HOXD13

Chr 2AD

homeobox D13

Also known as: BDE, BDSD, HOX4I, SPD, SPD1

NCBI Gene: 3239 ENSG00000128714 UniProt: P35453 OMIM: 142989

This gene belongs to the homeobox family of genes. The homeobox genes encode a highly conserved family of transcription factors that play an important role in morphogenesis in all multicellular organisms. Mammals possess four similar homeobox gene clusters, HOXA, HOXB, HOXC and HOXD, located on different chromosomes, consisting of 9 to 11 genes arranged in tandem. This gene is one of several homeobox HOXD genes located in a cluster on chromosome 2. Deletions that remove the entire HOXD gene cluster or the 5' end of this cluster have been associated with severe limb and genital abnormalities. Mutations in this particular gene cause synpolydactyly. [provided by RefSeq, Jul 2008]

GeneReviews OMIM Research

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.955 OMIM phenotypes

Clinical Summary— HOXD13

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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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ClinVar Variants

35 unique Pathogenic / Likely Pathogenic· 106 VUS of 191 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — HOXD13

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.95LOEUF

pLI 0.009

Z-score 1.69

OE 0.45 (0.24–0.95)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.04Z-score

OE missense 0.99 (0.87–1.13)

159 obs / 160.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.45 (0.24–0.95)

0≤0.351.4

Missense OE?0.99 (0.87–1.13)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 5 / 11.0Missense obs/exp: 159 / 160.5Syn Z: -0.96

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveHOXD13-related brachydactyly-syndactyly syndromeOTHERAD

This gene — mechanism propensity

0.6356th %ile

GOF

0.4678th %ile

LOF

0.70top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). 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.

LOFprediction above median · 1 literature citation · 51% of P/LP variants are LoF · ClinGen HI: Sufficient evidence for dosage pathogenicity

DNprediction above median · 1 literature citation

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.

Literature Evidence

DNIn both cases, however, these rearrangements brought HOXD13 closer to telomeric enhancers, suggesting that the alterations derive from the dominant-negative effect of this digit-specific protein when ectopically expressed during the early development of forearms, through the disruption of topologica1

LOFA Nonsense Mutation in HOXD13 Gene from A Chinese Family with Non-Syndromic Synpolydactyly2

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

References

ClinVar Variant Classifications

191 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29

Likely Pathogenic6

VUS106

Likely Benign22

Benign17

Conflicting10

Pathogenic

Likely Pathogenic

106

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	14	14	1	0	29
Likely Pathogenic	4	2	0	0	6
VUS	0	104	1	1	106
Likely Benign	0	5	6	11	22
Benign	0	1	13	3	17
Conflicting	—				10
Total	18	126	21	15	190

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 32) ClinVar copy-number / structural variants overlap HOXD13 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →