goiter, multinodular 1, with or without Sertoli-Leydig cell tumors

Summary

goiter, multinodular 1, with or without Sertoli-Leydig cell tumors (MONDO:0007681) is a disease with 2 cohort genes and 2 clinical trials.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 2
• ClinVar variants: 124
• Phenotypes (HPO): 14
• Clinical trials: 2

Clinical features

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0005987	Multinodular goiter	Obligate (100%)
HP:0002671	Basal cell carcinoma	Frequent (30-79%)
HP:0005584	Renal cell carcinoma	Frequent (30-79%)
HP:0100528	Pleuropulmonary blastoma	Frequent (30-79%)
HP:0100615	Ovarian neoplasm	Frequent (30-79%)
HP:0100617	Testicular seminoma	Frequent (30-79%)
HP:0100619	Sertoli cell neoplasm	Frequent (30-79%)
HP:0200063	Colorectal polyposis	Frequent (30-79%)
HP:0000836	Hyperthyroidism	Excluded (0%)
HP:0002890	Thyroid carcinoma	Very rare (<1-4%)
HP:0006779	Alveolar rhabdomyosarcoma	Very rare (<1-4%)
HP:0007129	Cerebellar medulloblastoma	Very rare (<1-4%)
HP:0030071	Medulloepithelioma	Very rare (<1-4%)
HP:0030434	Pilomatrixoma	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	goiter, multinodular 1, with or without Sertoli-Leydig cell tumors
Mondo ID	MONDO:0007681
MeSH	C562732
OMIM	138800
Orphanet	276399
SNOMED CT	267369002
UMLS	C0302859
MedGen	86230
GARD	0017278
Is cancer (heuristic)	no

Also known as: euthyroid goiter · euthyroid goitre · familial MNG · FMNG · goiter, multinodular 1, with or without Sertoli-Leydig cell tumors · goiter, nontoxic, with Intrathyroidal calcification · MNG1 · multinodular goiter, adolescent · simple goiter · simple goitre

Data availability: 124 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › multinodular goiter › goiter, multinodular 1, with or without Sertoli-Leydig cell tumors

Related subtypes (2): goiter, multinodular 2, goiter, multinodular 3

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

124 retrieved; paginated sample, class counts are floors:

54 uncertain significance, 18 conflicting classifications of pathogenicity, 12 benign/likely benign, 12 pathogenic, 11 likely benign, 10 likely pathogenic, 6 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1698845	NM_177438.3(DICER1):c.712del (p.Thr238fs)	DICER1	Pathogenic	criteria provided, single submitter
2039665	NM_177438.3(DICER1):c.5428del (p.Asp1810fs)	DICER1	Pathogenic	criteria provided, multiple submitters, no conflicts
254297	NM_177438.3(DICER1):c.1870C>T (p.Arg624Ter)	DICER1	Pathogenic	criteria provided, multiple submitters, no conflicts
254301	NM_177438.3(DICER1):c.1966C>T (p.Arg656Ter)	DICER1	Pathogenic	criteria provided, multiple submitters, no conflicts
254303	NM_177438.3(DICER1):c.2062C>T (p.Arg688Ter)	DICER1	Pathogenic	criteria provided, multiple submitters, no conflicts
254349	NM_177438.3(DICER1):c.5394del (p.Glu1799fs)	DICER1	Pathogenic	criteria provided, multiple submitters, no conflicts
30562	NM_177438.3(DICER1):c.5477C>A (p.Ser1826Ter)	DICER1	Pathogenic	criteria provided, single submitter
30564	NM_177438.3(DICER1):c.2805-1G>T	DICER1	Pathogenic	criteria provided, single submitter
3893094	NM_177438.3(DICER1):c.5446dup (p.Ala1816fs)	DICER1	Pathogenic	criteria provided, multiple submitters, no conflicts
3893095	NM_177438.3(DICER1):c.2518_2519del (p.Leu840fs)	DICER1	Pathogenic	criteria provided, multiple submitters, no conflicts
412119	NM_177438.3(DICER1):c.5441C>T (p.Ser1814Leu)	DICER1	Pathogenic	reviewed by expert panel
574777	NM_177438.3(DICER1):c.904-1G>C	DICER1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
997605	NM_177438.3(DICER1):c.2157dup (p.Val720fs)	DICER1	Pathogenic	criteria provided, single submitter
1687567	NM_177438.3(DICER1):c.5135dup (p.Leu1712fs)	DICER1	Likely pathogenic	reviewed by expert panel
1791218	NM_177438.3(DICER1):c.2436+1dup	DICER1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2020385	NM_177438.3(DICER1):c.3093+1G>A	DICER1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2692308	NM_177438.3(DICER1):c.4849del (p.Leu1617fs)	DICER1	Likely pathogenic	criteria provided, single submitter
30563	NM_177438.3(DICER1):c.873_877del (p.Glu292fs)	DICER1	Likely pathogenic	reviewed by expert panel
30565	NM_177438.3(DICER1):c.2457C>G (p.Tyr819Ter)	DICER1	Likely pathogenic	criteria provided, single submitter
30566	NM_177438.3(DICER1):c.2516C>T (p.Ser839Phe)	DICER1	Likely pathogenic	reviewed by expert panel
4086268	NM_177438.3(DICER1):c.2988-3C>G	DICER1	Likely pathogenic	criteria provided, single submitter
690474	NM_177438.3(DICER1):c.3988del (p.Tyr1330fs)	DICER1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
929411	NM_177438.3(DICER1):c.2685dup (p.Phe896fs)	DICER1	Likely pathogenic	reviewed by expert panel
1008871	NM_177438.3(DICER1):c.2510T>C (p.Met837Thr)	DICER1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1319726	NM_177438.3(DICER1):c.438+11T>C	DICER1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1407132	NM_177438.3(DICER1):c.1377-18T>A	DICER1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242064	NM_177438.3(DICER1):c.248A>G (p.Tyr83Cys)	DICER1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242090	NM_177438.3(DICER1):c.3674A>G (p.Tyr1225Cys)	DICER1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242126	NM_177438.3(DICER1):c.4901T>C (p.Leu1634Ser)	DICER1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242140	NM_177438.3(DICER1):c.5527+7T>A	DICER1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 8 · 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
KEAP1	Supportive	Autosomal dominant	goiter, multinodular 1, with or without Sertoli-Leydig cell tumors

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KEAP1	Orphanet:276399	Familial multinodular goiter
DICER1	Orphanet:276399	Familial multinodular goiter
DICER1	Orphanet:284343	DICER1 tumor-predisposition syndrome
DICER1	Orphanet:404476	Global developmental delay-lung cysts-overgrowth-Wilms tumor syndrome
DICER1	Orphanet:99757	Embryonal rhabdomyosarcoma
DICER1	Orphanet:99914	Gynandroblastoma
DICER1	Orphanet:99915	Malignant granulosa cell tumor of the ovary
DICER1	Orphanet:99916	Malignant Sertoli-Leydig cell tumor of the ovary

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KEAP1	HGNC:23177	ENSG00000079999	Q14145	Kelch-like ECH-associated protein 1	gencc
DICER1	HGNC:17098	ENSG00000100697	Q9UPY3	Endoribonuclease Dicer	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KEAP1	Kelch-like ECH-associated protein 1	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that regulates the response to oxidative stress by targeting NFE2L2/NRF2 for ubiquitination.
DICER1	Endoribonuclease Dicer	Double-stranded RNA (dsRNA) endoribonuclease playing a central role in short dsRNA-mediated post-transcriptional gene silencing.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KEAP1	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
DICER1	Enzyme (other)	yes	3.1.26.3	RNase_III_dom, Helicase_C-like, PAZ_dom

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
hindlimb stylopod muscle	1
muscle of leg	1
caput epididymis	1
cauda epididymis	1
tongue squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KEAP1	294	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, muscle of leg
DICER1	295	ubiquitous	marker	cauda epididymis, caput epididymis, tongue squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DICER1	8,268
KEAP1	5,022

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KEAP1	Q14145	122
DICER1	Q9UPY3	21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
tRNA-derived small RNA (tsRNA or tRNA-related fragment, tRF) biogenesis	1	1903.3×	0.013	DICER1
Small interfering RNA (siRNA) biogenesis	1	571.0×	0.021	DICER1
Regulation of MITF-M-dependent genes involved in apoptosis	1	317.2×	0.024	DICER1
MicroRNA (miRNA) biogenesis	1	228.4×	0.024	DICER1
Nuclear events mediated by NFE2L2	1	167.9×	0.024	KEAP1
M-decay: degradation of maternal mRNAs by maternally stored factors	1	163.1×	0.024	DICER1
Cellular response to chemical stress	1	71.4×	0.042	KEAP1
Deubiquitination	1	62.1×	0.042	KEAP1
KEAP1-NFE2L2 pathway	1	60.1×	0.042	KEAP1
Potential therapeutics for SARS	1	57.1×	0.042	KEAP1
Class I MHC mediated antigen processing & presentation	1	35.0×	0.062	KEAP1
SARS-CoV Infections	1	27.7×	0.069	KEAP1
Ub-specific processing proteases	1	26.6×	0.069	KEAP1
Neddylation	1	23.7×	0.072	KEAP1
Antigen processing: Ubiquitination & Proteasome degradation	1	18.6×	0.080	KEAP1
Cellular responses to stress	1	18.4×	0.080	KEAP1
Cellular responses to stimuli	1	15.7×	0.083	KEAP1
Viral Infection Pathways	1	15.4×	0.083	KEAP1
Adaptive Immune System	1	14.9×	0.083	KEAP1
Infectious disease	1	12.4×	0.095	KEAP1
Post-translational protein modification	1	9.6×	0.116	KEAP1
Disease	1	6.5×	0.155	KEAP1
Immune System	1	6.5×	0.155	KEAP1
Metabolism of proteins	1	6.2×	0.155	KEAP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of Schwann cell differentiation	1	4213.0×	0.003	DICER1
peripheral nervous system myelin formation	1	2808.7×	0.003	DICER1
global gene silencing by mRNA cleavage	1	2808.7×	0.003	DICER1
regulation of epidermal cell differentiation	1	2106.5×	0.003	KEAP1
tRNA decay	1	1685.2×	0.003	DICER1
negative regulation of Schwann cell proliferation	1	1203.7×	0.003	DICER1
negative regulation of response to oxidative stress	1	1203.7×	0.003	KEAP1
siRNA processing	1	936.2×	0.004	DICER1
RISC complex assembly	1	766.0×	0.004	DICER1
miRNA metabolic process	1	702.2×	0.004	DICER1
apoptotic DNA fragmentation	1	601.9×	0.004	DICER1
pre-miRNA processing	1	561.7×	0.004	DICER1
miRNA processing	1	526.6×	0.004	DICER1
nerve development	1	468.1×	0.004	DICER1
positive regulation of myelination	1	383.0×	0.005	DICER1
cellular response to interleukin-4	1	324.1×	0.005	KEAP1
negative regulation of transcription by RNA polymerase II	2	17.7×	0.005	DICER1, KEAP1
negative regulation of tumor necrosis factor-mediated signaling pathway	1	227.7×	0.007	DICER1
neuron projection morphogenesis	1	138.1×	0.011	DICER1
negative regulation of tumor necrosis factor production	1	125.8×	0.011	DICER1
regulation of autophagy	1	120.4×	0.011	KEAP1
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	1	105.3×	0.012	KEAP1
cellular response to oxidative stress	1	77.3×	0.016	KEAP1
ubiquitin-dependent protein catabolic process	1	37.1×	0.031	KEAP1
in utero embryonic development	1	36.0×	0.031	KEAP1
negative regulation of gene expression	1	34.5×	0.031	DICER1
proteasome-mediated ubiquitin-dependent protein catabolic process	1	26.1×	0.039	KEAP1
protein ubiquitination	1	20.7×	0.048	KEAP1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
KEAP1	DUTASTERIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KEAP1	9	4
DICER1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DUTASTERIDE	4	KEAP1
KETOCONAZOLE	4	KEAP1
TOPOTECAN HYDROCHLORIDE	4	KEAP1
DIMETHYL FUMARATE	4	KEAP1
DOXORUBICIN HYDROCHLORIDE	4	KEAP1
ZAFIRLUKAST	4	KEAP1
DIPYRIDAMOLE	4	KEAP1
SULFORAPHANE	3	KEAP1
BARDOXOLONE	2	KEAP1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
KEAP1	537	Binding:535, Functional:1, ADMET:1
DICER1	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DICER1	3.1.26.3	ribonuclease III

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
KEAP1	537

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

9 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)
DUTASTERIDE	4	KEAP1
KETOCONAZOLE	4	KEAP1
TOPOTECAN HYDROCHLORIDE	4	KEAP1
DIMETHYL FUMARATE	4	KEAP1
DOXORUBICIN HYDROCHLORIDE	4	KEAP1
ZAFIRLUKAST	4	KEAP1
DIPYRIDAMOLE	4	KEAP1
SULFORAPHANE	3	KEAP1
BARDOXOLONE	2	KEAP1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KEAP1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	DICER1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
DICER1	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04411290	Not specified	UNKNOWN	Malignancy Predictors, Bethesda and TI-RADS Scores Correlated With Final Histopathology in Thyroid Diseases
NCT05774535	Not specified	WITHDRAWN	Prospective, Observational Study on the Carotid Intima-media Thickness in Patients Undergoing Thyroid Surgery