Neonatal diabetes mellitus with congenital hypothyroidism

Summary

Neonatal diabetes mellitus with congenital hypothyroidism (MONDO:0012436) is a disease caused by variants in GLIS3 and IL2RA, with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal genes: GLIS3 (GenCC Definitive), IL2RA (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 431

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	neonatal diabetes mellitus with congenital hypothyroidism
Mondo ID	MONDO:0012436
MeSH	C565705
OMIM	610199
Orphanet	79118
DOID	DOID:0060638
UMLS	C1857775
MedGen	347541
GARD	0016699
Is cancer (heuristic)	no

Also known as: NDH · NDH syndrome · neonatal diabetes mellitus with congenital hypothyroidism

Data availability: 431 ClinVar variants · 7 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › pancreas disorder › endocrine pancreas disorder › diabetes mellitus › monogenic diabetes › neonatal diabetes mellitus › neonatal diabetes mellitus with congenital hypothyroidism

Related subtypes (3): permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome, transient neonatal diabetes mellitus, permanent neonatal diabetes mellitus

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

431 retrieved; paginated sample, class counts are floors:

294 uncertain significance, 45 conflicting classifications of pathogenicity, 38 benign, 28 likely benign, 14 benign/likely benign, 7 likely pathogenic, 4 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1325	NM_001042413.2(GLIS3):c.2338dup (p.Arg780fs)	GLIS3	Pathogenic	no assertion criteria provided
253043	NM_001042413.2(GLIS3):c.1608C>G (p.Cys536Trp)	GLIS3	Pathogenic	no assertion criteria provided
253044	NM_001042413.2(GLIS3):c.1681C>T (p.His561Tyr)	GLIS3	Pathogenic	no assertion criteria provided
253045	NM_001042413.2(GLIS3):c.932del (p.Gly311fs)	GLIS3	Pathogenic	no assertion criteria provided
667376	NM_001042413.2(GLIS3):c.571_572dup (p.Leu191_Asn192insTer)	GLIS3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2502239	NM_001042413.2(GLIS3):c.122C>A (p.Ser41Ter)	GLIS3	Likely pathogenic	criteria provided, single submitter
3030919	NM_001042413.2(GLIS3):c.8del (p.Gly3fs)	GLIS3	Likely pathogenic	criteria provided, single submitter
3597403	NM_001042413.2(GLIS3):c.1435C>T (p.Gln479Ter)	GLIS3	Likely pathogenic	criteria provided, single submitter
3597413	NM_001042413.2(GLIS3):c.1237del (p.Val413fs)	GLIS3	Likely pathogenic	criteria provided, single submitter
3597439	NM_001042413.2(GLIS3):c.565del (p.Ala189fs)	GLIS3	Likely pathogenic	criteria provided, single submitter
3597452	NM_001042413.2(GLIS3):c.304C>T (p.Gln102Ter)	GLIS3	Likely pathogenic	criteria provided, single submitter
4291924	NM_001042413.2(GLIS3):c.2038C>T (p.Gln680Ter)	GLIS3-AS1	Likely pathogenic	criteria provided, single submitter
1030060	NM_001042413.2(GLIS3):c.94C>T (p.Arg32Ter)	GLIS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1309872	NM_001042413.2(GLIS3):c.1779C>T (p.Gly593=)	GLIS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1338204	NM_001042413.2(GLIS3):c.3G>A (p.Met1Ile)	GLIS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1908126	NM_001042413.2(GLIS3):c.1073G>T (p.Cys358Phe)	GLIS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1987447	NM_001042413.2(GLIS3):c.2473+13C>G	GLIS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2176488	NM_001042413.2(GLIS3):c.759C>T (p.Ser253=)	GLIS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
221954	NM_001042413.2(GLIS3):c.2710G>C (p.Gly904Arg)	GLIS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2462615	NM_001042413.2(GLIS3):c.122C>T (p.Ser41Leu)	GLIS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3597410	NM_001042413.2(GLIS3):c.1320C>G (p.Thr440=)	GLIS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3597431	NM_001042413.2(GLIS3):c.716A>G (p.Asn239Ser)	GLIS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
366954	NM_001042413.2(GLIS3):c.2323C>T (p.His775Tyr)	GLIS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
366958	NM_001042413.2(GLIS3):c.2060C>T (p.Ser687Phe)	GLIS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
366978	NM_001042413.2(GLIS3):c.1452G>A (p.Gln484=)	GLIS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
366979	NM_001042413.2(GLIS3):c.1368A>T (p.Pro456=)	GLIS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
366986	NM_001042413.2(GLIS3):c.1056G>C (p.Leu352=)	GLIS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
366987	NM_001042413.2(GLIS3):c.1044C>T (p.Tyr348=)	GLIS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
366990	NM_001042413.2(GLIS3):c.844C>G (p.Pro282Ala)	GLIS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
366992	NM_001042413.2(GLIS3):c.496C>G (p.Pro166Ala)	GLIS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · 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
GLIS3	Definitive	Autosomal recessive	neonatal diabetes mellitus with congenital hypothyroidism	7
IL2RA	Strong	Autosomal recessive	neonatal diabetes mellitus with congenital hypothyroidism	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLIS3	Orphanet:79118	Neonatal diabetes-congenital hypothyroidism-congenital glaucoma-hepatic fibrosis-polycystic kidneys syndrome
IL2RA	Orphanet:169100	Immunodeficiency due to CD25 deficiency
IL2RA	Orphanet:85408	Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis
IL2RA	Orphanet:85410	Oligoarticular juvenile idiopathic arthritis

Cohort genes → proteins

4 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GLIS3	HGNC:28510	ENSG00000107249	Q8NEA6	Zinc finger protein GLIS3	gencc,clinvar
IL2RA	HGNC:6008	ENSG00000134460	P01589	Interleukin-2 receptor subunit alpha	gencc
GLIS3-AS1	HGNC:28260	ENSG00000237009		GLIS3 antisense RNA 1	clinvar
GLIS3-AS2	HGNC:55796	ENSG00000228322		GLIS3 antisense RNA 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GLIS3	Zinc finger protein GLIS3	Acts both as a repressor and an activator of transcription.
IL2RA	Interleukin-2 receptor subunit alpha	Receptor for interleukin-2.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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
Complement	1	67.0×	0.045
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GLIS3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like
IL2RA	Complement	yes		Sushi_SCR_CCP_dom, IL-2_rcpt_alpha, Sushi/SCR/CCP_sf
GLIS3-AS1	Other/Unknown	no
GLIS3-AS2	Other/Unknown	no

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	2
buccal mucosa cell	1
epithelial cell of pancreas	1
pancreatic ductal cell	1
caecum	1
lymph node	1
vermiform appendix	1
colonic epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1
right uterine tube	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLIS3	213	ubiquitous	marker	buccal mucosa cell, epithelial cell of pancreas, pancreatic ductal cell
IL2RA	153	broad	marker	lymph node, vermiform appendix, caecum
GLIS3-AS1	127	tissue_specific	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, colonic epithelium
GLIS3-AS2	91		yes	primordial germ cell in gonad, stromal cell of endometrium, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IL2RA	2,557
GLIS3	1,717
GLIS3-AS1	0
GLIS3-AS2	0

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IL2RA	P01589	10

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GLIS3	Q8NEA6	49.95

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 4 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
RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)	1	1142.0×	0.002	IL2RA
Interleukin-2 signaling	1	951.7×	0.002	IL2RA
Interleukin receptor SHC signaling	1	407.9×	0.003	IL2RA
RAF/MAP kinase cascade	1	61.1×	0.016	IL2RA

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
regulation of T cell tolerance induction	1	8426.0×	0.002	IL2RA
regulation of CD4-positive, alpha-beta T cell proliferation	1	4213.0×	0.002	IL2RA
regulation of T cell homeostatic proliferation	1	2808.7×	0.002	IL2RA
activation-induced cell death of T cells	1	1203.7×	0.004	IL2RA
interleukin-2-mediated signaling pathway	1	1053.2×	0.004	IL2RA
activated T cell proliferation	1	936.2×	0.004	IL2RA
inflammatory response to antigenic stimulus	1	468.1×	0.006	IL2RA
positive regulation of activated T cell proliferation	1	337.0×	0.007	IL2RA
positive regulation of T cell differentiation	1	227.7×	0.010	IL2RA
negative regulation of T cell proliferation	1	165.2×	0.012	IL2RA
Notch signaling pathway	1	70.8×	0.024	IL2RA
negative regulation of inflammatory response	1	68.5×	0.024	IL2RA
transcription by RNA polymerase II	1	35.3×	0.043	GLIS3
cell surface receptor signaling pathway	1	32.0×	0.044	IL2RA
immune response	1	23.5×	0.056	IL2RA
inflammatory response	1	18.9×	0.065	IL2RA
apoptotic process	1	14.3×	0.081	IL2RA
negative regulation of transcription by RNA polymerase II	1	8.9×	0.122	GLIS3
positive regulation of transcription by RNA polymerase II	1	7.4×	0.137	GLIS3
regulation of transcription by RNA polymerase II	1	5.8×	0.164	GLIS3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GLIS3	0	0
IL2RA	0	0
GLIS3-AS1	0	0
GLIS3-AS2	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
IL2RA	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	IL2RA
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	GLIS3, GLIS3-AS1, GLIS3-AS2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GLIS3	0	—
IL2RA	2	—
GLIS3-AS1	0	—
GLIS3-AS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.