Mandibulofacial dysostosis-microcephaly syndrome

Summary

Mandibulofacial dysostosis-microcephaly syndrome (MONDO:0012516) is a disease caused by EFTUD2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: EFTUD2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 143
• Phenotypes (HPO): 30

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		107	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0000175	Cleft palate	Very frequent (80-99%)
HP:0000243	Trigonocephaly	Very frequent (80-99%)
HP:0000272	Malar flattening	Very frequent (80-99%)
HP:0000327	Hypoplasia of the maxilla	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000356	Abnormality of the outer ear	Very frequent (80-99%)
HP:0000369	Low-set ears	Very frequent (80-99%)
HP:0000384	Preauricular skin tag	Very frequent (80-99%)
HP:0000582	Upslanted palpebral fissure	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0003196	Short nose	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0005484	Secondary microcephaly	Very frequent (80-99%)
HP:0008551	Microtia	Very frequent (80-99%)
HP:0008609	Morphological abnormality of the middle ear	Very frequent (80-99%)
HP:0009738	Abnormality of the antihelix	Very frequent (80-99%)
HP:0011268	Absent tragus	Very frequent (80-99%)
HP:0011272	Underdeveloped tragus	Very frequent (80-99%)
HP:0011968	Feeding difficulties	Very frequent (80-99%)
HP:0000191	Accessory oral frenulum	Frequent (30-79%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000396	Overfolded helix	Frequent (30-79%)
HP:0000413	Atresia of the external auditory canal	Frequent (30-79%)
HP:0000506	Telecanthus	Frequent (30-79%)
HP:0001177	Preaxial hand polydactyly	Frequent (30-79%)
HP:0009748	Large earlobe	Frequent (30-79%)
HP:0000405	Conductive hearing impairment	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001631	Atrial septal defect	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	mandibulofacial dysostosis-microcephaly syndrome
Mondo ID	MONDO:0012516
MeSH	C537405
OMIM	610536
Orphanet	79113
DOID	DOID:0080196
SNOMED CT	711543008
UMLS	C1864652
MedGen	355264
GARD	0010056
Is cancer (heuristic)	no

Also known as: Growth and mental retardation, mandibulofacial dysostosis, microcephaly, and cleft palate · Growth delay - intellectual disability - mandibulofacial dysostosis - microcephaly - cleft palate · Growth delay-intellectual disability-mandibulofacial dysostosis-microcephaly-cleft palate syndrome · mandibulofacial dysostosis with microcephaly · mandibulofacial dysostosis, Guion-Almeida type · mandibulofacial dysostosis-microcephaly syndrome · MFDGA · MFDM · MFDM syndrome

Data availability: 143 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › mandibulofacial dysostosis-microcephaly syndrome

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

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

143 retrieved; paginated sample, class counts are floors:

49 pathogenic, 44 likely pathogenic, 28 uncertain significance, 9 pathogenic/likely pathogenic, 6 conflicting classifications of pathogenicity, 4 benign, 2 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1029804	NM_004247.4(EFTUD2):c.1331del (p.Gly444fs)	EFTUD2	Pathogenic	criteria provided, single submitter
1029805	NM_004247.4(EFTUD2):c.378del (p.Glu127fs)	EFTUD2	Pathogenic	criteria provided, single submitter
1364366	NM_004247.4(EFTUD2):c.702+1del	EFTUD2	Pathogenic	criteria provided, multiple submitters, no conflicts
1454611	NM_004247.4(EFTUD2):c.2562-2del	EFTUD2	Pathogenic	criteria provided, multiple submitters, no conflicts
1485726	NM_004247.4(EFTUD2):c.857A>G (p.Asn286Ser)	EFTUD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1526378	NM_004247.4(EFTUD2):c.703-2A>G	EFTUD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1679931	NM_004247.4(EFTUD2):c.3G>T (p.Met1Ile)	EFTUD2	Pathogenic	no assertion criteria provided
1698725	NM_004247.4(EFTUD2):c.1719+1G>A	EFTUD2	Pathogenic	criteria provided, single submitter
1702966	NM_004247.4(EFTUD2):c.2199G>A (p.Trp733Ter)	EFTUD2	Pathogenic	criteria provided, multiple submitters, no conflicts
1703337	NM_004247.4(EFTUD2):c.1705C>T (p.Arg569Ter)	EFTUD2	Pathogenic	criteria provided, multiple submitters, no conflicts
1706532	NM_004247.4(EFTUD2):c.423del (p.Lys142fs)	EFTUD2	Pathogenic	criteria provided, single submitter
1710737	NM_004247.4(EFTUD2):c.2813G>A (p.Arg938His)	EFTUD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1804926	NM_004247.4(EFTUD2):c.509_519del (p.Ile170fs)	EFTUD2	Pathogenic	criteria provided, single submitter
1805784	NM_004247.4(EFTUD2):c.2133-2A>G	EFTUD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
203386	NM_004247.4(EFTUD2):c.764dup (p.Cys256fs)	EFTUD2	Pathogenic	no assertion criteria provided
210914	NM_004247.4(EFTUD2):c.1149+1G>C	EFTUD2	Pathogenic	criteria provided, single submitter
210915	NM_004247.4(EFTUD2):c.1297_1298del (p.Met433fs)	EFTUD2	Pathogenic	criteria provided, multiple submitters, no conflicts
2498220	NM_004247.4(EFTUD2):c.593dup (p.Tyr198Ter)	EFTUD2	Pathogenic	criteria provided, single submitter
2506543	GRCh37/hg19 17q21.31(chr17:42929777-42937911)	EFTUD2	Pathogenic	criteria provided, single submitter
2581074	NM_004247.4(EFTUD2):c.2643_2649del (p.Phe881fs)	EFTUD2	Pathogenic	criteria provided, single submitter
265116	NM_004247.4(EFTUD2):c.2698_2701del (p.Val900fs)	EFTUD2	Pathogenic	criteria provided, multiple submitters, no conflicts
2663771	NM_004247.4(EFTUD2):c.766_767del (p.Cys256fs)	EFTUD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2687899	NM_004247.4(EFTUD2):c.1421del (p.Leu474fs)	EFTUD2	Pathogenic	criteria provided, multiple submitters, no conflicts
3024246	NM_004247.4(EFTUD2):c.2678dup (p.Gln894fs)	EFTUD2	Pathogenic	criteria provided, single submitter
30400	NM_004247.4(EFTUD2):c.784C>T (p.Arg262Trp)	EFTUD2	Pathogenic	criteria provided, multiple submitters, no conflicts
30401	NM_004247.4(EFTUD2):c.2770C>T (p.Gln924Ter)	EFTUD2	Pathogenic	criteria provided, single submitter
30402	NM_004247.4(EFTUD2):c.1759_1760del (p.Val587fs)	EFTUD2	Pathogenic	no assertion criteria provided
30403	NM_004247.4(EFTUD2):c.2493C>A (p.Tyr831Ter)	EFTUD2	Pathogenic	no assertion criteria provided
30404	NM_004247.4(EFTUD2):c.1910T>G (p.Leu637Arg)	EFTUD2	Pathogenic	no assertion criteria provided
3062106	NM_004247.4(EFTUD2):c.1904dup (p.Tyr636fs)	EFTUD2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
EFTUD2	Definitive	Autosomal dominant	mandibulofacial dysostosis-microcephaly syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EFTUD2	Orphanet:79113	Mandibulofacial dysostosis-microcephaly syndrome

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
EFTUD2	HGNC:30858	ENSG00000108883	Q15029	116 kDa U5 small nuclear ribonucleoprotein component	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EFTUD2	116 kDa U5 small nuclear ribonucleoprotein component	Required for pre-mRNA splicing as component of the spliceosome, including pre-catalytic, catalytic and post-catalytic spliceosomal complexes.

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)
EFTUD2	Other/Unknown	no		EFG_V-like, T_Tr_GTP-bd_dom, EFTu-like_2

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
bone marrow cell	1
tibialis anterior	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EFTUD2	253	ubiquitous	marker	bone marrow cell, tibialis anterior, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EFTUD2	8,471

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EFTUD2	Q15029	68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 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
mRNA Splicing - Minor Pathway	1	223.9×	0.013	EFTUD2
mRNA Splicing - Major Pathway	1	54.6×	0.022	EFTUD2
Dengue Virus-Host Interactions	1	45.7×	0.022	EFTUD2

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
response to cocaine	1	581.1×	0.005	EFTUD2
cellular response to xenobiotic stimulus	1	240.7×	0.006	EFTUD2
mRNA splicing, via spliceosome	1	91.6×	0.011	EFTUD2

Therapeutics

Drug target analysis

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

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
EFTUD2	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	EFTUD2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
EFTUD2	8	Binding:8

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

1 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)
MOLIBRESIB	2	EFTUD2

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	1	EFTUD2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.