Singleton-Merten dysplasia

Summary

Singleton-Merten dysplasia (MONDO:0008429) is a disease with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		22	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Singleton-Merten dysplasia
Mondo ID	MONDO:0008429
MeSH	C537343
OMIM	182250
Orphanet	85191
ICD-11	1084593684
SNOMED CT	254114000
UMLS	C0432254
MedGen	98481
GARD	0000122
NORD	1718
Is cancer (heuristic)	no

Also known as: Merten-Singleton syndrome · SGMRT1 · Singleton Merten syndrome · singleton Merten syndrome · Singleton-Merten syndrome · SM syndrome · syndrome of widened medullary cavities of the metacarpals and phalanges, aortic calcification and abnormal dentition · widened medullary cavities of bone, aortic calcification, abnormal dentition, and muscular weakness

Data availability: 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary disorder of connective tissue › Singleton-Merten dysplasia

Related subtypes (86): Ewing sarcoma of bone, hereditary multiple osteochondromas, acroosteolysis dominant type, diaphyseal medullary stenosis-bone malignancy syndrome, cherubism, chondrocalcinosis 2, desmoid tumor, familial ossifying fibroma, hyperparathyroidism 1, hyperparathyroidism 2 with jaw tumors, uterine corpus leiomyoma, multiple symmetric lipomatosis, systemic lupus erythematosus, Ollier disease, Peyronie disease, Blau syndrome, inherited torticollis, arterial tortuosity syndrome, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, chondrosarcoma, trichohepatoenteric syndrome, brittle cornea syndrome, neonatal severe primary hyperparathyroidism, proteosome-associated autoinflammatory syndrome, chronic recurrent multifocal osteomyelitis, Pelger-Huet-like anomaly and episodic fever with abdominal pain, acquired polycythemia vera, autosomal recessive inherited pseudoxanthoma elasticum, X-linked reticulate pigmentary disorder, CHILD syndrome, ossification of the posterior longitudinal ligament of the spine, MASS syndrome, pyogenic arthritis-pyoderma gangrenosum-acne syndrome, Spondyloenchondrodysplasia with immune dysregulation, sweet syndrome, chronic myeloid leukemia, hyperparathyroidism 3, bone fragility with contractures, arterial rupture, and deafness, encephalocraniocutaneous lipomatosis, psoriasis 14, pustular, Maffucci syndrome, autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation, deficiency of adenosine deaminase 2, STING-associated vasculopathy with onset in infancy, autoimmune interstitial lung disease-arthritis syndrome, progeroid and marfanoid aspect-lipodystrophy syndrome, thrombocytopenia 6, multiple epiphyseal dysplasia due to collagen 9 anomaly, Ehlers-Danlos syndrome, kyphoscoliotic type 1, juvenile hyaline fibromatosis, IL10-related early-onset inflammatory bowel disease, infantile myofibromatosis, Marfan and Marfan-related disorder, neonatal inflammatory skin and bowel disease, familial isolated pituitary adenoma, inherited acute myeloid leukemia, hereditary periodic fever syndrome, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, aneurysmal bone cyst, familial chilblain lupus, pseudo-TORCH syndrome 2, Aicardi-Goutieres syndrome, jugulotympanic paraganglioma, type 2 collagenopathy, hyperparathyroidism 4, VEXAS syndrome, autoinflammatory syndrome, familial, Behcet-like, congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome, LAMA5-related multisystemic syndrome, EMILIN-1-related connective tissue disease, TREX1-related type 1 interferonopathy, RNASEH2B-related type 1 interferonopathy, RNASEH2C-related type 1 interferonopathy, RNASEH2A-related type 1 interferonopathy, SAMHD1-related type 1 interferonopathy, ADAR-related type 1 interferonopathy, IFIH1-related type 1 interferonopathy, RNU7-1-related type 1 interferonopathy, autoinflammatory disease, X-linked, autoinflammatory syndrome with immunodeficiency, autoinflammatory disease, systemic, with vasculitis, autoinflammatory disease, multisystem, with immune dysregulation, X-linked, arterial tortuosity-bone fragility syndrome, linkeropathy, hypermobility spectrum disorder, Sharpin-related autoinflammatory syndrome

Subtypes (2): Singleton-Merten syndrome 2, Singleton-Merten syndrome 1

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · 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
IFIH1	Strong	Autosomal dominant	Singleton-Merten syndrome 1	9
RIGI	Strong	Autosomal dominant	Singleton-Merten syndrome 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IFIH1	Orphanet:51	Aicardi-Goutières syndrome
IFIH1	Orphanet:689231	IFIH1-related hereditary spastic paraplegia
IFIH1	Orphanet:85191	Singleton-Merten dysplasia
RIGI	Orphanet:85191	Singleton-Merten dysplasia

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
IFIH1	HGNC:18873	ENSG00000115267	Q9BYX4	Interferon-induced helicase C domain-containing protein 1	gencc
RIGI	HGNC:19102	ENSG00000107201	O95786	Antiviral innate immune response receptor RIG-I	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IFIH1	Interferon-induced helicase C domain-containing protein 1	Innate immune receptor which acts as a cytoplasmic sensor of viral nucleic acids and plays a major role in sensing viral infection and in the activation of a cascade of antiviral responses including the induction of type I interferons and…
RIGI	Antiviral innate immune response receptor RIG-I	Innate immune receptor that senses cytoplasmic viral nucleic acids and activates a downstream signaling cascade leading to the production of type I interferons and pro-inflammatory cytokines.

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)
IFIH1	Other/Unknown	no		Helicase_C-like, Helicase/UvrB_N, DEATH-like_dom_sf
RIGI	Enzyme (other)	yes	3.6.4.13	Helicase_C-like, DEATH-like_dom_sf, DEAD/DEAH_box_helicase_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
jejunal mucosa	1
palpebral conjunctiva	1
parotid gland	1
buccal mucosa cell	1
tendon of biceps brachii	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IFIH1	276	ubiquitous	marker	palpebral conjunctiva, parotid gland, jejunal mucosa
RIGI	269	ubiquitous	marker	buccal mucosa cell, upper leg skin, tendon of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RIGI	6,038
IFIH1	3,706

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RIGI	O95786	44
IFIH1	Q9BYX4	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10	2	878.5×	1e-05	IFIH1, RIGI
TRAF3-dependent IRF activation pathway	2	761.3×	1e-05	IFIH1, RIGI
Modulation of host responses by IFN-stimulated genes	2	601.0×	1e-05	IFIH1, RIGI
TRAF6 mediated NF-kB activation	2	456.8×	2e-05	IFIH1, RIGI
TRAF6 mediated IRF7 activation	2	380.7×	2e-05	IFIH1, RIGI
Negative regulators of DDX58/IFIH1 signaling	2	326.3×	2e-05	IFIH1, RIGI
Evasion by RSV of host interferon responses	2	326.3×	2e-05	IFIH1, RIGI
Ovarian tumor domain proteases	2	278.5×	2e-05	IFIH1, RIGI
SARS-CoV-1 activates/modulates innate immune responses	2	271.9×	2e-05	IFIH1, RIGI
DDX58/IFIH1-mediated induction of interferon-alpha/beta	2	253.8×	2e-05	IFIH1, RIGI
SARS-CoV-2 activates/modulates innate and adaptive immune responses	2	89.2×	2e-04	IFIH1, RIGI
Ub-specific processing proteases	2	53.1×	5e-04	IFIH1, RIGI
OAS antiviral response	1	634.4×	0.002	RIGI
Dengue virus activates/modulates innate and adaptive immune responses	1	167.9×	0.007	IFIH1
RSV-host interactions	1	78.2×	0.013	RIGI
ISG15 antiviral mechanism	1	75.1×	0.013	RIGI

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 type III interferon production	2	8426.0×	2e-07	IFIH1, RIGI
detection of virus	2	4213.0×	6e-07	IFIH1, RIGI
positive regulation of response to cytokine stimulus	2	2407.4×	1e-06	IFIH1, RIGI
cellular response to exogenous dsRNA	2	1053.2×	6e-06	IFIH1, RIGI
cytoplasmic pattern recognition receptor signaling pathway	2	887.0×	7e-06	IFIH1, RIGI
positive regulation of interferon-alpha production	2	648.1×	1e-05	IFIH1, RIGI
positive regulation of interferon-beta production	2	391.9×	3e-05	IFIH1, RIGI
antiviral innate immune response	2	227.7×	7e-05	IFIH1, RIGI
positive regulation of interleukin-6 production	2	166.8×	1e-04	IFIH1, RIGI
positive regulation of tumor necrosis factor production	2	153.2×	1e-04	IFIH1, RIGI
response to virus	2	144.0×	1e-04	IFIH1, RIGI
defense response to virus	2	69.3×	5e-04	IFIH1, RIGI
MDA-5 signaling pathway	1	2106.5×	0.001	IFIH1
positive regulation of myeloid dendritic cell cytokine production	1	1404.3×	0.001	RIGI
RIG-I signaling pathway	1	1203.7×	0.002	RIGI
innate immune response	2	33.6×	0.002	IFIH1, RIGI
positive regulation of granulocyte macrophage colony-stimulating factor production	1	495.6×	0.003	RIGI
protein complex oligomerization	1	337.0×	0.005	IFIH1
positive regulation of defense response to virus by host	1	263.3×	0.006	RIGI
response to exogenous dsRNA	1	263.3×	0.006	RIGI
negative regulation of viral genome replication	1	187.2×	0.007	IFIH1
type I interferon-mediated signaling pathway	1	172.0×	0.008	IFIH1
protein sumoylation	1	162.0×	0.008	IFIH1
positive regulation of interleukin-8 production	1	122.1×	0.010	RIGI
cellular response to virus	1	100.3×	0.012	IFIH1
regulation of cell migration	1	78.8×	0.014	RIGI
gene expression	1	39.9×	0.027	RIGI
positive regulation of gene expression	1	19.4×	0.053	RIGI
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	RIGI

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IFIH1	0	0
RIGI	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
IFIH1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RIGI	3.6.4.13	RNA helicase

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

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	RIGI
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	IFIH1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
IFIH1	1	—
RIGI	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05204771	Not specified	COMPLETED	Prenatal US Assessment of Superior Mesenteric Vessels for Digestive Rotation