Terminal osseous dysplasia-pigmentary defects syndrome

Summary

Terminal osseous dysplasia-pigmentary defects syndrome (MONDO:0010279) is a disease caused by FLNA (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FLNA (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 65
• Phenotypes (HPO): 23

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

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

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0025197	Inclusion body fibromatosis	Very frequent (80-99%)
HP:0025473	Hyperpigmented papule	Very frequent (80-99%)
HP:0000191	Accessory oral frenulum	Frequent (30-79%)
HP:0001156	Brachydactyly	Frequent (30-79%)
HP:0001371	Flexion contracture	Frequent (30-79%)
HP:0001596	Alopecia	Frequent (30-79%)
HP:0030084	Clinodactyly	Frequent (30-79%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000437	Depressed nasal tip	Occasional (5-29%)
HP:0000612	Iris coloboma	Occasional (5-29%)
HP:0000685	Hypoplasia of teeth	Occasional (5-29%)
HP:0001159	Syndactyly	Occasional (5-29%)
HP:0001655	Patent foramen ovale	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0004467	Preauricular pit	Occasional (5-29%)
HP:0009139	Osteolysis involving bones of the lower limbs	Occasional (5-29%)
HP:0010306	Short thorax	Occasional (5-29%)
HP:0012385	Camptodactyly	Occasional (5-29%)
HP:0045039	Osteolysis involving bones of the upper limbs	Occasional (5-29%)
HP:0001653	Mitral regurgitation	Very rare (<1-4%)
HP:0001723	Restrictive cardiomyopathy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	terminal osseous dysplasia-pigmentary defects syndrome
Mondo ID	MONDO:0010279
MeSH	C564554
OMIM	300244
Orphanet	88630
DOID	DOID:0112149
UMLS	C1846129
MedGen	335344
GARD	0016769
Is cancer (heuristic)	no

Also known as: terminal osseous dysplasia · terminal osseous dysplasia, X-linked dominant · TOD

Data availability: 65 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › filamin-related bone disorder › terminal osseous dysplasia-pigmentary defects syndrome

Related subtypes (5): cardiospondylocarpofacial syndrome, Frank-Ter Haar syndrome, spondylocarpotarsal synostosis syndrome, otopalatodigital syndrome spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder

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

65 retrieved; paginated sample, class counts are floors:

21 conflicting classifications of pathogenicity, 18 uncertain significance, 15 benign/likely benign, 4 likely benign, 3 pathogenic, 2 benign, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
11775	NM_001110556.2(FLNA):c.5217G>A (p.Thr1739=)	FLNA	Pathogenic	criteria provided, multiple submitters, no conflicts
2035128	NM_001110556.2(FLNA):c.4598+1G>A	FLNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382382	NM_001110556.2(FLNA):c.6709_6710dup (p.Ala2238fs)	FLNA	Pathogenic	criteria provided, single submitter
3382665	NM_001110556.2(FLNA):c.5293C>T (p.Gln1765Ter)	FLNA	Pathogenic	criteria provided, single submitter
4294528	NM_001110556.2(FLNA):c.2193C>A (p.Tyr731Ter)	FLNA	Likely pathogenic	criteria provided, single submitter
1011953	NM_001110556.2(FLNA):c.2392G>A (p.Glu798Lys)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1041672	NM_001110556.2(FLNA):c.1060C>T (p.His354Tyr)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1063162	NM_001110556.2(FLNA):c.2590G>T (p.Val864Phe)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1500525	NM_001110556.2(FLNA):c.4625C>T (p.Thr1542Ile)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
198133	NM_001110556.2(FLNA):c.901C>T (p.Arg301Trp)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211017	NM_001110556.2(FLNA):c.4517C>T (p.Thr1506Ile)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211024	NM_001110556.2(FLNA):c.6719A>G (p.Lys2240Arg)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
213491	NM_001110556.2(FLNA):c.569G>A (p.Arg190Gln)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
213502	NM_001110556.2(FLNA):c.2410G>A (p.Val804Ile)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2500033	NM_001110556.2(FLNA):c.5406C>T (p.Gly1802=)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
435203	NM_001110556.2(FLNA):c.6725G>A (p.Arg2242Gln)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
449178	NM_001110556.2(FLNA):c.5138C>T (p.Thr1713Met)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
465015	NM_001110556.2(FLNA):c.6863G>A (p.Arg2288His)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
533577	NM_001110556.2(FLNA):c.6376C>T (p.Pro2126Ser)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
588444	NM_001110556.2(FLNA):c.1019G>A (p.Arg340His)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
588552	NM_001110556.2(FLNA):c.2974A>G (p.Thr992Ala)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
588806	NM_001110556.2(FLNA):c.1270A>G (p.Met424Val)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
847250	NM_001110556.2(FLNA):c.1633A>G (p.Met545Val)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
93756	NM_001110556.2(FLNA):c.3323G>A (p.Cys1108Tyr)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
939032	NM_001110556.2(FLNA):c.2981A>G (p.Lys994Arg)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
392335	NM_001110556.2(FLNA):c.7628G>A (p.Cys2543Tyr)	LOC107988032	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1381935	NM_001110556.2(FLNA):c.2464A>G (p.Ile822Val)	FLNA	Uncertain significance	criteria provided, multiple submitters, no conflicts
1695738	NM_001110556.2(FLNA):c.4730A>G (p.Glu1577Gly)	FLNA	Uncertain significance	criteria provided, multiple submitters, no conflicts
2149931	NM_001110556.2(FLNA):c.1396C>T (p.Pro466Ser)	FLNA	Uncertain significance	criteria provided, multiple submitters, no conflicts
3367185	NM_001110556.2(FLNA):c.289C>T (p.Pro97Ser)	FLNA	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 30 · Orphanet: 11 · 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
FLNA	Definitive	X-linked	terminal osseous dysplasia-pigmentary defects syndrome	30

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FLNA	Orphanet:1826	Frontometaphyseal dysplasia
FLNA	Orphanet:2301	Congenital short bowel syndrome
FLNA	Orphanet:2484	Melnick-Needles syndrome
FLNA	Orphanet:482606	X-linked keloid scarring-reduced joint mobility-increased optic cup-to-disc ratio syndrome
FLNA	Orphanet:555877	FLNA-related X-linked myxomatous valvular dysplasia
FLNA	Orphanet:75497	X-linked Ehlers-Danlos syndrome
FLNA	Orphanet:88630	Terminal osseous dysplasia-pigmentary defects syndrome
FLNA	Orphanet:90650	Otopalatodigital syndrome type 1
FLNA	Orphanet:90652	Otopalatodigital syndrome type 2
FLNA	Orphanet:98892	Periventricular nodular heterotopia
FLNA	Orphanet:99811	Neuronal intestinal pseudoobstruction

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
FLNA	HGNC:3754	ENSG00000196924	P21333	Filamin-A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FLNA	Filamin-A	Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Antibody/Immunoglobulin	1	29.2×	0.034

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FLNA	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom

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
popliteal artery	1
right coronary artery	1
tibial artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FLNA	285	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FLNA	5,321

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FLNA	P21333	26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
OAS antiviral response	1	1268.9×	0.002	FLNA
GP1b-IX-V activation signalling	1	951.7×	0.002	FLNA
Cell-extracellular matrix interactions	1	671.8×	0.002	FLNA
RHO GTPases activate PAKs	1	543.8×	0.002	FLNA
Platelet degranulation	1	87.8×	0.011	FLNA

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
regulation of membrane repolarization during atrial cardiac muscle cell action potential	1	16852.0×	0.001	FLNA
regulation of membrane repolarization during cardiac muscle cell action potential	1	16852.0×	0.001	FLNA
tubulin deacetylation	1	5617.3×	0.002	FLNA
formation of radial glial scaffolds	1	4213.0×	0.002	FLNA
adenylate cyclase-inhibiting dopamine receptor signaling pathway	1	3370.4×	0.002	FLNA
establishment of Sertoli cell barrier	1	3370.4×	0.002	FLNA
protein localization to bicellular tight junction	1	2808.7×	0.002	FLNA
negative regulation of transcription by RNA polymerase I	1	2407.4×	0.002	FLNA
blood coagulation, intrinsic pathway	1	2106.5×	0.002	FLNA
positive regulation of platelet activation	1	1296.3×	0.002	FLNA
positive regulation of integrin-mediated signaling pathway	1	1296.3×	0.002	FLNA
positive regulation of actin filament bundle assembly	1	1203.7×	0.002	FLNA
actin crosslink formation	1	1203.7×	0.002	FLNA
wound healing, spreading of cells	1	1123.5×	0.002	FLNA
positive regulation of potassium ion transmembrane transport	1	991.3×	0.002	FLNA
positive regulation of neuron migration	1	991.3×	0.002	FLNA
positive regulation of neural precursor cell proliferation	1	766.0×	0.003	FLNA
obsolete negative regulation of DNA-binding transcription factor activity	1	732.7×	0.003	FLNA
megakaryocyte development	1	702.2×	0.003	FLNA
receptor clustering	1	624.1×	0.003	FLNA
protein localization to cell surface	1	495.6×	0.004	FLNA
establishment of protein localization	1	432.1×	0.004	FLNA
positive regulation of protein import into nucleus	1	421.3×	0.004	FLNA
semaphorin-plexin signaling pathway	1	401.2×	0.004	FLNA
positive regulation of substrate adhesion-dependent cell spreading	1	374.5×	0.004	FLNA
negative regulation of protein catabolic process	1	366.4×	0.004	FLNA
release of sequestered calcium ion into cytosol	1	343.9×	0.004	FLNA
mitotic spindle assembly	1	343.9×	0.004	FLNA
platelet aggregation	1	337.0×	0.004	FLNA
mRNA transcription by RNA polymerase II	1	330.4×	0.004	FLNA

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
FLNA	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	FLNA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
FLNA	7	Binding:7

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	FLNA

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	FLNA
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.