Developmental defect during embryogenesis

Summary

Developmental defect during embryogenesis (MONDO:0019755) is a disease (an umbrella term covering 52 Mondo subtypes) with 3 cohort genes.

At a glance

• Prevalence: 1-9 / 100 000 (France) [Orphanet-validated]
• Umbrella term: 52 Mondo subtypes
• Cohort genes: 3
• ClinVar variants: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	3.3	France	Validated
Prevalence at birth	1-9 / 100 000	2.42	France	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental defect during embryogenesis
Mondo ID	MONDO:0019755
Orphanet	93890
NCIT	C99267
SNOMED CT	400038003
UMLS	C5680284
MedGen	1825997
Is cancer (heuristic)	no

Also known as: congenital malformation syndrome · developmental defect during embryogenesis · disorder of embryonic morphogenesis · embryonic morphogenesis disease · malformation syndrome · rare developmental defect during embryogenesis

Data availability: 2 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 52 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis

Related subtypes (189): precocious puberty, complex cortical dysplasia with other brain malformations, imperforate anus, microcephaly, demyelinating disease, hypospadias, bone development disease, primary basilar invagination, familial bicuspid aortic valve, camptodactyly of fingers, isolated congenital digital clubbing, aorta coarctation, gingival fibromatosis-progressive deafness syndrome, Eng-Strom syndrome, Morgagni-Stewart-Morel syndrome, familial partial lipodystrophy, Dunnigan type, megalodactyly, odontomatosis-aortae esophagus stenosis syndrome, otodental syndrome, oculodental syndrome, Rutherfurd type, spina bifida, steatocystoma multiplex-natal teeth syndrome, distal symphalangism, thumb deformity-alopecia-pigmentation anomaly syndrome, double uterus-hemivagina-renal agenesis syndrome, amelogenesis imperfecta type 1G, Bloom syndrome, cardiac valvular defect, developmental, isolated cerebellar hypoplasia/agenesis, cleft palate-stapes fixation-oligodontia syndrome, Jalili syndrome, craniodiaphyseal dysplasia, craniofacial dyssynostosis, deafness-oligodontia syndrome, duodenal atresia, Fowler syndrome, multiple intestinal atresia, natal teeth-intestinal pseudoobstruction-patent ductus syndrome, atresia of small intestine, mulibrey nanism, oculocerebral hypopigmentation syndrome, Cross type, familial osteodysplasia, Anderson type, pancreatic agenesis, postaxial polydactyly-dental and vertebral anomalies syndrome, familial primary pulmonary hypoplasia, renal tubular dysgenesis of genetic origin, Rothmund-Thomson syndrome, familial isolated congenital asplenia, subaortic stenosis, membranous, non-eruption of teeth-maxillary hypoplasia-genu valgum syndrome, corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome, CK syndrome, Ogden syndrome, Nance-Horan syndrome, colonic atresia, Aicardi syndrome, torticollis-keloids-cryptorchidism-renal dysplasia syndrome, 46,XY complete gonadal dysgenesis, loose anagen syndrome, lung agenesis-heart defect-thumb anomalies syndrome, Chudley-McCullough syndrome, macrocephaly-autism syndrome, DNA ligase IV deficiency, horizontal gaze palsy with progressive scoliosis, cataract - congenital heart disease - neural tube defect syndrome, autosomal recessive frontotemporal pachygyria, craniofacial dysplasia - osteopenia syndrome, porencephaly-microcephaly-bilateral congenital cataract syndrome, congenital short bowel syndrome, familial median cleft of the upper and lower lips, progeroid features-hepatocellular carcinoma predisposition syndrome, progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, aneurysm of sinus of Valsalva, blepharoptosis-cleft palate-ectrodactyly-dental anomalies syndrome, medullary sponge kidney, isolated congenital syngnathia, cleft lip and alveolus, diprosopus, T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency, high anorectal malformation, intermediate anorectal malformation, low anorectal malformation, microcephaly-polymicrogyria-corpus callosum agenesis syndrome, cordiform uterus, septate uterus, bicornuate uterus, uterine hypoplasia, agenesis and aplasia of uterine body, uterine cervical aplasia and agenesis, longitudinal vaginal septum, transverse vaginal septum, axial mesodermal dysplasia spectrum, multicystic dysplastic kidney, diabetic embryopathy, congenital microgastria, isolated cleft lip, cleft lip/palate, hereditary gingival fibromatosis, congenital bronchobiliary fistula, congenital hydrocephalus, maternal hyperthermia induced birth defects, diphallia, epibulbar lipodermoid-preauricular appendage-polythelia syndrome, bronchogenic cyst, duplication of urethra, hypohidrotic ectodermal dysplasia, Lowe-Kohn-Cohen syndrome, biliary atresia with splenic malformation syndrome, congenital pulmonary airway malformation, familial intestinal malrotation-facial anomalies syndrome, megalencephaly, cephalocele, cerebral cortical dysplasia, L1 syndrome, familial omphalocele syndrome with facial dysmorphism, penoscrotal transposition, pericardial and diaphragmatic defect, hypogonadotropic hypogonadism-severe microcephaly-sensorineural hearing loss-dysmorphism syndrome, congenital deformities of limbs, familial isolated clinodactyly of fingers, congenital shoulder dislocation, congenital elbow dislocation, congenital knee dislocation, congenital patella dislocation, macrodactyly of fingers, macrodactyly of toes, upper limb hypertrophy, lower limb hypertrophy, duplication of the pituitary gland, diencephalic-mesencephalic junction dysplasia, steroid dehydrogenase deficiency-dental anomalies syndrome, congenital achiasma, tracheal agenesis, renal agenesis, hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome, isolated splenogonadal fusion, Joubert syndrome, congenital generalized hypercontractile muscle stiffness syndrome, congenital bilateral absence of vas deferens, congenital portosystemic shunt, lissencephaly spectrum disorders, Berardinelli-Seip congenital lipodystrophy, congenital primary megaureter, craniorachischisis, vaginal atresia, bronchopulmonary dysplasia, dentinogenesis imperfecta-short stature-hearing loss-intellectual disability syndrome, aniridia, atypical Werner syndrome, X-linked intellectual disability-corpus callosum agenesis-spastic quadriparesis syndrome, anterior segment dysgenesis, congenital esophageal diverticulum, renal hypoplasia, renal dysplasia, overgrowth syndrome, acalvaria, congenital aortic valve insufficiency, congenital anomaly of superior vena cava, congenital anomaly of hepatic vein, posterior hypospadias, isolated micropenis, isolated partial vaginal agenesis, anorectal malformation, pulmonary agenesis, congenital tricuspid malformation, Noonan syndrome and Noonan-related syndrome, coronary sinus stenosis, coronary sinus atresia, cartilage development disorder, syndactyly, polydactyly, brachydactyly, neurocristopathy, congenital absence of septum pellucidum, branchial arch disease, congenital anomaly of cardiovascular system, atelencephaly, aprosencephaly, aortic valve stenosis, hereditary lethal multiple congenital anomalies/dysmorphic syndrome, congenital agenesis of the scrotum, keratinization disease, lactation disease, COACH syndrome, constitutional delay of growth and puberty, isolated congenital femoral bifurcation, congenital peritoneal encapsulation, isolated short stature, congenital high airway obstruction syndrome

Subtypes (52): disorder of sexual differentiation, hereditary neurocutaneous angioma, nevoid basal cell carcinoma syndrome, angioosteohypertrophic syndrome, Larsen syndrome, schwannomatosis, linear nevus sebaceous syndrome, lethal Larsen-like syndrome, pseudodiastrophic dysplasia, focal dermal hypoplasia, microtia, neurofibromatosis-Noonan syndrome, Becker nevus syndrome, Legius syndrome, bone fragility with contractures, arterial rupture, and deafness, blindness - scoliosis - arachnodactyly syndrome, cutis laxa - Marfanoid syndrome, Maffucci syndrome, hydrops fetalis, ankyloblepharon filiforme-imperforate anus syndrome, developmental anomaly of metabolic origin, progeroid syndrome, facial cleft, Desbuquois dysplasia, cysts and fistulae of the face and oral cavity, macroglossia, middle ear anomaly, cleft palate, cutis laxa, infectious embryofetopathy, toxic or drug-related embryofetopathy, hemihyperplasia-multiple lipomatosis syndrome, phakomatosis pigmentokeratotica, phakomatosis pigmentovascularis, PTEN hamartoma tumor syndrome, marfanoid habitus-inguinal hernia-advanced bone age syndrome, neurofibromatosis type 1, multiple congenital anomalies/dysmorphic syndrome, congenital limb malformation, hereditary hemorrhagic telangiectasia, urogenital tract malformation, congenital anomaly of kidney and urinary tract, anotia, central nervous system malformation, Ehlers-Danlos syndrome, X-linked external auditory canal atresia-dilated internal auditory canal-facial dysmorphism syndrome, joint laxity, short stature, and myopia, diaphragmatic malformation, abdominal wall malformation, port-wine nevi-mega cisterna magna-hydrocephalus syndrome, conjoined twins, TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations

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

2 retrieved; paginated sample, class counts are floors:

1 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4074757	NM_001042492.3(NF1):c.3053_3054insTTCAACTAATTGTTGTTGAAA (p.Leu1018delinsPheSerThrAsnCysCysTer)	NF1	Pathogenic	criteria provided, single submitter
198347	NM_001277115.2(DNAH11):c.10472G>A (p.Arg3491His)	DNAH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 10 · 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
NMNAT2	Moderate	Autosomal recessive	developmental defect during embryogenesis	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DNAH11	Orphanet:244	Primary ciliary dyskinesia
NF1	Orphanet:139474	17q11.2 microduplication syndrome
NF1	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
NF1	Orphanet:293199	Pleomorphic rhabdomyosarcoma
NF1	Orphanet:363700	Neurofibromatosis type 1 due to NF1 mutation or intragenic deletion
NF1	Orphanet:638	Neurofibromatosis-Noonan syndrome
NF1	Orphanet:86834	Juvenile myelomonocytic leukemia
NF1	Orphanet:97685	17q11 microdeletion syndrome
NF1	Orphanet:99756	Alveolar rhabdomyosarcoma
NF1	Orphanet:99757	Embryonal rhabdomyosarcoma

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
NMNAT2	HGNC:16789	ENSG00000157064	Q9BZQ4	Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2	gencc
DNAH11	HGNC:2942	ENSG00000105877	Q96DT5	Dynein axonemal heavy chain 11	clinvar
NF1	HGNC:7765	ENSG00000196712	P21359	Neurofibromin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NMNAT2	Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2	Nicotinamide/nicotinate-nucleotide adenylyltransferase that acts as an axon maintenance factor.
DNAH11	Dynein axonemal heavy chain 11	Force generating protein required for cilia beating in respiratory epithelia.
NF1	Neurofibromin	Stimulates the GTPase activity of Ras.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NMNAT2	Enzyme (other)	yes	2.7.7.1	Cyt_trans-like, Rossmann-like_a/b/a_fold, NMNAT_euk
DNAH11	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
NF1	Other/Unknown	no		CRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot

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
cortical plate	1
frontal pole	1
middle temporal gyrus	1
bronchial epithelial cell	1
bronchus	1
right uterine tube	1
adrenal tissue	1
calcaneal tendon	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NMNAT2	208	broad	marker	middle temporal gyrus, cortical plate, frontal pole
DNAH11	163	broad	marker	right uterine tube, bronchial epithelial cell, bronchus
NF1	283	ubiquitous	marker	colonic epithelium, calcaneal tendon, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NF1	5,540
NMNAT2	1,875
DNAH11	1,666

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NF1	P21359	26

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NMNAT2	Q9BZQ4	80.34
DNAH11	Q96DT5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 3 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
RAS signaling downstream of NF1 loss-of-function variants	1	815.7×	0.012	NF1
Nicotinate metabolism	1	196.9×	0.025	NMNAT2
Oncogenic MAPK signaling	1	124.1×	0.026	NF1
Regulation of RAS by GAPs	1	96.8×	0.026	NF1
MAPK1/MAPK3 signaling	1	65.6×	0.030	NF1
MAPK family signaling cascades	1	51.4×	0.032	NF1
RAF/MAP kinase cascade	1	30.5×	0.044	NF1
Diseases of signal transduction by growth factor receptors and second messengers	1	28.4×	0.044	NF1
Disease	1	6.5×	0.163	NF1
Signal Transduction	1	5.1×	0.187	NF1

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
positive regulation of mast cell apoptotic process	1	5617.3×	0.005	NF1
regulation of glial cell differentiation	1	5617.3×	0.005	NF1
observational learning	1	5617.3×	0.005	NF1
determination of left/right asymmetry in nervous system	1	2808.7×	0.005	DNAH11
gamma-aminobutyric acid secretion, neurotransmission	1	2808.7×	0.005	NF1
Schwann cell proliferation	1	1872.4×	0.005	NF1
forebrain astrocyte development	1	1872.4×	0.005	NF1
Schwann cell migration	1	1872.4×	0.005	NF1
nicotinamide riboside metabolic process	1	1872.4×	0.005	NMNAT2
glutamate secretion, neurotransmission	1	1872.4×	0.005	NF1
negative regulation of mast cell proliferation	1	1872.4×	0.005	NF1
negative regulation of Schwann cell migration	1	1872.4×	0.005	NF1
vascular associated smooth muscle cell migration	1	1872.4×	0.005	NF1
mast cell apoptotic process	1	1404.3×	0.005	NF1
negative regulation of Rac protein signal transduction	1	1404.3×	0.005	NF1
myeloid leukocyte migration	1	1404.3×	0.005	NF1
nicotinamide metabolic process	1	1123.5×	0.005	NMNAT2
nucleotide biosynthetic process	1	1123.5×	0.005	NMNAT2
mast cell proliferation	1	1123.5×	0.005	NF1
protein localization to motile cilium	1	1123.5×	0.005	DNAH11
amygdala development	1	936.2×	0.005	NF1
regulation of blood vessel endothelial cell migration	1	936.2×	0.005	NF1
vascular associated smooth muscle cell proliferation	1	936.2×	0.005	NF1
NADP+ biosynthetic process	1	802.5×	0.005	NMNAT2
negative regulation of Schwann cell proliferation	1	802.5×	0.005	NF1
negative regulation of neurotransmitter secretion	1	802.5×	0.005	NF1
regulation of cilium beat frequency	1	702.2×	0.006	DNAH11
hair follicle maturation	1	702.2×	0.006	NF1
NAD+ biosynthetic process	1	624.1×	0.006	NMNAT2
‘de novo’ NAD+ biosynthetic process from L-tryptophan	1	624.1×	0.006	NMNAT2

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
NMNAT2	0	0
DNAH11	0	0
NF1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NMNAT2	2.7.7.1, 2.7.7.18	nicotinamide-nucleotide adenylyltransferase, nicotinate-nucleotide adenylyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	NMNAT2
E	Difficult family or no structure, no drug	2	DNAH11, NF1

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)
NMNAT2	0	—
DNAH11	0	—
NF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.