Wolfram-like syndrome

Summary

Wolfram-like syndrome (MONDO:0013673) is a disease caused by WFS1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: WFS1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 483
• Phenotypes (HPO): 22

Clinical features

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0000648	Optic atrophy	Very frequent (80-99%)
HP:0000709	Psychosis	Very frequent (80-99%)
HP:0000716	Depression	Very frequent (80-99%)
HP:0000726	Dementia	Very frequent (80-99%)
HP:0000729	Autistic behavior	Very frequent (80-99%)
HP:0000739	Anxiety	Very frequent (80-99%)
HP:0000819	Diabetes mellitus	Very frequent (80-99%)
HP:0000026	Male hypogonadism	Frequent (30-79%)
HP:0000377	Abnormal pinna morphology	Frequent (30-79%)
HP:0000501	Glaucoma	Frequent (30-79%)
HP:0000823	Delayed puberty	Frequent (30-79%)
HP:0000863	Central diabetes insipidus	Frequent (30-79%)
HP:0001952	Glucose intolerance	Frequent (30-79%)
HP:0002073	Progressive cerebellar ataxia	Frequent (30-79%)
HP:0002579	Gastrointestinal dysmotility	Frequent (30-79%)
HP:0003477	Peripheral axonal neuropathy	Frequent (30-79%)
HP:0008193	Primary gonadal insufficiency	Frequent (30-79%)
HP:0008527	Congenital sensorineural hearing impairment	Frequent (30-79%)
HP:0010935	Abnormality of the upper urinary tract	Frequent (30-79%)
HP:0000821	Hypothyroidism	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0008850	Severe postnatal growth retardation	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Wolfram-like syndrome
Mondo ID	MONDO:0013673
MeSH	C565631
OMIM	614296
Orphanet	411590
DOID	DOID:0080584
SNOMED CT	734022008
UMLS	C3280358
MedGen	481988
GARD	0017683
Is cancer (heuristic)	no

Also known as: WFSL · Wolfram-like syndrome · Wolfram-like syndrome, autosomal dominant

Data availability: 483 ClinVar variants · 8 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › Wolfram-like syndrome

Related subtypes (47): autoimmune disorder of endocrine system, parathyroid gland disorder, endocrine gland neoplasm, gonadal disorder, pancreas disorder, thyroid gland disorder, pituitary gland disorder, thymus gland disorder, liver disorder, adrenal gland disorder, hyperinsulinemic hypoglycemia, non-neoplastic bile duct disorder, endocrine tuberculosis, campomelic dysplasia, polycystic ovary syndrome, dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome, hypohidrotic ectodermal dysplasia-hypothyroidism-ciliary dyskinesia syndrome, genito-palato-cardiac syndrome, hypoinsulinemic hypoglycemia and body hemihypertrophy, Bamforth-Lazarus syndrome, blepharophimosis - intellectual disability syndrome, SBBYS type, hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism, estrogen resistance syndrome, short stature, microcephaly, and endocrine dysfunction, polyendocrinopathy, pituitary deficiency, hereditary endocrine growth disease, diencephalic syndrome, muscular pseudohypertrophy-hypothyroidism syndrome, neonatal iodine exposure, disorders of vitamin D metabolism, rapid-onset childhood obesity-hypothalamic dysfunction-hypoventilation-autonomic dysregulation syndrome, duplication of the pituitary gland, familial hypocalciuric hypercalcemia, hypothalamic adipsic hypernatraemia syndrome, Leydig cell hypoplasia, inherited obesity, beta thalassemia, thyroid hormone metabolism, abnormal, neuroendocrine disorder, NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction, parneoplastic endocrine syndrome, 17,20-lyase deficiency, isolated, 17-alpha-hydroxylase/17,20-lyase deficiency, combined complete, 17-alpha-hydroxylase/17,20-lyase deficiency, combined partial, disorder of GNAS inactivation, acquired hypothalamic obesity

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

483 retrieved; paginated sample, class counts are floors:

257 uncertain significance, 84 conflicting classifications of pathogenicity, 33 pathogenic/likely pathogenic, 33 benign/likely benign, 30 likely benign, 21 uncertain significance/uncertain risk allele, 12 pathogenic, 12 likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012716	NM_006005.3(WFS1):c.1096C>T (p.Gln366Ter)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075961	NM_006005.3(WFS1):c.9dup (p.Asn4fs)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179030	NM_006005.3(WFS1):c.76C>T (p.Arg26Ter)	WFS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1179097	NM_006005.3(WFS1):c.1956C>G (p.Tyr652Ter)	WFS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1179192	NM_006005.3(WFS1):c.2293del (p.Cys765fs)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1205588	NM_006005.3(WFS1):c.1549del (p.Arg517fs)	WFS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1264331	NM_006005.3(WFS1):c.387G>A (p.Trp129Ter)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1298955	NM_006005.3(WFS1):c.1543TTC[1] (p.Phe516del)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1328696	NM_006005.3(WFS1):c.2206G>A (p.Gly736Ser)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453842	NM_006005.3(WFS1):c.1525_1539del (p.Val509_Tyr513del)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455530	NM_006005.3(WFS1):c.1558C>T (p.Gln520Ter)	WFS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1456380	NM_006005.3(WFS1):c.1619G>A (p.Trp540Ter)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458000	NM_006005.3(WFS1):c.1234_1237del (p.Val412fs)	WFS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1458815	NM_006005.3(WFS1):c.1611_1624del (p.Cys537_Glu542delinsTer)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189251	NM_006005.3(WFS1):c.124C>T (p.Arg42Ter)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
198835	NM_006005.3(WFS1):c.1672C>T (p.Arg558Cys)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
209207	NM_006005.3(WFS1):c.2648_2651del (p.Phe883fs)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
212612	NM_006005.3(WFS1):c.1692CCTCTT[1] (p.565LF[1])	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215376	NM_006005.3(WFS1):c.505G>A (p.Glu169Lys)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215378	NM_006005.3(WFS1):c.631G>A (p.Asp211Asn)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215399	NM_006005.3(WFS1):c.2254G>T (p.Glu752Ter)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215405	NM_006005.3(WFS1):c.911_914dup (p.Asp305_Met306insTer)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215406	NM_006005.3(WFS1):c.1243_1245del (p.Val415del)	WFS1	Pathogenic	criteria provided, multiple submitters, no conflicts
215409	NM_006005.3(WFS1):c.2643_2644del (p.Phe883fs)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215413	NM_006005.3(WFS1):c.2425G>A (p.Glu809Lys)	WFS1	Pathogenic	criteria provided, multiple submitters, no conflicts
2193625	NM_006005.3(WFS1):c.559C>T (p.Leu187Phe)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2203519	NM_006005.3(WFS1):c.1523_1524del (p.Tyr508fs)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2203523	NM_006005.3(WFS1):c.1628T>G (p.Leu543Arg)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2418916	NM_006005.3(WFS1):c.643C>T (p.Gln215Ter)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2734648	NM_006005.3(WFS1):c.2314_2315insT (p.Arg772fs)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 4 · 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
WFS1	Definitive	Autosomal dominant	Wolfram-like syndrome	19

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WFS1	Orphanet:3463	Wolfram syndrome
WFS1	Orphanet:411590	Wolfram-like syndrome
WFS1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
WFS1	Orphanet:98991	Early-onset nuclear cataract

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
WFS1	HGNC:12762	ENSG00000109501	O76024	Wolframin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WFS1	Wolframin	Participates in the regulation of cellular Ca(2+) homeostasis, at least partly, by modulating the filling state of the endoplasmic reticulum Ca(2+) store.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WFS1	Other/Unknown	no		TPR-like_helical_dom_sf, Wolframin, Wolframin_fam

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
body of uterus	1
left ovary	1
right ovary	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WFS1	280	ubiquitous	marker	right ovary, left ovary, body of uterus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WFS1	3,409

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
WFS1	O76024	73.85

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
XBP1(S) activates chaperone genes	1	215.5×	0.012	WFS1
Post-translational protein phosphorylation	1	100.2×	0.012	WFS1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.012	WFS1

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
negative regulation of ATF6-mediated unfolded protein response	1	8426.0×	0.003	WFS1
positive regulation of growth	1	4213.0×	0.003	WFS1
negative regulation of response to endoplasmic reticulum stress	1	2407.4×	0.003	WFS1
negative regulation of type B pancreatic cell apoptotic process	1	2106.5×	0.003	WFS1
olfactory behavior	1	1872.4×	0.003	WFS1
ER overload response	1	1532.0×	0.003	WFS1
nervous system process	1	1203.7×	0.003	WFS1
positive regulation of protein metabolic process	1	991.3×	0.003	WFS1
positive regulation of ERAD pathway	1	887.0×	0.003	WFS1
endoplasmic reticulum calcium ion homeostasis	1	842.6×	0.003	WFS1
negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	1	842.6×	0.003	WFS1
negative regulation of programmed cell death	1	732.7×	0.003	WFS1
pancreas development	1	674.1×	0.003	WFS1
positive regulation of calcium ion transport	1	581.1×	0.004	WFS1
renal water homeostasis	1	510.7×	0.004	WFS1
calcium ion homeostasis	1	443.5×	0.004	WFS1
intrinsic apoptotic signaling pathway	1	358.6×	0.005	WFS1
endoplasmic reticulum unfolded protein response	1	295.6×	0.006	WFS1
positive regulation of protein ubiquitination	1	213.3×	0.007	WFS1
negative regulation of translation	1	195.9×	0.008	WFS1
ERAD pathway	1	181.2×	0.008	WFS1
response to endoplasmic reticulum stress	1	166.8×	0.008	WFS1
kidney development	1	140.4×	0.009	WFS1
glucose homeostasis	1	130.6×	0.010	WFS1
negative regulation of neuron apoptotic process	1	110.9×	0.011	WFS1
sensory perception of sound	1	100.9×	0.011	WFS1
visual perception	1	79.5×	0.014	WFS1
protein stabilization	1	66.9×	0.016	WFS1
negative regulation of apoptotic process	1	34.8×	0.030	WFS1
negative regulation of transcription by RNA polymerase II	1	17.7×	0.056	WFS1

Therapeutics

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
WFS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
WFS1	1	Binding:1

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	1	WFS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
WFS1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.