DLX5

Chr 7ARAD

distal-less homeobox 5

Also known as: SHFM1, SHFM1D

NCBI Gene: 1749ENSG00000105880UniProt: P56178

This gene encodes a member of a homeobox transcription factor gene family similiar to the Drosophila distal-less gene. The encoded protein may play a role in bone development and fracture healing. Mutation in this gene, which is located in a tail-to-tail configuration with another member of the family on the long arm of chromosome 7, may be associated with split-hand/split-foot malformation. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

?Split-hand/foot malformation 1 with sensorineural hearing lossMIM #220600
AR
Split-hand/foot malformation 1MIM #183600
AD
112
ClinVar variants
28
Pathogenic / LP
0.22
pLI score
0
Active trials
Clinical Summary— DLX5
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.
📋
ClinVar Variants
28 Pathogenic / Likely Pathogenic· 56 VUS of 112 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.68LOEUF
pLI 0.218
Z-score 2.30
OE 0.26 (0.12–0.68)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.04Z-score
OE missense 0.99 (0.87–1.13)
166 obs / 167.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.26 (0.12–0.68)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.99 (0.87–1.13)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.19
0≤1.21.6
LoF obs/exp: 3 / 11.4Missense obs/exp: 166 / 167.4Syn Z: -1.29

ClinVar Variant Classifications

112 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21
Likely Pathogenic7
VUS56
Likely Benign18
Benign9
Conflicting1
21
Pathogenic
7
Likely Pathogenic
56
VUS
18
Likely Benign
9
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
2
18
0
21
Likely Pathogenic
1
3
3
0
7
VUS
6
44
5
1
56
Likely Benign
0
3
4
11
18
Benign
0
0
7
2
9
Conflicting
—1
Total8523714112

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

View in ClinVar →

Protein Context — Lollipop Plot

DLX5 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

DLX5-related split-hand and foot malformation

limited
ARUndeterminedAltered Gene Product Structure
Dev. DisordersSkeletal
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Split-hand/foot malformation 1 with sensorineural hearing loss

MIM #220600

Molecular basis of disorder known

Autosomal recessive

Split-hand/foot malformation 1

MIM #183600

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Regulation of Skeletal Development and Maintenance by Runx2 and Sp7.
Komori T·Int J Mol Sci
2024Review
Split Hand-Foot and Deafness in a Patient with 7q21.13-q21.3 Deletion Not Including the DLX5/6 Genes.
Ambrosetti I et al.·Genes (Basel)
2023Review
Genetic regulatory pathways of split-hand/foot malformation.
Kantaputra PN et al.·Clin Genet
2019Review
Role and regulatory mechanism of DLX5 in rhabdomyosarcoma tumorigenesis.
Zhao Y et al.·Biochim Biophys Acta Mol Cell Res
2025Functional
Effects of diabetes drugs on the skeleton.
Meier C et al.·Bone
2016Review
[Autism, epilepsy and genetics].
Muñoz-Yunta JA et al.·Rev Neurol
2008Review
Split-hand/foot malformation - molecular cause and implications in genetic counseling.
Sowińska-Seidler A et al.·J Appl Genet
2014Review
Rett syndrome and neuronal development.
Johnston MV et al.·J Child Neurol
2005Review
FAM20A Deficiency Drives Transcriptomic Dysregulation and Functional Impairment in Gingival Fibroblasts.
Sriwattanapong K et al.·Cell Prolif
2026Functional
Distal-less homeobox 5 transactivated by MYCN contributes to progression of neuroblastoma through AKT signaling pathway.
He Y et al.·Cell Signal
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Integrating bulk and single cell RNA sequencing to predict the potential therapeutic efficacy of DLX5 in hypopharyngeal squamous cell carcinoma.
Jiang Y et al.·Eur J Med Res
2026
Novel Homozygous DLX5 and WNT10B Variants Expand the Genetic and Phenotypic Spectrum of Autosomal Recessive Split-Hand/Foot Malformations (SHFM1D and SHFM6).
Hassan HA et al.·Birth Defects Res
2026
Bone marrow endosteum houses Hedgehog-susceptible Dlx5-expressing osteoblast precursor cells.
Kondo K et al.·Commun Biol
2026
Apigenin 7-glucoside reprograms tumor metabolism and enhances immunotherapy efficacy in colorectal cancer via DLX5.
Zou G et al.·Clin Transl Oncol
2026
DLX5 regulates nasal Epithelial Mesenchymal Transition and inflammation in EosCRSwNPs via the COL1A1-mediated Wnt/β-catenin Signaling.
Zhang H et al.·Int Immunopharmacol
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools