orofaciodigital syndrome type II

Summary

orofaciodigital syndrome type II (MONDO:0009642) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 10
• Phenotypes (HPO): 49

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)

49 HPO clinical features (Orphanet curated; top 49 by frequency):

HPO ID	Term	Frequency
HP:0000175	Cleft palate	Very frequent (80-99%)
HP:0000161	Median cleft lip	Frequent (30-79%)
HP:0000190	Abnormal oral frenulum morphology	Frequent (30-79%)
HP:0000199	Tongue nodules	Frequent (30-79%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000685	Hypoplasia of teeth	Frequent (30-79%)
HP:0001841	Preaxial foot polydactyly	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0006042	Y-shaped metacarpals	Frequent (30-79%)
HP:0006101	Finger syndactyly	Frequent (30-79%)
HP:0006289	Agenesis of central incisor	Frequent (30-79%)
HP:0010055	Broad hallux	Frequent (30-79%)
HP:0010068	Broad first metatarsal	Frequent (30-79%)
HP:0010100	Complete duplication of hallux phalanx	Frequent (30-79%)
HP:0010297	Bifid tongue	Frequent (30-79%)
HP:0011802	Hamartoma of tongue	Frequent (30-79%)
HP:0011819	Submucous cleft soft palate	Frequent (30-79%)
HP:0040019	Finger clinodactyly	Frequent (30-79%)
HP:0000220	Velopharyngeal insufficiency	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000405	Conductive hearing impairment	Occasional (5-29%)
HP:0000411	Protruding ear	Occasional (5-29%)
HP:0000506	Telecanthus	Occasional (5-29%)
HP:0000679	Taurodontia	Occasional (5-29%)
HP:0001161	Hand polydactyly	Occasional (5-29%)
HP:0001162	Postaxial hand polydactyly	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0002104	Apnea	Occasional (5-29%)
HP:0002789	Tachypnea	Occasional (5-29%)
HP:0004987	Mesomelic leg shortening	Occasional (5-29%)
HP:0005349	Hypoplasia of the epiglottis	Occasional (5-29%)
HP:0005736	Short tibia	Occasional (5-29%)
HP:0005873	Polysyndactyly of hallux	Occasional (5-29%)
HP:0006342	Peg-shaped maxillary lateral incisors	Occasional (5-29%)
HP:0006695	Atrioventricular canal defect	Occasional (5-29%)
HP:0007768	Central retinal vessel vascular tortuosity	Occasional (5-29%)
HP:0008947	Floppy infant	Occasional (5-29%)
HP:0009826	Limb undergrowth	Occasional (5-29%)
HP:0010230	Cone-shaped epiphyses of the phalanges of the hand	Occasional (5-29%)
HP:0011087	Talon cusp	Occasional (5-29%)
HP:0030680	Abnormal cardiovascular system morphology	Occasional (5-29%)
HP:0100702	Arachnoid cyst	Occasional (5-29%)
HP:0100874	Thick hair	Occasional (5-29%)
HP:0410033	Unilateral alveolar cleft of maxilla	Occasional (5-29%)
HP:0000050	Hypoplastic male external genitalia	Very rare (<1-4%)
HP:0000695	Natal tooth	Very rare (<1-4%)
HP:0002069	Bilateral tonic-clonic seizure	Very rare (<1-4%)
HP:0009776	Adactyly	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	orofaciodigital syndrome type II
Mondo ID	MONDO:0009642
OMIM	252100
Orphanet	2751
DOID	DOID:0060959
SNOMED CT	1779005
UMLS	C0026363
MedGen	10077
GARD	0003701
Is cancer (heuristic)	no

Also known as: MOHR syndrome · Mohr syndrome · OFD syndrome 2 · OFD2 · oral facial digital syndrome 2 · oral facial digital syndrome type 2 · oral-facial-digital syndrome type 2 · orofaciodigital syndrome II

Data availability: 10 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › orofaciodigital syndrome › orofaciodigital syndrome type II

Related subtypes (18): orofaciodigital syndrome X, orofaciodigital syndrome V, orofaciodigital syndrome III, orofaciodigital syndrome IV, orofaciodigital syndrome IX, orofaciodigital syndrome type 6, orofaciodigital syndrome VIII, orofaciodigital syndrome VII, orofaciodigital syndrome XI, orofaciodigital syndrome type 14, orofaciodigital syndrome XV, orofaciodigital syndrome type 12, orofaciodigital syndrome 16, orofaciodigital syndrome 17, orofaciodigital syndrome 18, orofaciodigital syndrome 19, orofaciodigital syndrome 20, orofaciodigital syndrome 21

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

10 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 2 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
504484	NM_015693.4(INTU):c.396del (p.Asn132fs)	INTU	Pathogenic/Likely pathogenic	no assertion criteria provided
3024122	NM_001199397.3(NEK1):c.464G>C (p.Ser155Thr)	NEK1	Pathogenic	no assertion criteria provided
446672	NM_001199397.3(NEK1):c.1226G>A (p.Trp409Ter)	NEK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4849318	NM_001199397.3(NEK1):c.598A>T (p.Lys200Ter)	NEK1	Likely pathogenic	criteria provided, single submitter
348122	NM_001199397.3(NEK1):c.642G>A (p.Lys214=)	NEK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
446674	NM_001199397.3(NEK1):c.418G>A (p.Gly140Arg)	NEK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1493572	NM_001199397.3(NEK1):c.3437G>A (p.Arg1146Lys)	NEK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3590450	NM_001199397.3(NEK1):c.1267G>A (p.Ala423Thr)	NEK1	Uncertain significance	criteria provided, single submitter
3891824	NM_001199397.3(NEK1):c.2590A>G (p.Ile864Val)	NEK1	Uncertain significance	criteria provided, single submitter
900737	NM_001199397.3(NEK1):c.1080G>C (p.Glu360Asp)	NEK1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
NEK1	Supportive	Autosomal recessive	orofaciodigital syndrome type II	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NEK1	Orphanet:2751	Orofaciodigital syndrome type 2
NEK1	Orphanet:803	Amyotrophic lateral sclerosis
NEK1	Orphanet:93269	Short rib-polydactyly syndrome, Majewski type

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
NEK1	HGNC:7744	ENSG00000137601	Q96PY6	Serine/threonine-protein kinase Nek1	gencc,clinvar
INTU	HGNC:29239	ENSG00000164066	Q9ULD6	Protein inturned	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NEK1	Serine/threonine-protein kinase Nek1	Phosphorylates serines and threonines, but also appears to possess tyrosine kinase activity.
INTU	Protein inturned	Plays a key role in ciliogenesis and embryonic development.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Kinase	1	13.9×	0.112
Scaffold/PPI	1	8.6×	0.112

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NEK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
INTU	Scaffold/PPI	no		PDZ, PDZ_sf, INTU

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
oocyte	1
secondary oocyte	1
trigeminal ganglion	1
bronchial epithelial cell	1
right uterine tube	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NEK1	288	ubiquitous	marker	secondary oocyte, trigeminal ganglion, oocyte
INTU	226	ubiquitous	marker	right uterine tube, bronchial epithelial cell, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
INTU	2,947
NEK1	1,512

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
INTU	Q9ULD6	4
NEK1	Q96PY6	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Regulation of pyruvate metabolism	1	285.5×	0.017	NEK1
Pyruvate metabolism	1	203.9×	0.017	NEK1
Signaling by Hedgehog	1	92.1×	0.020	INTU
Hedgehog ‘off’ state	1	89.2×	0.020	INTU
Aerobic respiration and respiratory electron transport	1	44.3×	0.031	NEK1
Metabolism	1	5.8×	0.187	NEK1
Signal Transduction	1	5.1×	0.187	INTU

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
cilium assembly	2	73.6×	0.004	NEK1, INTU
tongue morphogenesis	1	1685.2×	0.005	INTU
negative regulation of cell division	1	1203.7×	0.005	INTU
spinal cord dorsal/ventral patterning	1	1053.2×	0.005	INTU
cell division	2	46.2×	0.005	NEK1, INTU
regulation of ossification	1	601.9×	0.007	INTU
establishment of planar polarity	1	526.6×	0.007	INTU
negative regulation of keratinocyte proliferation	1	351.1×	0.007	INTU
regulation of smoothened signaling pathway	1	312.1×	0.007	INTU
regulation of cilium assembly	1	300.9×	0.007	INTU
motile cilium assembly	1	290.6×	0.007	INTU
intraciliary transport	1	280.9×	0.007	INTU
neural tube development	1	263.3×	0.007	INTU
hair follicle morphogenesis	1	247.8×	0.007	INTU
positive regulation of smoothened signaling pathway	1	210.7×	0.007	INTU
limb development	1	205.5×	0.007	INTU
embryonic digit morphogenesis	1	150.5×	0.009	INTU
non-motile cilium assembly	1	145.3×	0.009	INTU
keratinocyte differentiation	1	123.9×	0.010	INTU
roof of mouth development	1	123.9×	0.010	INTU
smoothened signaling pathway	1	90.6×	0.013	INTU
vesicle-mediated transport	1	48.1×	0.023	INTU
protein phosphorylation	1	34.0×	0.030	NEK1
nervous system development	1	23.0×	0.043	INTU

Therapeutics

Drug target analysis

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

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

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
NEK1	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NEK1	12	4
INTU	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	NEK1
DABRAFENIB	4	NEK1
LESTAURTINIB	3	NEK1
TG100-115	2	NEK1
R-406	2	NEK1
PELITINIB	2	NEK1
GSK-461364	1	NEK1
KW-2449	1	NEK1
AMG-900	1	NEK1
TAK-593	1	NEK1
CYC-116	1	NEK1
AST-487	1	NEK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NEK1	288	Binding:288

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
NEK1	288

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

12 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.

Compound	Max phase	Cohort target (bioactivity)
FEDRATINIB	4	NEK1
DABRAFENIB	4	NEK1
LESTAURTINIB	3	NEK1
TG100-115	2	NEK1
R-406	2	NEK1
PELITINIB	2	NEK1
GSK-461364	1	NEK1
KW-2449	1	NEK1
AMG-900	1	NEK1
TAK-593	1	NEK1
CYC-116	1	NEK1
AST-487	1	NEK1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NEK1
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	INTU

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)
INTU	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.