Tietz syndrome

Summary

Tietz syndrome (MONDO:0007077) is a disease caused by MITF (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MITF (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 915
• Phenotypes (HPO): 6

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

6 HPO clinical features (Orphanet curated; top 6 by frequency):

HPO ID	Term	Frequency
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000593	Abnormal anterior chamber morphology	Very frequent (80-99%)
HP:0001000	Abnormality of skin pigmentation	Very frequent (80-99%)
HP:0001010	Hypopigmentation of the skin	Very frequent (80-99%)
HP:0002226	White eyebrow	Very frequent (80-99%)
HP:0005599	Hypopigmentation of hair	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Tietz syndrome
Mondo ID	MONDO:0007077
MeSH	C536919
OMIM	103500
Orphanet	42665
DOID	DOID:0090002
SNOMED CT	403805009
UMLS	C0391816
MedGen	98213
GARD	0007772
Is cancer (heuristic)	no

Also known as: albinism-deafness of Tietz · hypopigmentation-deafness syndrome · hypopigmentation/deafness of Tietz · TADS · Tietz albinism-deafness syndrome · Tietz syndrome

Data availability: 915 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › Tietz syndrome

Related subtypes (119): ptosis, eye accommodation disease, corneal disorder, asthenopia, lens disorder, keratomalacia, scleral disorder, ocular siderosis, coloboma, luxation of globe, mucopolysaccharidosis type 1, lacrimal apparatus disorder, Foster-Kennedy syndrome, anterior dislocation of lens, uveal disorder, eyelid disorder, ocular hypotension, scotoma, exophthalmos, ophthalmia nodosa, eye degenerative disorder, refractive error, glaucoma, retinal disorder, eye allergy, ocular vascular disorder, optic neuritis, conjunctival disorder, ocular hypertension, Alagille syndrome, glaucoma-sleep apnea syndrome, Marshall syndrome, microcornea-glaucoma-absent frontal sinuses syndrome, nail-patella syndrome, oculodentodigital dysplasia, piebaldism, Sturge-Weber syndrome, cerebrotendinous xanthomatosis, ocular cystinosis, alpha-mannosidosis, megalocornea-intellectual disability syndrome, mucolipidosis type IV, mucopolysaccharidosis type 6, Netherton syndrome, galactosialidosis, Niemann-Pick disease type A, ocular motor apraxia, Cogan type, Peters plus syndrome, isolated Pierre-Robin syndrome, ectodermal dysplasia-blindness syndrome, Sandhoff disease, SHORT syndrome, Sjogren-Larsson syndrome, Smith-Lemli-Opitz syndrome, Tay-Sachs disease, tyrosinemia type II, Ito hypomelanosis, X-linked cone dysfunction syndrome with myopia, red color blindness, oculocerebrorenal syndrome, Lowry-MacLean syndrome, pigment dispersion syndrome, hereditary hyperferritinemia with congenital cataracts, dyssegmental dysplasia-glaucoma syndrome, mevalonic aciduria, familial cavitary optic disk anomaly, blindness - scoliosis - arachnodactyly syndrome, fatty acyl-CoA reductase 1 deficiency, microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome, neurotrophic keratopathy, Cogan syndrome, atopic keratoconjunctivitis, rhizomelic chondrodysplasia punctata, Ehlers-Danlos syndrome, kyphoscoliotic type 1, IRVAN syndrome, Rothmund-Thomson syndrome type 2, microcornea-corectopia-macular hypoplasia syndrome, isolated anophthalmia-microphthalmia syndrome, Spasmus nutans, toxic maculopathy due to antimalarial drugs, syndromic recessive X-linked ichthyosis, acute zonal occult outer retinopathy, acute annular outer retinopathy, phakomatosis pigmentovascularis, lamellar ichthyosis, idiopathic linear interstitial keratitis, chondroectodermal dysplasia with night blindness, galactosemia, GM1 gangliosidosis, Gaucher disease, visual snow syndrome, extensive peripapillary myelinated nerve fibers, IgG4-related ophthalmic disorder, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, vernal keratoconjunctivitis, Gardner syndrome, anterior segment dysgenesis, isolated ankyloblepharon filiforme adnatum, hereditary optic neuropathy, essential strabismus, Axenfeld anomaly, eye neoplasm, isolated blepharochalasis, punctate inner choroidopathy, eye infectious disorder, vitreous body disorder, 9q33.3q34.11 microdeletion syndrome, autoimmune/inflammatory optic neuropathy, LTBP2-related ocular dysgenesis, ocular growth disorder, ocular dysgenesis caused by defects in PAX6 regulation, choroidal neovascularization, anterior segment developmental abnormality with extraocular manifestations, congenital optic disk excavation, neuroocular syndrome, isolated angioid streaks, multiple evanescent white dot syndrome, stellate multiform amelanotic choroidopathy, macular telangiectasia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

320 uncertain significance, 190 likely benign, 32 conflicting classifications of pathogenicity, 22 benign, 16 pathogenic, 9 benign/likely benign, 7 likely pathogenic, 3 pathogenic/likely pathogenic, 1 pathogenic/likely pathogenic; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
1324720	NM_001354604.2(MITF):c.1061T>G (p.Leu354Ter)	MITF	Pathogenic	criteria provided, single submitter
14272	NM_001354604.2(MITF):c.964AGA[2] (p.Arg324del)	MITF	Pathogenic	criteria provided, multiple submitters, no conflicts
14275	NM_001354604.2(MITF):c.951C>G (p.Asn317Lys)	MITF	Pathogenic	no assertion criteria provided
2020473	NM_001354604.2(MITF):c.764T>A (p.Leu255Ter)	MITF	Pathogenic	criteria provided, single submitter
2024980	NM_001354604.2(MITF):c.643_644dup (p.Ser216fs)	MITF	Pathogenic	criteria provided, single submitter
2203401	NM_001354604.2(MITF):c.815del (p.Pro272fs)	MITF	Pathogenic	criteria provided, multiple submitters, no conflicts
228363	NM_001354604.2(MITF):c.1129C>T (p.Arg377Ter)	MITF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2422628	NC_000003.11:g.(?69985874)(70014399_?)del	MITF	Pathogenic	criteria provided, single submitter
2422629	NC_000003.11:g.(?70013978)(70014399_?)del	MITF	Pathogenic	criteria provided, single submitter
2422630	NC_000003.11:g.(?69985874)(69990502_?)del	MITF	Pathogenic	criteria provided, single submitter
2922420	NM_001354604.2(MITF):c.367del (p.Leu123fs)	MITF	Pathogenic	criteria provided, single submitter
2947585	NM_001354604.2(MITF):c.440T>G (p.Leu147Ter)	MITF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29792	NM_001354604.2(MITF):c.1273G>A (p.Glu425Lys)	MITF	Pathogenic/Likely pathogenic; risk factor	criteria provided, multiple submitters, no conflicts
3601242	NM_001354604.2(MITF):c.673del (p.Asp225fs)	MITF	Pathogenic	criteria provided, multiple submitters, no conflicts
3601257	NM_001354604.2(MITF):c.896_897del (p.Thr299fs)	MITF	Pathogenic	criteria provided, multiple submitters, no conflicts
3601267	NM_001354604.2(MITF):c.970A>T (p.Arg324Ter)	MITF	Pathogenic	criteria provided, multiple submitters, no conflicts
372755	NM_001354604.2(MITF):c.1084C>T (p.Arg362Ter)	MITF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3749427	NM_001354604.2(MITF):c.887_894dup (p.Thr299fs)	MITF	Pathogenic	criteria provided, single submitter
375217	NM_001354604.2(MITF):c.956-1G>A	MITF	Pathogenic	criteria provided, multiple submitters, no conflicts
3754752	NM_001354604.2(MITF):c.670del (p.Asp224fs)	MITF	Pathogenic	criteria provided, single submitter
2034856	NM_001354604.2(MITF):c.953_955+3del	MITF	Likely pathogenic	criteria provided, single submitter
2422632	NC_000003.11:g.(?69987065)(69997137_?)del	MITF	Likely pathogenic	criteria provided, single submitter
2943395	NM_001354604.2(MITF):c.666+1G>A	MITF	Likely pathogenic	criteria provided, single submitter
2949158	NM_001354604.2(MITF):c.762+1G>A	MITF	Likely pathogenic	criteria provided, single submitter
2954027	NM_001354604.2(MITF):c.660_666+6del	MITF	Likely pathogenic	criteria provided, single submitter
3381833	NM_001354604.2(MITF):c.957T>G (p.Ile319Met)	MITF	Likely pathogenic	criteria provided, single submitter
3601255	NM_001354604.2(MITF):c.880+1G>A	MITF	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1186984	NM_001354604.2(MITF):c.1384G>A (p.Gly462Arg)	MITF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1196734	NM_001354604.2(MITF):c.956-3A>T	MITF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1197613	NM_001354604.2(MITF):c.1388C>A (p.Thr463Asn)	MITF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MITF	Definitive	Autosomal dominant	Tietz syndrome	19

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MITF	Orphanet:293822	MITF-related melanoma and renal cell carcinoma predisposition syndrome
MITF	Orphanet:319298	Papillary renal cell carcinoma
MITF	Orphanet:404511	Clear cell papillary renal cell carcinoma
MITF	Orphanet:42665	Tietz syndrome
MITF	Orphanet:618	Familial melanoma
MITF	Orphanet:895	Waardenburg syndrome type 2
MITF	Orphanet:897	Waardenburg-Shah syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MITF	HGNC:7105	ENSG00000187098	O75030	Microphthalmia-associated transcription factor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MITF	Microphthalmia-associated transcription factor	Transcription factor that acts as a master regulator of melanocyte survival and differentiation as well as melanosome biogenesis.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MITF	Transcription factor	no		bHLH_dom, MiT/TFE_C, MiT/TFE_N

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
pigmented layer of retina	1
retina	1
skeletal muscle tissue of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MITF	293	ubiquitous	marker	pigmented layer of retina, retina, skeletal muscle tissue of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MITF	2,908

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MITF	O75030	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of MITF-M dependent genes involved in metabolism	1	3806.7×	0.003	MITF
Regulation of MITF-M dependent genes involved in invasion	1	2855.0×	0.003	MITF
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	1631.4×	0.003	MITF
Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition	1	878.5×	0.004	MITF
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	1	671.8×	0.004	MITF
Regulation of MITF-M-dependent genes involved in apoptosis	1	634.4×	0.004	MITF
SUMOylation of transcription factors	1	571.0×	0.004	MITF
Regulation of MITF-M-dependent genes involved in cell cycle and proliferation	1	571.0×	0.004	MITF
Regulation of MITF-M-dependent genes involved in pigmentation	1	265.6×	0.007	MITF
SUMO E3 ligases SUMOylate target proteins	1	178.4×	0.008	MITF
Transcriptional and post-translational regulation of MITF-M expression and activity	1	178.4×	0.008	MITF
SUMOylation	1	163.1×	0.008	MITF
MITF-M-regulated melanocyte development	1	114.2×	0.011	MITF
Post-translational protein modification	1	19.2×	0.060	MITF
Developmental Biology	1	14.5×	0.074	MITF
Metabolism of proteins	1	12.4×	0.081	MITF

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
melanocyte apoptotic process	1	8426.0×	0.001	MITF
regulation of RNA biosynthetic process	1	8426.0×	0.001	MITF
positive regulation of DNA-templated transcription initiation	1	1872.4×	0.003	MITF
regulation of osteoclast differentiation	1	1532.0×	0.003	MITF
bone remodeling	1	936.2×	0.004	MITF
melanocyte differentiation	1	802.5×	0.004	MITF
camera-type eye development	1	358.6×	0.007	MITF
osteoclast differentiation	1	343.9×	0.007	MITF
cell fate commitment	1	295.6×	0.008	MITF
regulation of cell population proliferation	1	115.4×	0.015	MITF
protein-containing complex assembly	1	113.9×	0.015	MITF
negative regulation of cell migration	1	111.6×	0.015	MITF
Wnt signaling pathway	1	99.7×	0.015	MITF
positive regulation of gene expression	1	38.7×	0.037	MITF
negative regulation of apoptotic process	1	34.8×	0.038	MITF
regulation of DNA-templated transcription	1	31.6×	0.040	MITF
positive regulation of DNA-templated transcription	1	27.9×	0.042	MITF
negative regulation of transcription by RNA polymerase II	1	17.7×	0.063	MITF
positive regulation of transcription by RNA polymerase II	1	14.9×	0.071	MITF
regulation of transcription by RNA polymerase II	1	11.7×	0.086	MITF

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MITF	PERHEXILINE MALEATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MITF	3	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PERHEXILINE MALEATE	4	MITF
NIFUROXAZIDE	3	MITF
HOMIDIUM BROMIDE	2	MITF

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MITF	10	Functional:10

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

3 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PERHEXILINE MALEATE	4	MITF
NIFUROXAZIDE	3	MITF
HOMIDIUM BROMIDE	2	MITF

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MITF
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.