Meckel syndrome, type 1

Summary

Meckel syndrome, type 1 (MONDO:0009571) is a disease caused by MKS1 (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Causal gene: MKS1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 359
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Meckel syndrome, type 1
Mondo ID	MONDO:0009571
MeSH	C536133
OMIM	249000
DOID	DOID:0070115
UMLS	C3714506
MedGen	811346
GARD	0024681
Is cancer (heuristic)	no

Also known as: Dysencephalia splachnocystica · Dysencephalia Splanchnocystica · Gruber syndrome · Meckel Gruber syndrome · Meckel syndrome · Meckel syndrome caused by mutation in MKS1 · Meckel syndrome type1 · Meckel syndrome, type 1 · Meckel-Gruber syndrome · Meckel-Gruber syndrome, type 1 · Mes · MKS · MKS1 · MKS1 Meckel syndrome

Data availability: 359 ClinVar variants · 2 GenCC gene-disease records · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Meckel syndrome › Meckel syndrome, type 1

Related subtypes (13): NPHP3-related Meckel-like syndrome, Meckel syndrome, type 2, Meckel syndrome, type 3, Meckel syndrome, type 4, Meckel syndrome, type 5, Meckel syndrome, type 6, Meckel syndrome, type 8, Meckel syndrome, type 10, Meckel syndrome, type 9, Meckel syndrome, type 11, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, meckel syndrome 14, Meckel syndrome 13

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

359 retrieved; paginated sample, class counts are floors:

193 uncertain significance, 51 conflicting classifications of pathogenicity, 44 likely pathogenic, 32 pathogenic/likely pathogenic, 21 likely benign, 11 pathogenic, 5 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1389	NM_017777.4(MKS1):c.50_54dup (p.Asp19fs)	LOC130061271	Pathogenic	no assertion criteria provided
1390	NM_017777.4(MKS1):c.80+2T>C	LOC130061271	Pathogenic/Likely pathogenic	no assertion criteria provided
56625	NM_017777.4(MKS1):c.51_55dup (p.Asp19fs)	LOC130061271	Pathogenic	criteria provided, multiple submitters, no conflicts
955851	NM_017777.4(MKS1):c.79C>T (p.Arg27Ter)	LOC130061271	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066216	NM_017777.4(MKS1):c.1273+1G>C	MKS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073914	NM_017777.4(MKS1):c.1031C>G (p.Ser344Ter)	MKS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074274	NM_017777.4(MKS1):c.811del (p.His271fs)	MKS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1252059	NM_017777.4(MKS1):c.1126dup (p.Thr376fs)	MKS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1363964	NM_017777.4(MKS1):c.805dup (p.Ser269fs)	MKS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1379652	NM_017777.4(MKS1):c.658A>T (p.Lys220Ter)	MKS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1387955	NM_017777.4(MKS1):c.1071del (p.Cys358fs)	MKS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1391	NM_017777.4(MKS1):c.1024+1G>A	MKS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1431885	NM_017777.4(MKS1):c.515+2T>C	MKS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1456980	NM_017777.4(MKS1):c.191-1G>A	MKS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1725690	NM_017777.4(MKS1):c.1480C>T (p.Gln494Ter)	MKS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188334	NM_017777.4(MKS1):c.233T>G (p.Ile78Ser)	MKS1	Pathogenic	criteria provided, multiple submitters, no conflicts
188400	NM_017777.4(MKS1):c.1408-34_1408-6del	MKS1	Pathogenic	criteria provided, multiple submitters, no conflicts
191084	NM_017777.4(MKS1):c.417+1G>A	MKS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
194102	NM_017777.4(MKS1):c.1025-2A>C	MKS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1943755	NM_017777.4(MKS1):c.1024+1G>T	MKS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1949214	NM_017777.4(MKS1):c.812dup (p.His271fs)	MKS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2026409	NM_017777.4(MKS1):c.81_82del	MKS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2071903	NM_017777.4(MKS1):c.1074C>A (p.Cys358Ter)	MKS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
211503	NM_017777.4(MKS1):c.844C>T (p.Arg282Ter)	MKS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2160287	NM_017777.4(MKS1):c.1408-14A>G	MKS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217672	NM_017777.4(MKS1):c.1208C>T (p.Ser403Leu)	MKS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217677	NM_017777.4(MKS1):c.1115_1117del (p.Ser372del)	MKS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2196405	NM_017777.4(MKS1):c.149del (p.Asp50fs)	MKS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235405	NM_017777.4(MKS1):c.508C>T (p.Arg170Ter)	MKS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
266091	NM_017777.4(MKS1):c.261+2T>A	MKS1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 5 · 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
MKS1	Definitive	Autosomal recessive	Meckel syndrome, type 1	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MKS1	Orphanet:110	Bardet-Biedl syndrome
MKS1	Orphanet:220493	Joubert syndrome with ocular defect
MKS1	Orphanet:475	Isolated Joubert syndrome
MKS1	Orphanet:564	Meckel syndrome
TMEM107	Orphanet:564	Meckel syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MKS1	HGNC:7121	ENSG00000011143	Q9NXB0	Tectonic-like complex member MKS1	gencc,clinvar
TMEM107	HGNC:28128	ENSG00000179029	Q6UX40	Transmembrane protein 107	clinvar
HOXB-AS3	HGNC:40283	ENSG00000233101	C0HLZ6	HOXB-AS3 peptide	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MKS1	Tectonic-like complex member MKS1	Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes.
TMEM107	Transmembrane protein 107	Plays a role in cilia formation and embryonic patterning.
HOXB-AS3	HOXB-AS3 peptide	Blocks the binding of HNRNPA1 to the intronic sequences flanking exon 9 of the PKM gene by competitively binding to the HNRNPA1 RGG-box motif.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MKS1	Other/Unknown	no		C2_B9-type_dom
TMEM107	Other/Unknown	no		TMEM107
HOXB-AS3	Other/Unknown	no		HOXB-AS3

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right uterine tube	2
left ovary	1
olfactory segment of nasal mucosa	1
bronchial epithelial cell	1
bronchus	1
corpus epididymis	1
metanephros cortex	1
muscle layer of sigmoid colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MKS1	182	ubiquitous	marker	right uterine tube, olfactory segment of nasal mucosa, left ovary
TMEM107	240	ubiquitous	marker	bronchial epithelial cell, bronchus, right uterine tube
HOXB-AS3	158	broad	marker	corpus epididymis, muscle layer of sigmoid colon, metanephros cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MKS1	1,087
TMEM107	656
HOXB-AS3	0

Intra-cohort edges

A	B	Sources
MKS1	TMEM107	intact

Structural data

PDB: 0 · AlphaFold-only: 3 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMEM107	Q6UX40	94.21
MKS1	Q9NXB0	74.05
HOXB-AS3	C0HLZ6	60.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 3 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
Signaling by Hedgehog	1	184.2×	0.014	MKS1
Hedgehog ‘off’ state	1	178.4×	0.014	MKS1
Anchoring of the basal body to the plasma membrane	1	113.1×	0.014	MKS1
Cilium Assembly	1	108.8×	0.014	MKS1
Organelle biogenesis and maintenance	1	66.0×	0.018	MKS1
Signal Transduction	1	10.2×	0.098	MKS1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
embryonic digit morphogenesis	2	200.6×	5e-04	MKS1, TMEM107
non-motile cilium assembly	2	193.7×	5e-04	MKS1, TMEM107
smoothened signaling pathway involved in regulation of secondary heart field cardioblast proliferation	1	5617.3×	0.002	MKS1
detection of nodal flow	1	1872.4×	0.002	TMEM107
common bile duct development	1	1872.4×	0.002	MKS1
negative regulation of pre-miRNA processing	1	1872.4×	0.002	HOXB-AS3
cilium assembly	2	49.1×	0.002	MKS1, TMEM107
regulation of Wnt signaling pathway, planar cell polarity pathway	1	1123.5×	0.003	MKS1
neural tube patterning	1	936.2×	0.004	TMEM107
protein localization to ciliary transition zone	1	802.5×	0.004	TMEM107
craniofacial suture morphogenesis	1	561.7×	0.005	TMEM107
epithelial structure maintenance	1	401.2×	0.005	MKS1
head development	1	401.2×	0.005	MKS1
cardiac septum morphogenesis	1	401.2×	0.005	MKS1
inner ear receptor cell stereocilium organization	1	280.9×	0.007	MKS1
dorsal/ventral neural tube patterning	1	267.5×	0.007	MKS1
embryonic brain development	1	267.5×	0.007	MKS1
branching morphogenesis of an epithelial tube	1	244.2×	0.007	MKS1
regulation of smoothened signaling pathway	1	208.1×	0.008	MKS1
motile cilium assembly	1	193.7×	0.008	MKS1
regulation of canonical Wnt signaling pathway	1	181.2×	0.008	MKS1
embryonic skeletal system development	1	130.6×	0.010	MKS1
determination of left/right symmetry	1	85.1×	0.015	MKS1
roof of mouth development	1	82.6×	0.015	TMEM107
regulation of RNA splicing	1	73.0×	0.016	HOXB-AS3
neural tube closure	1	62.4×	0.018	MKS1
RNA splicing	1	29.4×	0.037	HOXB-AS3
regulation of gene expression	1	27.8×	0.038	TMEM107
mRNA processing	1	26.2×	0.039	HOXB-AS3
protein stabilization	1	22.3×	0.044	HOXB-AS3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MKS1	0	0
TMEM107	0	0
HOXB-AS3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	MKS1, TMEM107, HOXB-AS3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MKS1	0	—
TMEM107	0	—
HOXB-AS3	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
NCT01401998	Not specified	RECRUITING	ARPKD Database Study