DMXL2

Chr 15ADAR

Dmx like 2

Also known as: DEE81, DFNA71, EIEE81, PEPNS, RC3

NCBI Gene: 23312ENSG00000104093UniProt: Q8TDJ6

This gene encodes a protein with 12 WD domains. Proteins with WD domains are involved in many functions including participation in signal transduction pathways. Participation of the encoded protein in regulation of the Notch signaling pathway has been demonstrated in vitro using several human cell lines (PMID:20810660). A gene encoding a similar protein is located on chromosome 5. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

Primary Disease Associations & Inheritance

?Deafness, autosomal dominant 71MIM #617605
AD
?Polyendocrine-polyneuropathy syndromeMIM #616113
AR
Developmental and epileptic encephalopathy 81MIM #618663
AR
472
ClinVar variants
19
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— DMXL2
🧬
Gene-Disease Validity (ClinGen)
nonsyndromic genetic hearing loss · ADLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
19 Pathogenic / Likely Pathogenic· 267 VUS of 472 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.16LOEUF
pLI 1.000
Z-score 10.06
OE 0.10 (0.07–0.16)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
2.37Z-score
OE missense 0.83 (0.79–0.87)
1297 obs / 1560.0 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.10 (0.07–0.16)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.83 (0.79–0.87)
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.1.03
0≤1.21.6
LoF obs/exp: 15 / 146.4Missense obs/exp: 1297 / 1560.0Syn Z: -0.61

ClinVar Variant Classifications

472 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18
Likely Pathogenic1
VUS267
Likely Benign176
Benign8
Conflicting2
18
Pathogenic
1
Likely Pathogenic
267
VUS
176
Likely Benign
8
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
0
16
0
18
Likely Pathogenic
0
0
1
0
1
VUS
0
251
16
0
267
Likely Benign
1
3
81
91
176
Benign
0
2
5
1
8
Conflicting
—2
Total325611992472

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

View in ClinVar →

Protein Context — Lollipop Plot

DMXL2 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
DMX-LIKE 2; DMXL2
MIM #612186 · *

?Deafness, autosomal dominant 71

MIM #617605

Molecular basis of disorder known

Autosomal dominant

?Polyendocrine-polyneuropathy syndrome

MIM #616113

Molecular basis of disorder known

Autosomal recessive

Developmental and epileptic encephalopathy 81

MIM #618663

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Autozygome and high throughput confirmation of disease genes candidacy.
Maddirevula S et al.·Genet Med
2019
Epileptic encephalopathies and progressive neurodegeneration.
Guerrini R et al.·Rev Neurol (Paris)
2024Review
A dominant variant in DMXL2 is linked to nonsyndromic hearing loss.
Chen DY et al.·Genet Med
2017
A novel variant in DMXL2 gene is associated with autosomal dominant non-syndromic hearing impairment (DFNA71) in a Cameroonian family.
Wonkam-Tingang E et al.·Exp Biol Med (Maywood)
2021Case report
Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders.
Costain G et al.·J Neurodev Disord
2019
Biallelic DMXL2 mutations impair autophagy and cause Ohtahara syndrome with progressive course.
Esposito A et al.·Brain
2019
Clinical Characteristics and Genetic Analyses of Patients with Idiopathic Hypogonadotropic Hypogonadism.
Çiftci N et al.·J Clin Res Pediatr Endocrinol
2023Cohort
DMXL2 drives epithelial to mesenchymal transition in hormonal therapy resistant breast cancer through Notch hyper-activation.
Faronato M et al.·Oncotarget
2015
Potential susceptibility genes in patients with stage III and IV periodontitis: A whole-exome sequencing pilot study.
Xue F et al.·Biomol Biomed
2024Cohort
Genomic alterations as independent prognostic factors to predict the type of lung cancer recurrence.
Valter A et al.·Gene
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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