DMXL2

Summary

DMXL2 (Dmx like 2, HGNC:2938) is a protein-coding gene on chromosome 15q21.2, encoding DmX-like protein 2 (Q8TDJ6). May serve as a scaffold protein for MADD and RAB3GA on synaptic vesicles.

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.

Source: NCBI Gene 23312 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental and epileptic encephalopathy, 81 (Strong, GenCC) — +5 more curated relationships
• GWAS associations: 8
• Clinical variants (ClinVar): 1,968 total — 52 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 112
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001378457

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2938
Approved symbol	DMXL2
Name	Dmx like 2
Location	15q21.2
Locus type	gene with protein product
Status	Approved
Aliases	RC3, KIAA0856, DFNA71
Ensembl gene	ENSG00000104093
Ensembl biotype	protein_coding
OMIM	612186
Entrez	23312

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 6 retained_intron, 5 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000251076, ENST00000449909, ENST00000543779, ENST00000558124, ENST00000558507, ENST00000559059, ENST00000559062, ENST00000559498, ENST00000559769, ENST00000559868, ENST00000560211, ENST00000560421, ENST00000560891, ENST00000561079, ENST00000927394

RefSeq mRNA: 11 — MANE Select: NM_001378457 NM_001174116, NM_001174117, NM_001378457, NM_001378458, NM_001378459, NM_001378460, NM_001378461, NM_001378462, NM_001378463, NM_001378464, NM_015263

CCDS: CCDS10141, CCDS53945, CCDS53946, CCDS91998

Canonical transcript exons

ENST00000560891 — 44 exons

Exon	Start	End
ENSE00001015448	51538213	51538452
ENSE00001172522	51498552	51500231
ENSE00001172529	51502806	51503033
ENSE00001172568	51537488	51537759
ENSE00001605718	51545583	51545766
ENSE00001606558	51487954	51488119
ENSE00001607906	51480542	51481623
ENSE00001641367	51547230	51547408
ENSE00001643944	51456309	51456369
ENSE00001668621	51514442	51514559
ENSE00001685195	51535663	51535784
ENSE00001699457	51474344	51474592
ENSE00001699741	51491578	51491747
ENSE00001704039	51507134	51507253
ENSE00001716330	51451645	51451697
ENSE00001717683	51471223	51471401
ENSE00001721152	51488548	51488645
ENSE00001725854	51463379	51463496
ENSE00001766589	51495024	51495134
ENSE00001769575	51453550	51453641
ENSE00001776993	51478271	51478347
ENSE00001780287	51450129	51450346
ENSE00001787123	51517078	51517167
ENSE00001797177	51479948	51480139
ENSE00001801413	51542333	51542507
ENSE00001802512	51486073	51486337
ENSE00002203366	51459598	51459660
ENSE00002271863	51536166	51536862
ENSE00002292365	51476589	51476719
ENSE00002549083	51447791	51449193
ENSE00003476083	51576056	51576181
ENSE00003477178	51464675	51464876
ENSE00003478391	51466184	51466311
ENSE00003489103	51568487	51568558
ENSE00003494857	51564125	51564260
ENSE00003496487	51455151	51455228
ENSE00003521308	51458709	51458795
ENSE00003545996	51465566	51465651
ENSE00003563925	51565088	51565166
ENSE00003564122	51458506	51458627
ENSE00003585589	51456066	51456193
ENSE00003648780	51563381	51563447
ENSE00003654639	51457328	51457466
ENSE00003903056	51622459	51622771

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 98.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.6001 / max 574.2584, expressed in 1635 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
149938	8.2109	1520
149939	2.5820	589
149941	1.4917	542
149940	0.9871	319
149933	0.9441	159
149937	0.7822	336
149935	0.6544	228
149932	0.3206	64
149931	0.2581	63
149936	0.1559	71

Top tissues by expression

289 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	98.58	gold quality
mononuclear cell	CL:0000842	98.52	gold quality
leukocyte	CL:0000738	98.26	gold quality
granulocyte	CL:0000094	96.42	gold quality
postcentral gyrus	UBERON:0002581	95.39	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.38	gold quality
corpus epididymis	UBERON:0004359	95.32	gold quality
substantia nigra pars compacta	UBERON:0001965	95.28	gold quality
right uterine tube	UBERON:0001302	95.27	gold quality
cerebellar cortex	UBERON:0002129	95.23	gold quality
cerebellar hemisphere	UBERON:0002245	95.23	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.23	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.22	gold quality
pons	UBERON:0000988	95.08	gold quality
pituitary gland	UBERON:0000007	94.94	gold quality
superior frontal gyrus	UBERON:0002661	94.86	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.79	gold quality
adenohypophysis	UBERON:0002196	94.69	gold quality
parietal lobe	UBERON:0001872	94.68	gold quality
right frontal lobe	UBERON:0002810	94.64	gold quality
cerebellum	UBERON:0002037	94.47	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.42	gold quality
cortical plate	UBERON:0005343	94.40	gold quality
rectum	UBERON:0001052	94.30	gold quality
endothelial cell	CL:0000115	94.24	gold quality
Ammon’s horn	UBERON:0001954	94.24	gold quality
right lung	UBERON:0002167	94.12	gold quality
prefrontal cortex	UBERON:0000451	94.04	gold quality
transverse colon	UBERON:0001157	93.98	gold quality
tibial nerve	UBERON:0001323	93.93	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	24.69
E-MTAB-9801	yes	6.09

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

116 targeting DMXL2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4262	100.00	73.26	3931
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-5688	99.96	73.23	4504

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 7)

• an important role for Rabconnectin-3 and V-ATPase activity in the Notch signaling pathway in mammalian cells. (PMID:20810660)
• Haploinsufficiency of Dmxl2, encoding a synaptic protein, causes infertility associated with a loss of GnRH neurons in humans and mice. (PMID:25248098)
• authors demonstrate that DMXL2 is a transmembrane protein with a potential extra-cellular domain. These findings identify DMXL2 as a novel, functional biomarker for ERalpha positive breast cancer. (PMID:26093085)
• Data indicated that the p.Arg2417His variant in DMXL2 is associated with dominant, nonsyndromic hearing loss and suggested an important role of DMXL2 in inner ear function. (PMID:27657680)
• Disruption of DMXL2 may predispose to NDDs including autism spectrum disorder. (PMID:30732576)
• Impaired lysosomal function and autophagy caused by biallelic DMXL2 mutations affect neuronal development and synapse formation and result in Ohtahara syndrome with profound developmental impairment and reduced life expectancy. (PMID:31688942)
• A novel variant in DMXL2 gene is associated with autosomal dominant non-syndromic hearing impairment (DFNA71) in a Cameroonian family. (PMID:33715530)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dmxl2	ENSDARG00000091293
mus_musculus	Dmxl2	ENSMUSG00000041268
rattus_norvegicus	Dmxl2	ENSRNOG00000009170
drosophila_melanogaster	Rbcn-3A	FBGN0023458
caenorhabditis_elegans		WBGENE00004313

Paralogs (1): DMXL1 (ENSG00000172869)

Protein

Protein identifiers

DmX-like protein 2 — Q8TDJ6 (reviewed: Q8TDJ6)

Alternative names: Rabconnectin-3

All UniProt accessions (3): Q8TDJ6, H0YLM8, H0YM41

UniProt curated annotations — full annotation on UniProt →

Function. May serve as a scaffold protein for MADD and RAB3GA on synaptic vesicles. Plays a role in the brain as a key controller of neuronal and endocrine homeostatic processes.

Subunit / interactions. Interacts with MADD and RAB3GAP.

Subcellular location. Cytoplasmic vesicle. Secretory vesicle. Synaptic vesicle membrane. Neuronal dense core vesicle.

Disease relevance. Polyendocrine-polyneuropathy syndrome (PEPNS) [MIM:616113] A progressive endocrine and neurodevelopmental disorder manifesting early in childhood with growth retardation and recurrent episodes of profound asymptomatic hypoglycemia. PEPNS is characterized by central hypothyroidism, hypogonadotropic hypogonadism, incomplete puberty, progressive non-autoimmune insulin-dependent diabetes mellitus, peripheral demyelinating sensorimotor polyneuropathy, and cerebellar and pyramidal signs. The disease is caused by variants affecting the gene represented in this entry. Deafness, autosomal dominant, 71 (DFNA71) [MIM:617605] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA71 is characterized by bilateral mild to moderate hearing loss before age 20 years, which gradually progresses to severe to profound hearing loss. The disease is caused by variants affecting the gene represented in this entry. Developmental and epileptic encephalopathy 81 (DEE81) [MIM:618663] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE81 is an autosomal recessive form characterized by onset soon after birth, little developmental progress with no eye contact and no motor or cognitive development. Other features may include facial dysmorphism, such as hypotonic facies and epicanthal folds, as well as sensorineural hearing loss and peripheral neuropathy. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8TDJ6-1	1	yes
Q8TDJ6-2	2
Q8TDJ6-3	3

RefSeq proteins (11): NP_001167587, NP_001167588, NP_001365386, NP_001365387, NP_001365388, NP_001365389, NP_001365390, NP_001365391, NP_001365392, NP_001365393, NP_056078 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR022033	Rav1p_C	Domain
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR052208	DmX-like/RAVE_component	Family

Pfam: PF00400, PF12234

UniProt features (59 total): repeat 16, modified residue 16, sequence variant 10, compositionally biased region 6, region of interest 4, sequence conflict 3, splice variant 2, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for Q8TDJ6 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (16): 326, 473, 588, 944, 945, 1140, 1143, 1151, 1287, 1400, 1417, 1857, 1984, 2022, 2399, 2640

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 446 (showing top): GOCC_SECRETORY_GRANULE, GOMF_GTPASE_BINDING, HASLINGER_B_CLL_WITH_11Q23_DELETION, GOBP_VACUOLAR_ACIDIFICATION, SCHLOSSER_SERUM_RESPONSE_DN, GOBP_REGULATION_OF_PH, GOBP_MONOATOMIC_ION_HOMEOSTASIS, BASAKI_YBX1_TARGETS_DN, MODULE_48, MODULE_95, ZHAN_MULTIPLE_MYELOMA_CD1_AND_CD2_DN, GOCC_EXOCYTIC_VESICLE, GOCC_SECRETORY_VESICLE, YAGI_AML_WITH_11Q23_REARRANGED, GOBP_HOMEOSTATIC_PROCESS

GO Biological Process (1): vacuolar acidification (GO:0007035)

GO Molecular Function (2): small GTPase binding (GO:0031267), protein binding (GO:0005515)

GO Cellular Component (8): obsolete extracellular space (GO:0005615), synaptic vesicle (GO:0008021), synaptic vesicle membrane (GO:0030672), RAVE complex (GO:0043291), neuronal dense core vesicle (GO:0098992), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), synapse (GO:0045202)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
intracellular pH reduction	1
GTPase binding	1
binding	1
exocytic vesicle	1
presynapse	1
synaptic vesicle	1
exocytic vesicle membrane	1
protein-containing complex	1
dense core granule	1
cellular anatomical structure	1
intracellular vesicle	1
cell junction	1

Protein interactions and networks

STRING

912 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DMXL2	WDR7	Q9Y4E6	978
DMXL2	MADD	Q8WXG6	937
DMXL2	RAB3GAP2	Q9H2M9	900
DMXL2	RAB3GAP1	Q15042	868
DMXL2	ROGDI	Q9GZN7	722
DMXL2	RAB3A	P20336	645
DMXL2	OTUD4	Q01804	498
DMXL2	CPLX4	Q7Z7G2	457
DMXL2	PNPLA6	Q8IY17	456
DMXL2	RASA1	P20936	446
DMXL2	RNF216	Q9NWF9	443
DMXL2	POLR3A	O14802	438
DMXL2	RAC2	P15153	409
DMXL2	ATP6V0A4	Q9HBG4	405
DMXL2	LHX4	Q969G2	399

IntAct

77 interactions, top by confidence:

A	B	Type	Score
FAF2	UBB	psi-mi:“MI:0914”(association)	0.640
ATP6V1C2	ATP6V1G1	psi-mi:“MI:0914”(association)	0.640
ANTXR1	POTEF	psi-mi:“MI:0914”(association)	0.530
NPY2R	RTL8C	psi-mi:“MI:0914”(association)	0.530
TSPYL6	NME4	psi-mi:“MI:0914”(association)	0.530
GLUL	DMXL2	psi-mi:“MI:0914”(association)	0.530
ATP6V1B2	ATP6V1G1	psi-mi:“MI:0914”(association)	0.530
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
YBEY	NME4	psi-mi:“MI:0914”(association)	0.530
ANKRD22	ESYT2	psi-mi:“MI:0914”(association)	0.530
ATP6V1G2	ATP6V1B1	psi-mi:“MI:0914”(association)	0.530
NTAQ1	SBNO1	psi-mi:“MI:0914”(association)	0.350
YBEY	NUDT19	psi-mi:“MI:0914”(association)	0.350
C1QTNF2	GNPAT	psi-mi:“MI:0914”(association)	0.350
RP2	QSOX1	psi-mi:“MI:0914”(association)	0.350
DEF8	DPYSL4	psi-mi:“MI:0914”(association)	0.350
ROGDI		psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
ATP6V1E1	ATP6V1D	psi-mi:“MI:0914”(association)	0.350
ATP6V1F	MID1	psi-mi:“MI:0914”(association)	0.350
ATP6V1G1	MRPL3	psi-mi:“MI:0914”(association)	0.350
ATP6V1H	ATP6V1G1	psi-mi:“MI:0914”(association)	0.350
WDR7	DMXL2	psi-mi:“MI:0914”(association)	0.350
atp6v1g_human	HSPA8	psi-mi:“MI:0914”(association)	0.350
HCST	TMEM120B	psi-mi:“MI:0914”(association)	0.350

BioGRID (101): DMXL2 (Affinity Capture-MS), DMXL2 (Affinity Capture-MS), DMXL2 (Affinity Capture-MS), DMXL2 (Affinity Capture-MS), DMXL2 (Affinity Capture-MS), DMXL2 (Affinity Capture-MS), DMXL2 (Affinity Capture-MS), DMXL2 (Affinity Capture-MS), DMXL2 (Affinity Capture-MS), DMXL2 (Affinity Capture-MS), DMXL2 (Affinity Capture-MS), DMXL2 (Affinity Capture-MS), DMXL2 (Affinity Capture-MS), DMXL2 (Affinity Capture-MS), DMXL2 (Affinity Capture-MS)

ESM2 similar proteins: A2VDJ0, A2VE78, A4D1B5, A6NFN9, D3YYM4, O15040, O95714, O95876, Q3MJ13, Q3U1D0, Q3U3D7, Q3U3S3, Q3UFT3, Q4AC94, Q4KM95, Q4U2R1, Q52KB6, Q562E2, Q5F479, Q5R6E1, Q5RFQ4, Q5SUS0, Q5XGI3, Q5XX13, Q6GQ34, Q6INS1, Q6NRE4, Q6P2C0, Q6ZPF3, Q7TP65, Q86VV8, Q8BPN8, Q8C0W1, Q8C2S5, Q8IV35, Q8IVF5, Q8NDB2, Q8NG48, Q8R2U7, Q8R3C1

Diamond homologs: P87314, Q6PNC0, Q8BPN8, Q8TDJ6, Q9Y485

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
DMXL2	“up-regulates quantity”	MADD	binding
DMXL2	“up-regulates quantity”	RAB3GAP1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 107 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	6	56.8×	4e-08
Insulin receptor recycling	9	48.2×	3e-11
Transferrin endocytosis and recycling	9	46.7×	3e-11
ROS and RNS production in phagocytes	9	42.6×	6e-11
Amino acids regulate mTORC1	9	25.4×	7e-09
Ion channel transport	11	14.9×	1e-08

GO biological processes:

GO term	Partners	Fold	FDR
synaptic vesicle lumen acidification	7	69.7×	3e-09
vacuolar acidification	5	39.0×	3e-05
regulation of macroautophagy	8	25.2×	3e-07
proton transmembrane transport	7	23.2×	5e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

1968 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	52
Likely pathogenic	12
Uncertain significance	852
Likely benign	865
Benign	103

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1065611	NM_001378457.1(DMXL2):c.918G>T (p.Gln306His)	Pathogenic
1451384	NM_001378457.1(DMXL2):c.6955C>T (p.Gln2319Ter)	Pathogenic
1452030	NM_001378457.1(DMXL2):c.6430C>T (p.Arg2144Ter)	Pathogenic
1949879	NM_001378457.1(DMXL2):c.5428C>T (p.Arg1810Ter)	Pathogenic
1993189	NM_001378457.1(DMXL2):c.6960G>A (p.Trp2320Ter)	Pathogenic
2004424	NM_001378457.1(DMXL2):c.326dup (p.Leu109fs)	Pathogenic
2013536	NM_001378457.1(DMXL2):c.4739T>A (p.Leu1580Ter)	Pathogenic
2018934	NM_001378457.1(DMXL2):c.326del (p.Phe108_Leu109insTer)	Pathogenic
2028810	NM_001378457.1(DMXL2):c.4876C>T (p.Gln1626Ter)	Pathogenic
2029733	NM_001378457.1(DMXL2):c.710del (p.Gly237fs)	Pathogenic
2030888	NM_001378457.1(DMXL2):c.7031del (p.Leu2344fs)	Pathogenic
2035321	NM_001378457.1(DMXL2):c.5112G>A (p.Trp1704Ter)	Pathogenic
2083352	NM_001378457.1(DMXL2):c.2485C>T (p.Arg829Ter)	Pathogenic
2099131	NM_001378457.1(DMXL2):c.1519_1520insGCGGAGCTTGCAGTGAGCCGAGATCCCGCCACTGCACTCCAGCCTGGGCGACAGAGCGAGACTCCGTCTCAAANNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGAATCCTG (p.Asp507fs)	Pathogenic
2100882	NM_001378457.1(DMXL2):c.342C>G (p.Tyr114Ter)	Pathogenic
2106016	NM_001378457.1(DMXL2):c.4252C>T (p.Arg1418Ter)	Pathogenic
2121098	NM_001378457.1(DMXL2):c.3437_3440del (p.Phe1146fs)	Pathogenic
2125986	NM_001378457.1(DMXL2):c.7365del (p.Ser2456fs)	Pathogenic
2126948	NM_001378457.1(DMXL2):c.6319_6320del (p.Glu2106_Ser2107insTer)	Pathogenic
2423928	NC_000015.9:g.(?51745727)(51745858_?)del	Pathogenic
2423929	NC_000015.9:g.(?51755556)(51773840_?)del	Pathogenic
2743205	NM_001378457.1(DMXL2):c.8542G>T (p.Gly2848Ter)	Pathogenic
2743898	NM_001378457.1(DMXL2):c.2457dup (p.Asn820Ter)	Pathogenic
2754193	NM_001378457.1(DMXL2):c.1315G>T (p.Glu439Ter)	Pathogenic
2818107	NM_001378457.1(DMXL2):c.7689del (p.Gln2564fs)	Pathogenic
2825102	NM_001378457.1(DMXL2):c.5554C>T (p.Arg1852Ter)	Pathogenic
3637966	NM_001378457.1(DMXL2):c.8180_8181del (p.Glu2726_Tyr2727insTer)	Pathogenic
3643536	NM_001378457.1(DMXL2):c.5294C>G (p.Ser1765Ter)	Pathogenic
3646545	NM_001378457.1(DMXL2):c.7138C>T (p.Arg2380Ter)	Pathogenic
3650540	NM_001378457.1(DMXL2):c.4768C>T (p.Gln1590Ter)	Pathogenic

SpliceAI

6617 predictions. Top by Δscore:

Variant	Effect	Δscore
15:51450344:AACC:A	acceptor_loss	1.0000
15:51450346:CCT:C	acceptor_loss	1.0000
15:51450347:C:CC	acceptor_gain	1.0000
15:51450347:CTG:C	acceptor_loss	1.0000
15:51453642:C:CC	acceptor_gain	1.0000
15:51455224:CCACA:C	acceptor_gain	1.0000
15:51455225:CACAC:C	acceptor_gain	1.0000
15:51456061:CTAA:C	donor_loss	1.0000
15:51456062:TAA:T	donor_loss	1.0000
15:51456063:AAC:A	donor_loss	1.0000
15:51456100:A:C	donor_gain	1.0000
15:51456106:G:A	donor_gain	1.0000
15:51456189:AAGAT:A	acceptor_gain	1.0000
15:51456190:AGAT:A	acceptor_gain	1.0000
15:51456191:GAT:G	acceptor_gain	1.0000
15:51456192:AT:A	acceptor_gain	1.0000
15:51456194:C:CC	acceptor_gain	1.0000
15:51456200:C:CT	acceptor_gain	1.0000
15:51456202:C:CT	acceptor_gain	1.0000
15:51456203:A:T	acceptor_gain	1.0000
15:51458501:CAAA:C	donor_loss	1.0000
15:51458502:AAAC:A	donor_loss	1.0000
15:51458503:AACC:A	donor_loss	1.0000
15:51458505:C:CG	donor_loss	1.0000
15:51458591:CATG:C	acceptor_gain	1.0000
15:51458594:G:C	acceptor_gain	1.0000
15:51458623:TTTGC:T	acceptor_gain	1.0000
15:51458624:TTGC:T	acceptor_gain	1.0000
15:51458626:GCC:G	acceptor_loss	1.0000
15:51458628:C:CC	acceptor_gain	1.0000

AlphaMissense

20140 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:51451684:A:G	W2882R	1.000
15:51451684:A:T	W2882R	1.000
15:51451686:A:G	L2881P	1.000
15:51456172:C:A	G2785V	1.000
15:51456172:C:T	G2785D	1.000
15:51456176:C:G	D2784H	1.000
15:51456184:C:T	G2781D	1.000
15:51458587:A:T	V2684D	1.000
15:51474397:C:T	G2386E	1.000
15:51476595:A:G	W2319R	1.000
15:51476595:A:T	W2319R	1.000
15:51480558:A:G	L2183P	1.000
15:51480570:A:G	L2179P	1.000
15:51480876:A:G	L2077P	1.000
15:51480880:A:G	W2076R	1.000
15:51480880:A:T	W2076R	1.000
15:51480888:A:G	L2073P	1.000
15:51480981:A:G	L2042P	1.000
15:51488012:C:G	R1720P	1.000
15:51488032:A:C	F1713L	1.000
15:51488032:A:T	F1713L	1.000
15:51488034:A:G	F1713L	1.000
15:51488036:G:T	A1712D	1.000
15:51488043:T:C	K1710E	1.000
15:51488048:G:T	A1708D	1.000
15:51488057:C:G	R1705P	1.000
15:51488061:A:G	W1704R	1.000
15:51488061:A:T	W1704R	1.000
15:51491652:A:G	W1627R	1.000
15:51491652:A:T	W1627R	1.000

dbSNP variants (sampled 300 via entrez): RS1000010664 (15:51495380 G>A), RS1000025138 (15:51536094 T>A,C), RS1000029669 (15:51540001 T>C), RS1000030974 (15:51503771 C>T), RS1000055469 (15:51597128 C>A,G,T), RS1000057779 (15:51535802 G>A), RS1000069321 (15:51581945 A>G), RS1000070539 (15:51578066 A>G), RS1000097918 (15:51593123 T>C), RS1000134188 (15:51607374 C>T), RS1000168491 (15:51561993 G>T), RS1000193890 (15:51468292 A>C), RS1000200227 (15:51561719 G>A), RS1000206119 (15:51521498 T>G), RS1000232720 (15:51559111 C>A,G,T)

Disease associations

OMIM: gene MIM:612186 | disease phenotypes: MIM:616113, MIM:617605, MIM:618663

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 81	Strong	Autosomal recessive
polyendocrine-polyneuropathy syndrome	Supportive	Autosomal recessive
genetic developmental and epileptic encephalopathy	Supportive	Autosomal dominant
autosomal dominant nonsyndromic hearing loss	Supportive	Autosomal dominant
hearing loss, autosomal dominant 71	Limited	Autosomal dominant
nonsyndromic genetic hearing loss	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Limited	AD

Mondo (10): polyendocrine-polyneuropathy syndrome (MONDO:0014497), hearing loss, autosomal dominant 71 (MONDO:0033258), hearing loss disorder (MONDO:0005365), developmental and epileptic encephalopathy, 81 (MONDO:0032858), amenorrhea (MONDO:0001836), nonsyndromic genetic hearing loss (MONDO:0019497), pituitary stalk interruption syndrome (MONDO:0019828), autism spectrum disorder (MONDO:0005258), genetic developmental and epileptic encephalopathy (MONDO:0100062), autosomal dominant nonsyndromic hearing loss (MONDO:0019587)

Orphanet (4): Polyendocrine-polyneuropathy syndrome (Orphanet:453533), Rare non-syndromic genetic deafness (Orphanet:87884), Pituitary stalk interruption syndrome (Orphanet:95496), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

112 total (30 of 112 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000044	Hypogonadotropic hypogonadism
HP:0000054	Micropenis
HP:0000070	Ureterocele
HP:0000110	Renal dysplasia
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000286	Epicanthus
HP:0000340	Sloping forehead
HP:0000350	Small forehead
HP:0000407	Sensorineural hearing impairment
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000729	Autistic behavior
HP:0000752	Hyperactivity
HP:0000826	Precocious puberty
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001254	Lethargy
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001270	Motor delay
HP:0001271	Polyneuropathy

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002783_108	Body mass index	3.000000e-06
GCST002783_194	Body mass index	7.000000e-09
GCST002783_349	Body mass index	5.000000e-08
GCST004495_24	BMI (adjusted for smoking behaviour)	2.000000e-06
GCST004497_121	Body mass index (joint analysis main effects and smoking interaction)	6.000000e-06
GCST005316_543	Intelligence (MTAG)	2.000000e-08
GCST007614_27	C-reactive protein levels	3.000000e-08
GCST010244_86	Triglyceride levels	2.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004318	smoking behavior
EFO:0004337	intelligence
EFO:0004458	C-reactive protein measurement
EFO:0004530	triglyceride measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D000568	Amenorrhea	C23.550.568.500
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

39 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
potassium chromate(VI)	affects cotreatment, decreases expression	2
Acetaminophen	decreases expression, increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Valproic Acid	affects expression, increases expression	2
FR900359	affects phosphorylation	1
bisphenol A	increases expression	1
trichostatin A	increases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
coumarin	decreases phosphorylation	1
2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline	decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression	1
jinfukang	decreases expression	1
(+)-JQ1 compound	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Air Pollutants	decreases expression	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Vehicle Emissions	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	increases expression	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Manganese	increases abundance, affects cotreatment, decreases expression	1
Methotrexate	increases expression	1
Nickel	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

313 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT05364021	PHASE1/PHASE2	COMPLETED	Study to Investigate LP352 in Subjects With Developmental and Epileptic Encephalopathies
NCT06983158	PHASE1/PHASE2	SUSPENDED	A Clinical Trial of CAP-002 Gene Therapy in Pediatric Patients With Syntaxin-Binding Protein 1 (STXBP1) Encephalopathy
NCT04937062	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Phenylbutyrate for Monogenetic Developmental and Epileptic Encephalopathy
NCT06149663	Not specified	AVAILABLE	Intermediate-Size Expanded Access Protocol (EAP) for LP352
NCT06380192	Not specified	RECRUITING	Developmental and Epileptic Encephalopathy of Genetic Etiology: Natural History Through Reuse of Clinical Data