Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1

Summary

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1 (MONDO:0800436) is a disease caused by TMCO1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TMCO1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 15
• Phenotypes (HPO): 35

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

35 HPO clinical features (Orphanet curated; top 35 by frequency):

HPO ID	Term	Frequency
HP:0000154	Wide mouth	Very frequent (80-99%)
HP:0000248	Brachycephaly	Very frequent (80-99%)
HP:0000289	Broad philtrum	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000445	Wide nose	Very frequent (80-99%)
HP:0000470	Short neck	Very frequent (80-99%)
HP:0000574	Thick eyebrow	Very frequent (80-99%)
HP:0000774	Narrow chest	Very frequent (80-99%)
HP:0000892	Bifid ribs	Very frequent (80-99%)
HP:0000902	Rib fusion	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0002079	Hypoplasia of the corpus callosum	Very frequent (80-99%)
HP:0002937	Hemivertebrae	Very frequent (80-99%)
HP:0011800	Midface retrusion	Very frequent (80-99%)
HP:0000358	Posteriorly rotated ears	Very frequent (80-99%)
HP:0000256	Macrocephaly	Frequent (30-79%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000494	Downslanted palpebral fissures	Frequent (30-79%)
HP:0000664	Synophrys	Frequent (30-79%)
HP:0000912	Sprengel anomaly	Frequent (30-79%)
HP:0001320	Cerebellar vermis hypoplasia	Frequent (30-79%)
HP:0001561	Polyhydramnios	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Frequent (30-79%)
HP:0002162	Low posterior hairline	Frequent (30-79%)
HP:0002208	Coarse hair	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0003196	Short nose	Frequent (30-79%)
HP:0003422	Vertebral segmentation defect	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0010720	Abnormal hair pattern	Frequent (30-79%)
HP:0100790	Hernia	Frequent (30-79%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000204	Cleft upper lip	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1
Mondo ID	MONDO:0800436
MeSH	C565862
OMIM	213980
Orphanet	1394
DOID	DOID:0081124
SNOMED CT	720635002
UMLS	C5677021
MedGen	1808104
GARD	0001210
Is cancer (heuristic)	no

Also known as: cerebro facio thoracic dysplasia · cerebrofaciothoracic dysplasia · CFSMR · CFSMR1 · pascual-Castroviejo syndrome · pascual-Castroviejo syndrome type 1

Data availability: 15 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome › craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1

Related subtypes (1): craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome 2

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

15 retrieved; paginated sample, class counts are floors:

5 pathogenic, 4 pathogenic/likely pathogenic, 3 likely pathogenic, 1 benign/likely benign, 1 benign, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
996015	NM_018840.5(RAB5IF):c.75G>A (p.Trp25Ter)	LOC130065793	Pathogenic/Likely pathogenic	no assertion criteria provided
1696843	NM_019026.6(TMCO1):c.70G>C (p.Gly24Arg)	TMCO1	Pathogenic	criteria provided, single submitter
189248	NM_019026.6(TMCO1):c.87_90del (p.Val30fs)	TMCO1	Pathogenic	criteria provided, single submitter
218899	NM_019026.6(TMCO1):c.323+3G>C	TMCO1	Pathogenic	criteria provided, single submitter
265628	NM_019026.6(TMCO1):c.187C>T (p.Arg63Ter)	TMCO1	Pathogenic	criteria provided, multiple submitters, no conflicts
3616104	NM_019026.6(TMCO1):c.376C>T (p.Gln126Ter)	TMCO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
420165	NM_019026.6(TMCO1):c.139_140del (p.Gln46_Ser47insTer)	TMCO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
598963	NM_019026.6(TMCO1):c.463C>T (p.Arg155Ter)	TMCO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
88739	NM_019026.6(TMCO1):c.259C>T (p.Arg87Ter)	TMCO1	Pathogenic	no assertion criteria provided
1325197	NM_019026.6(TMCO1):c.-33del	TMCO1	Likely pathogenic	criteria provided, single submitter
1711875	NM_019026.6(TMCO1):c.70G>A (p.Gly24Ser)	TMCO1	Likely pathogenic	criteria provided, single submitter
3780713	NM_019026.6(TMCO1):c.-54_-35dup	TMCO1	Likely pathogenic	criteria provided, single submitter
873451	NM_019026.6(TMCO1):c.44C>T (p.Ser15Phe)	TMCO1	Uncertain significance	criteria provided, single submitter
1198076	NM_019026.6(TMCO1):c.256-12G>A	TMCO1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1235043	NM_019026.6(TMCO1):c.486C>T (p.Leu162=)	TMCO1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · 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
TMCO1	Definitive	Autosomal recessive	craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMCO1	Orphanet:1394	Cerebrofaciothoracic dysplasia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TMCO1	HGNC:18188	ENSG00000143183	Q9UM00	Calcium load-activated calcium channel	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMCO1	Calcium load-activated calcium channel	Endoplasmic reticulum (ER) calcium-selective channel preventing intracellular Ca2(+) stores from overfilling and maintaining calcium homeostasis in the ER.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMCO1	Other/Unknown	no		EMC3/TMCO1, TMCO1

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
choroid plexus epithelium	1
rectum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMCO1	290	ubiquitous	marker	calcaneal tendon, choroid plexus epithelium, rectum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TMCO1	1,673

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TMCO1	Q9UM00	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
multi-pass transmembrane protein insertion into ER membrane	1	1872.4×	0.002	TMCO1
ER overload response	1	1532.0×	0.002	TMCO1
endoplasmic reticulum calcium ion homeostasis	1	842.6×	0.002	TMCO1
ossification	1	227.7×	0.005	TMCO1
calcium ion transmembrane transport	1	210.7×	0.005	TMCO1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TMCO1	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
TMCO1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	TMCO1

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)
TMCO1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.