE missense 1.36 (1.25–1.49)

350 obs / 257.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.38 (0.21–0.76)

0≤0.351.4

Missense OE?1.36 (1.25–1.49)

0≤0.61.4

Synonymous OE?1.34

0≤1.21.6

LoF obs/exp: 6 / 15.7Missense obs/exp: 350 / 257.0Syn Z: -2.74

Background carrier burden — how many people carry a rare variant somewhere in DMRT2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 63

1,161 rare PASS variants

Rare truncating (LoF)

1 in 2,600

82 rare PASS variants

Rare synonymous (reference)

1 in 120

416 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DMRT2. 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 79	1 in 2,500
South Asian	~43k	1 in 47	1 in 3,400
Remaining (unassigned)	~30k	1 in 44	1 in 1,500
European (Finnish)	~27k	1 in 240	1 in 1,600
Admixed American	~22k	1 in 46	1 in 4,200
African / African American	~21k	1 in 41	≈ 1 in 5,200
East Asian	~20k	1 in 63	1 in 3,200
Ashkenazi Jewish	~13k	1 in 190	1 in 2,300
Middle Eastern	~2,884	1 in 46	≈ 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): 2 of 3 coding exons well covered in gnomAD exomes; exon 2 marginal. Genomes: all 3.? see exons ↓