Meckel syndrome, type 11

Summary

Meckel syndrome, type 11 (MONDO:0014164) is a disease caused by TMEM231 (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: TMEM231 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 452

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Meckel syndrome, type 11
Mondo ID	MONDO:0014164
OMIM	615397
UMLS	C3809352
MedGen	815682
GARD	0015957
Is cancer (heuristic)	no

Also known as: meckel syndrome 11 · Meckel syndrome caused by mutation in TMEM231 · Meckel syndrome, type 11 · MKS11 · TMEM231 Meckel syndrome

Data availability: 452 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Meckel syndrome › Meckel syndrome, type 11

Related subtypes (13): Meckel syndrome, type 1, 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, 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

452 retrieved; paginated sample, class counts are floors:

198 uncertain significance, 156 likely benign, 31 pathogenic, 27 conflicting classifications of pathogenicity, 13 likely pathogenic, 10 benign, 9 pathogenic/likely pathogenic, 8 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2423621	NC_000016.9:g.(?75512539)(75576601_?)del	CHST6	Pathogenic	criteria provided, single submitter
1456039	NM_001077418.3(TMEM231):c.140-3C>G	LOC130059440	Pathogenic	criteria provided, single submitter
2947948	NM_001077418.3(TMEM231):c.140-8dup	LOC130059440	Pathogenic	criteria provided, single submitter
4788994	NM_001077418.3(TMEM231):c.169del (p.Glu57fs)	LOC130059440	Pathogenic	criteria provided, single submitter
1028502	NM_001077418.3(TMEM231):c.248G>A (p.Trp83Ter)	TMEM231	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1192252	NM_001077418.3(TMEM231):c.438+1G>C	TMEM231	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1252091	NM_001077418.3(TMEM231):c.316G>A (p.Glu106Lys)	TMEM231	Pathogenic	no assertion criteria provided
1351746	NC_000016.9:g.(?75573892)(75690509_?)del	TMEM231	Pathogenic	criteria provided, single submitter
1362349	NM_001077418.3(TMEM231):c.284del (p.Asp95fs)	TMEM231	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1368287	NM_001077418.3(TMEM231):c.139+1del	TMEM231	Pathogenic	criteria provided, single submitter
1388711	NM_001077418.3(TMEM231):c.583-1_583delinsAG	TMEM231	Pathogenic	criteria provided, single submitter
1398946	NM_001077418.3(TMEM231):c.354dup (p.His119fs)	TMEM231	Pathogenic	criteria provided, single submitter
1418103	NC_000016.9:g.(?75573892)(75575373_?)del	TMEM231	Pathogenic	criteria provided, single submitter
1430979	NM_001077418.3(TMEM231):c.4G>A (p.Ala2Thr)	TMEM231	Pathogenic	criteria provided, single submitter
1448559	NM_001077418.3(TMEM231):c.535C>T (p.Gln179Ter)	TMEM231	Pathogenic	criteria provided, single submitter
1454613	NM_001077418.3(TMEM231):c.582+1G>A	TMEM231	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457752	NC_000016.9:g.(?75490611)(75576599_?)del	TMEM231	Pathogenic	criteria provided, single submitter
1458388	NM_001077418.3(TMEM231):c.124G>A (p.Ala42Thr)	TMEM231	Pathogenic	criteria provided, single submitter
1459430	NC_000016.9:g.(?75573892)(75579413_?)del	TMEM231	Pathogenic	criteria provided, single submitter
1802034	NM_001077418.3(TMEM231):c.544C>T (p.Gln182Ter)	TMEM231	Pathogenic	criteria provided, multiple submitters, no conflicts
1960880	NM_001077418.3(TMEM231):c.583-1_593delinsAGTATCTGTGAC	TMEM231	Pathogenic	criteria provided, single submitter
2054331	NM_001077418.3(TMEM231):c.-37G>A	TMEM231	Pathogenic	criteria provided, single submitter
2165068	NM_001077418.3(TMEM231):c.139+39_139+40del	TMEM231	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2423617	NC_000016.9:g.(?75589682)(75590169_?)del	TMEM231	Pathogenic	criteria provided, single submitter
2921947	NM_001077418.3(TMEM231):c.3_4insAGCTCTATGAGCTCATG (p.Ala2fs)	TMEM231	Pathogenic	criteria provided, single submitter
2934525	NM_001077418.3(TMEM231):c.140-9_140-8del	TMEM231	Pathogenic	criteria provided, single submitter
2941997	NM_001077418.3(TMEM231):c.33C>A (p.Val11=)	TMEM231	Pathogenic	criteria provided, single submitter
3243522	NC_000016.9:g.(?75579704)(75579872_?)del	TMEM231	Pathogenic	criteria provided, single submitter
3749689	NM_001077418.3(TMEM231):c.164_176dup (p.Thr60fs)	TMEM231	Pathogenic	criteria provided, single submitter
3756171	NM_001077418.3(TMEM231):c.379C>T (p.Gln127Ter)	TMEM231	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 6 · 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
TMEM231	Strong	Autosomal recessive	Meckel syndrome, type 11	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMEM231	Orphanet:2318	Joubert syndrome with oculorenal defect
TMEM231	Orphanet:2754	Orofaciodigital syndrome type 6
TMEM231	Orphanet:564	Meckel syndrome
DUOX2	Orphanet:226316	Genetic transient congenital hypothyroidism
DUOX2	Orphanet:95716	Familial thyroid dyshormonogenesis
CHST6	Orphanet:98969	Macular corneal dystrophy

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TMEM231	HGNC:37234	ENSG00000205084	Q9H6L2	Transmembrane protein 231	gencc,clinvar
DUOX2	HGNC:13273	ENSG00000140279	Q9NRD8	Dual oxidase 2	clinvar
ADAT1	HGNC:228	ENSG00000065457	Q9BUB4	tRNA-specific adenosine deaminase 1	clinvar
CHST6	HGNC:6938	ENSG00000183196	Q9GZX3	Carbohydrate sulfotransferase 6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMEM231	Transmembrane protein 231	Transmembrane 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.
DUOX2	Dual oxidase 2	Generates hydrogen peroxide which is required for the activity of thyroid peroxidase/TPO and lactoperoxidase/LPO.
ADAT1	tRNA-specific adenosine deaminase 1	Specifically deaminates adenosine-37 to inosine in tRNA-Ala.
CHST6	Carbohydrate sulfotransferase 6	Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the transfer of sulfate to position 6 of non-reducing N-acetylglucosamine (GlcNAc) residues of keratan.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · 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)	2	6.0×	0.074
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMEM231	Other/Unknown	no		TMEM231
DUOX2	Enzyme (other)	yes	1.6.3.1	EF_hand_dom, Haem_peroxidase_sf, EF-hand-dom_pair
ADAT1	Enzyme (other)	yes	3.5.4.34	A_deamin
CHST6	Other/Unknown	no		Sulfotransferase_dom, Carbohydrate_sulfotransferase, P-loop_NTPase

Expression context

Cohort genes with no expression data: 0.

4 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
bronchial epithelial cell	2
bronchus	2
nasal cavity epithelium	2
epithelium of bronchus	1
gall bladder	1
palpebral conjunctiva	1
left testis	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMEM231	257	ubiquitous	marker	bronchial epithelial cell, epithelium of bronchus, bronchus
DUOX2	191	tissue_specific	marker	gall bladder, nasal cavity epithelium, palpebral conjunctiva
ADAT1	255	ubiquitous	marker	oocyte, secondary oocyte, left testis
CHST6	162	broad	marker	bronchial epithelial cell, bronchus, nasal cavity epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DUOX2	1,639
TMEM231	858
ADAT1	596
CHST6	523

Structural data

PDB: 0 · AlphaFold-only: 4 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CHST6	Q9GZX3	90.66
TMEM231	Q9H6L2	88.65
DUOX2	Q9NRD8	84.37
ADAT1	Q9BUB4	82.40

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective CHST6 causes MCDC1	1	475.8×	0.011	CHST6
Thyroxine biosynthesis	1	271.9×	0.011	DUOX2
Keratan sulfate biosynthesis	1	126.9×	0.012	CHST6
tRNA processing	1	119.0×	0.012	ADAT1
tRNA modification in the nucleus and cytosol	1	97.6×	0.012	ADAT1
Metabolism of RNA	1	13.9×	0.070	ADAT1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cuticle development	1	1404.3×	0.012	DUOX2
neuroepithelial cell differentiation	1	383.0×	0.012	TMEM231
hormone biosynthetic process	1	351.1×	0.012	DUOX2
hydrogen peroxide biosynthetic process	1	351.1×	0.012	DUOX2
N-acetylglucosamine metabolic process	1	300.9×	0.012	CHST6
vasculature development	1	280.9×	0.012	TMEM231
sulfur compound metabolic process	1	280.9×	0.012	CHST6
thyroid hormone generation	1	247.8×	0.012	DUOX2
keratan sulfate proteoglycan biosynthetic process	1	247.8×	0.012	CHST6
tRNA processing	1	210.7×	0.012	ADAT1
positive regulation of cell motility	1	191.5×	0.012	DUOX2
superoxide anion generation	1	168.5×	0.012	DUOX2
hydrogen peroxide catabolic process	1	168.5×	0.012	DUOX2
positive regulation of wound healing	1	131.7×	0.014	DUOX2
response to cAMP	1	127.7×	0.014	DUOX2
camera-type eye development	1	89.6×	0.018	TMEM231
embryonic digit morphogenesis	1	75.2×	0.020	TMEM231
defense response	1	54.0×	0.026	DUOX2
regulation of protein localization	1	51.4×	0.026	TMEM231
smoothened signaling pathway	1	45.3×	0.028	TMEM231
response to virus	1	36.0×	0.033	DUOX2
carbohydrate metabolic process	1	34.0×	0.033	CHST6
response to oxidative stress	1	32.7×	0.033	DUOX2
cytokine-mediated signaling pathway	1	32.7×	0.033	DUOX2
cilium assembly	1	18.4×	0.054	TMEM231
in utero embryonic development	1	18.0×	0.054	TMEM231

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
TMEM231	0	0
DUOX2	0	0
ADAT1	0	0
CHST6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
DUOX2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DUOX2	1.6.3.1	NAD(P)H oxidase (H2O2-forming)
ADAT1	3.5.4.34	tRNAAla(adenine37) deaminase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	2	DUOX2, ADAT1
E	Difficult family or no structure, no drug	2	TMEM231, CHST6

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)
TMEM231	0	—
DUOX2	1	—
ADAT1	0	—
CHST6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.