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…

DNmechanismARLOEUF 0.761 OMIM phenotype

Clinical Summary— DMRT2

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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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

This gene — mechanism propensity

0.6259th %ile

GOF

0.3887th %ile

LOF

0.50top 25%

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.