Femoral agenesis/hypoplasia

Summary

Femoral agenesis/hypoplasia (MONDO:0016032) is a disease with 4 cohort genes.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 4
• ClinVar variants: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1.6	Worldwide	Validated
Prevalence at birth	1-9 / 100 000	1.6	Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	femoral agenesis/hypoplasia
Mondo ID	MONDO:0016032
Orphanet	1987
ICD-11	662157487
SNOMED CT	93255008
UMLS	C0345375
MedGen	87499
GARD	0001503
Is cancer (heuristic)	no

Also known as: congenital short femur · femoral intercalary meromelia

Data availability: 3 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › dysostosis › femoral agenesis/hypoplasia

Related subtypes (107): trigonocephaly, spondylocostal dysostosis, synostosis, Adams-Oliver syndrome, adactylia, unilateral, ADULT syndrome, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, Cooks syndrome, brachydactyly-arterial hypertension syndrome, fibular aplasia-ectrodactyly syndrome, brachytelephalangy-dysmorphism-Kallmann syndrome, congenital pseudoarthrosis of clavicle, external auditory canal atresia-vertical talus-hypertelorism syndrome, femoral-facial syndrome, hand-foot-genital syndrome, oculoauriculovertebral spectrum with radial defects, IVIC syndrome, nail-patella syndrome, patella aplasia/hypoplasia, pelvis-shoulder dysplasia, phocomelia-ectrodactyly-deafness-sinus arrhythmia syndrome, postaxial tetramelic oligodactyly, Currarino triad, radio-renal syndrome, splenogonadal fusion-limb defects-micrognathia syndrome, Karsch-Neugebauer syndrome, tetramelic monodactyly, tibia, hypoplasia or aplasia of, with polydactyly, humerus trochlea aplasia, Aphalangy-hemivertebrae-urogenital-intestinal dysgenesis syndrome, camptodactyly syndrome, Guadalajara type 2, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, split hand-foot malformation 1 with sensorineural hearing loss, EEM syndrome, lethal faciocardiomelic dysplasia, femur-fibula-ulna complex, Gollop-Wolfgang complex, acromesomelic dysplasia 2B, Fuhrmann syndrome, absence deformity of leg-cataract syndrome, intellectual disability-spasticity-ectrodactyly syndrome, fibular aplasia, tibial campomelia, and oligosyndactyly syndrome, otoonychoperoneal syndrome, pelviscapular dysplasia, rapadilino syndrome, EEC syndrome, spondylocostal dysostosis-anal and genitourinary malformations syndrome, tetraamelia-multiple malformations syndrome, thrombocytopenia-absent radius syndrome, phocomelia, Schinzel type, ulna hypoplasia-intellectual disability syndrome, absent radius-anogenital anomalies syndrome, ulnar hypoplasia-split foot syndrome, aphalangy-syndactyly-microcephaly syndrome, absent tibia-polydactyly-arachnoid cyst syndrome, autosomal recessive amelia, pelvic dysplasia-arthrogryposis of lower limbs syndrome, camptodactyly, myopia, and fibrosis of the medial rectus muscle of eye, radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome, genitopatellar syndrome, Duane-radial ray syndrome, intellectual disability-brachydactyly-Pierre Robin syndrome, camptodactyly syndrome, Guadalajara type 3, mammary-digital-nail syndrome, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, split-foot malformation-mesoaxial polydactyly syndrome, amniotic band syndrome, radial deficiency-tibial hypoplasia syndrome, mandibulofacial dysostosis, oromandibular-limb anomalies syndrome, congenital pseudoarthrosis of the limbs, oculomaxillofacial dysostosis, shoulder and thorax deformity-congenital heart disease syndrome, progressive non-infectious anterior vertebral fusion, hemimelia, heart-hand syndrome, split hand-foot malformation, Melhem-Fahl syndrome, limb transversal defect-cardiac anomaly syndrome, frontonasal dysplasia, imperforate oropharynx-costo vetebral anomalies syndrome, non-syndromic amelia, congenital absence of upper arm and forearm with hand present, congenital absence of thigh and lower leg with foot present, congenital absence of both forearm and hand, congenital absence of both lower leg and foot, acheiria, apodia, split hand, split foot, hyperphalangy, Prata-Liberal-Goncalves syndrome, syngnathia multiple anomalies, hereditary thrombocytosis with transverse limb defect, thalidomide embryopathy, tibial aplasia-ectrodactyly syndrome, bipartite talus, acrofacial dysostosis, adactyly of foot, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, Rubinstein-Taybi syndrome, ischio-vertebral syndrome, congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome, omphalocele-diaphragmatic hernia-cardiovascular anomalies-radial ray defect syndrome, preaxial digit brachydactyly-webbed fingers, proximal femoral focal deficiency, dysostosis multiplex, Ain-Naz type

Subtypes (2): femoral agenesis/hypoplasia, unilateral, femoral agenesis/hypoplasia, bilateral

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

3 retrieved; paginated sample, class counts are floors:

2 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
400	NM_019892.6(INPP5E):c.1132C>T (p.Arg378Cys)	INPP5E	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374012	NM_182943.3(PLOD2):c.2038C>T (p.Arg680Ter)	PLOD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374011	NM_182943.3(PLOD2):c.1361G>T (p.Gly454Val)	PLOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 14 · 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
FGF8	Moderate	Autosomal dominant	femoral agenesis/hypoplasia	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FGF8	Orphanet:220386	Semilobar holoprosencephaly
FGF8	Orphanet:280195	Septopreoptic holoprosencephaly
FGF8	Orphanet:280200	Microform holoprosencephaly
FGF8	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
FGF8	Orphanet:478	Kallmann syndrome
FGF8	Orphanet:93924	Lobar holoprosencephaly
FGF8	Orphanet:93925	Alobar holoprosencephaly
FGF8	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
PMPCA	Orphanet:1170	Autosomal recessive cerebelloparenchymal disorder type 3
INPP5E	Orphanet:1454	Joubert syndrome with hepatic defect
INPP5E	Orphanet:220493	Joubert syndrome with ocular defect
INPP5E	Orphanet:475	Isolated Joubert syndrome
INPP5E	Orphanet:75858	MORM syndrome
PLOD2	Orphanet:2771	Bruck syndrome

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
FGF8	HGNC:3686	ENSG00000107831	P55075	Fibroblast growth factor 8	gencc
PMPCA	HGNC:18667	ENSG00000165688	Q10713	Mitochondrial-processing peptidase subunit alpha	clinvar
INPP5E	HGNC:21474	ENSG00000148384	Q9NRR6	Phosphatidylinositol polyphosphate 5-phosphatase type IV	clinvar
PLOD2	HGNC:9082	ENSG00000152952	O00469	Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FGF8	Fibroblast growth factor 8	Plays an important role in the regulation of embryonic development, cell proliferation, cell differentiation and cell migration.
PMPCA	Mitochondrial-processing peptidase subunit alpha	Substrate recognition and binding subunit of the essential mitochondrial processing protease (MPP), which cleaves the mitochondrial sequence off newly imported precursors proteins.
INPP5E	Phosphatidylinositol polyphosphate 5-phosphatase type IV	Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3), phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol 3,5-bispho…
PLOD2	Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2	Forms hydroxylysine residues in -Xaa-Lys-Gly- sequences in collagens.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.75

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×	0.112
Protease	1	9.2×	0.157
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FGF8	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF
PMPCA	Protease	yes	3.4.24.64	Pept_M16_Zn_BS, Peptidase_M16_C, Metalloenz_LuxS/M16
INPP5E	Enzyme (other)	yes	3.1.3.36	IPPc, Endo/exonu/phosph_ase_sf, INPP5E
PLOD2	Enzyme (other)	yes	1.14.11.4	Procol_lys_dOase, Oxoglu/Fe-dep_dioxygenase_dom, Pro_4_hyd_alph

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endometrium epithelium	1
metanephric glomerulus	1
primordial germ cell in gonad	1
adrenal tissue	1
apex of heart	1
right lobe of liver	1
oocyte	1
right uterine tube	1
secondary oocyte	1
calcaneal tendon	1
jejunal mucosa	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FGF8	109	tissue_specific	yes	primordial germ cell in gonad, metanephric glomerulus, endometrium epithelium
PMPCA	276	ubiquitous	marker	right lobe of liver, adrenal tissue, apex of heart
INPP5E	279	ubiquitous	yes	right uterine tube, secondary oocyte, oocyte
PLOD2	288	ubiquitous	marker	tibia, calcaneal tendon, jejunal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGF8	4,536
PMPCA	3,679
PLOD2	1,703
INPP5E	1,309

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGF8	P55075	1
INPP5E	Q9NRR6	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLOD2	O00469	92.63
PMPCA	Q10713	88.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 57. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
ARL13B-mediated ciliary trafficking of INPP5E	1	951.7×	0.016	INPP5E
FGFR3b ligand binding and activation	1	407.9×	0.016	FGF8
Formation of the posterior neural plate	1	285.5×	0.016	FGF8
Signaling by activated point mutants of FGFR1	1	237.9×	0.016	FGF8
Signaling by activated point mutants of FGFR3	1	237.9×	0.016	FGF8
FGFR3c ligand binding and activation	1	219.6×	0.016	FGF8
FGFR2c ligand binding and activation	1	219.6×	0.016	FGF8
Phospholipase C-mediated cascade; FGFR3	1	219.6×	0.016	FGF8
FGFRL1 modulation of FGFR1 signaling	1	219.6×	0.016	FGF8
FGFR4 ligand binding and activation	1	203.9×	0.016	FGF8
FGFR1c ligand binding and activation	1	190.3×	0.016	FGF8
Phospholipase C-mediated cascade; FGFR4	1	190.3×	0.016	FGF8
Activated point mutants of FGFR2	1	167.9×	0.016	FGF8
Phospholipase C-mediated cascade: FGFR1	1	167.9×	0.016	FGF8
Synthesis of PIPs at the Golgi membrane	1	158.6×	0.016	INPP5E
Phospholipase C-mediated cascade; FGFR2	1	158.6×	0.016	FGF8
PI-3K cascade:FGFR3	1	158.6×	0.016	FGF8
Processing of SMDT1	1	158.6×	0.016	PMPCA
SHC-mediated cascade:FGFR3	1	150.3×	0.016	FGF8
PI-3K cascade:FGFR4	1	142.8×	0.016	FGF8
Downstream signaling of activated FGFR1	1	135.9×	0.016	FGF8
FRS-mediated FGFR3 signaling	1	135.9×	0.016	FGF8
SHC-mediated cascade:FGFR4	1	135.9×	0.016	FGF8
Mitochondrial calcium ion transport	1	135.9×	0.016	PMPCA
PI-3K cascade:FGFR1	1	129.8×	0.016	FGF8
SHC-mediated cascade:FGFR1	1	124.1×	0.016	FGF8
PI-3K cascade:FGFR2	1	124.1×	0.016	FGF8
FRS-mediated FGFR4 signaling	1	124.1×	0.016	FGF8
Signaling by FGFR3 in disease	1	124.1×	0.016	FGF8
SHC-mediated cascade:FGFR2	1	119.0×	0.016	FGF8

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
pallium development	1	4213.0×	0.006	FGF8
midbrain-hindbrain boundary development	1	2106.5×	0.006	FGF8
negative regulation of cardiac muscle tissue development	1	2106.5×	0.006	FGF8
cell migration involved in mesendoderm migration	1	2106.5×	0.006	FGF8
larynx morphogenesis	1	2106.5×	0.006	FGF8
neural plate morphogenesis	1	1404.3×	0.006	FGF8
subpallium development	1	1404.3×	0.006	FGF8
obsolete hydroxylysine biosynthetic process	1	1404.3×	0.006	PLOD2
corticotropin hormone secreting cell differentiation	1	1404.3×	0.006	FGF8
negative regulation of protein localization to cilium	1	1404.3×	0.006	INPP5E
dorsal/ventral axon guidance	1	1053.2×	0.006	FGF8
response to inositol	1	1053.2×	0.006	INPP5E
mesodermal cell migration	1	842.6×	0.007	FGF8
thyroid-stimulating hormone-secreting cell differentiation	1	702.2×	0.007	FGF8
mitotic nuclear division	1	702.2×	0.007	FGF8
forebrain neuron development	1	601.9×	0.007	FGF8
regulation of odontogenesis of dentin-containing tooth	1	601.9×	0.007	FGF8
obsolete protein processing involved in protein targeting to mitochondrion	1	526.6×	0.007	PMPCA
forebrain dorsal/ventral pattern formation	1	526.6×	0.007	FGF8
otic vesicle formation	1	526.6×	0.007	FGF8
embryonic neurocranium morphogenesis	1	468.1×	0.008	FGF8
mesonephros development	1	383.0×	0.008	FGF8
neuroepithelial cell differentiation	1	383.0×	0.008	FGF8
epithelial to mesenchymal transition involved in endocardial cushion formation	1	351.1×	0.008	FGF8
positive regulation of organ growth	1	351.1×	0.008	FGF8
forebrain morphogenesis	1	351.1×	0.008	FGF8
branching involved in salivary gland morphogenesis	1	351.1×	0.008	FGF8
cell proliferation in forebrain	1	324.1×	0.009	FGF8
organ induction	1	300.9×	0.009	FGF8
gonad development	1	280.9×	0.009	FGF8

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGF8	0	0
PMPCA	0	0
INPP5E	0	0
PLOD2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
PLOD2	2	Binding:2
PMPCA	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PMPCA	3.4.24.64	mitochondrial processing peptidase
INPP5E	3.1.3.36	phosphoinositide 5-phosphatase
PLOD2	1.14.11.4, 2.4.1.50	procollagen-lysine 5-dioxygenase, procollagen galactosyltransferase

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	1	INPP5E
D	Druggable family + AlphaFold only, no drug	2	PMPCA, PLOD2
E	Difficult family or no structure, no drug	1	FGF8

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)
FGF8	0	—
PMPCA	1	—
INPP5E	0	—
PLOD2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.