Frontometaphyseal dysplasia 1

Summary

Frontometaphyseal dysplasia 1 (MONDO:0024550) is a disease caused by FLNA (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: FLNA (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 81

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	frontometaphyseal dysplasia 1
Mondo ID	MONDO:0024550
OMIM	305620
DOID	DOID:0111786
UMLS	C4281559
MedGen	923943
GARD	0015293
Is cancer (heuristic)	no

Also known as: FLNA frontometaphyseal dysplasia · FMD1 · frontometaphyseal dysplasia 1, X-linked recessive · frontometaphyseal dysplasia caused by mutation in FLNA

Data availability: 81 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 › skeletal dysplasia › filamin-related bone disorder › otopalatodigital syndrome spectrum disorder › frontometaphyseal dysplasia › frontometaphyseal dysplasia 1

Related subtypes (1): frontometaphyseal dysplasia 2

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

81 retrieved; paginated sample, class counts are floors:

27 uncertain significance, 24 conflicting classifications of pathogenicity, 15 benign/likely benign, 5 likely benign, 3 pathogenic, 3 likely pathogenic, 2 pathogenic/likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
11757	NM_001110556.2(FLNA):c.3476A>C (p.Asp1159Ala)	FLNA	Pathogenic	no assertion criteria provided
11761	NM_001110556.2(FLNA):c.3557C>T (p.Ser1186Leu)	FLNA	Pathogenic/Likely 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
2692562	NM_001110556.2(FLNA):c.7732T>C (p.Phe2578Leu)	FLNA	Likely pathogenic	criteria provided, single submitter
3342232	NM_001110556.2(FLNA):c.4726G>T (p.Gly1576Trp)	FLNA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
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
1493937	NM_001110556.2(FLNA):c.3755C>T (p.Ala1252Val)	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
197727	NM_001110556.2(FLNA):c.733G>A (p.Glu245Lys)	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
587465	NM_001110556.2(FLNA):c.2122C>T (p.Arg708Trp)	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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 30 · Orphanet: 12 · 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
EMD	Orphanet:98863	X-linked Emery-Dreifuss muscular dystrophy

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
FLNA	HGNC:3754	ENSG00000196924	P21333	Filamin-A	gencc,clinvar
DNASE1L1	HGNC:2957	ENSG00000013563	P49184	Deoxyribonuclease-1-like 1	clinvar
EMD	HGNC:3331	ENSG00000102119	P50402	Emerin	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.
EMD	Emerin	Stabilizes and promotes the formation of a nuclear actin cortical network.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Phosphatase	1	28.0×	0.106
Antibody/Immunoglobulin	1	9.7×	0.149
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FLNA	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
DNASE1L1	Phosphatase	yes		Endo/exonuclease/phosphatase, DNase_I, Deoxyribonuclease-1_AS
EMD	Other/Unknown	no		LEM_dom, LEM/LEM-like_dom_sf, LEM_emerin

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
popliteal artery	2
right coronary artery	1
tibial artery	1
gastrocnemius	1
gluteal muscle	1
hindlimb stylopod muscle	1
left ovary	1
left uterine tube	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
DNASE1L1	283	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, gluteal muscle
EMD	284	ubiquitous	marker	left ovary, left uterine tube, popliteal artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FLNA	5,321
EMD	3,503
DNASE1L1	1,012

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FLNA	P21333	26
EMD	P50402	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNASE1L1	P49184	90.83

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 3 evidence-associated genes (3 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 3 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	423.0×	0.012	FLNA
GP1b-IX-V activation signalling	1	317.2×	0.012	FLNA
Depolymerization of the Nuclear Lamina	1	253.8×	0.012	EMD
Cell-extracellular matrix interactions	1	223.9×	0.012	FLNA
Initiation of Nuclear Envelope (NE) Reformation	1	200.3×	0.012	EMD
RHO GTPases activate PAKs	1	181.3×	0.012	FLNA
Insertion of tail-anchored proteins into the endoplasmic reticulum membrane	1	158.6×	0.012	EMD
Nuclear Envelope Breakdown	1	152.3×	0.012	EMD
RHOD GTPase cycle	1	68.0×	0.024	EMD
RHOG GTPase cycle	1	49.4×	0.030	EMD
RAC2 GTPase cycle	1	42.3×	0.031	EMD
RAC3 GTPase cycle	1	39.6×	0.031	EMD
Platelet degranulation	1	29.3×	0.039	FLNA
RAC1 GTPase cycle	1	20.4×	0.052	EMD
Neutrophil degranulation	1	7.7×	0.124	DNASE1L1

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
regulation of membrane repolarization during atrial cardiac muscle cell action potential	1	5617.3×	0.004	FLNA
regulation of membrane repolarization during cardiac muscle cell action potential	1	5617.3×	0.004	FLNA
tubulin deacetylation	1	1872.4×	0.007	FLNA
formation of radial glial scaffolds	1	1404.3×	0.007	FLNA
adenylate cyclase-inhibiting dopamine receptor signaling pathway	1	1123.5×	0.007	FLNA
establishment of Sertoli cell barrier	1	1123.5×	0.007	FLNA
protein localization to bicellular tight junction	1	936.2×	0.007	FLNA
negative regulation of transcription by RNA polymerase I	1	802.5×	0.007	FLNA
nuclear membrane organization	1	802.5×	0.007	EMD
blood coagulation, intrinsic pathway	1	702.2×	0.007	FLNA
positive regulation of platelet activation	1	432.1×	0.008	FLNA
positive regulation of integrin-mediated signaling pathway	1	432.1×	0.008	FLNA
positive regulation of actin filament bundle assembly	1	401.2×	0.008	FLNA
actin crosslink formation	1	401.2×	0.008	FLNA
wound healing, spreading of cells	1	374.5×	0.008	FLNA
DNA metabolic process	1	351.1×	0.008	DNASE1L1
positive regulation of potassium ion transmembrane transport	1	330.4×	0.008	FLNA
positive regulation of neuron migration	1	330.4×	0.008	FLNA
DNA catabolic process	1	312.1×	0.008	DNASE1L1
positive regulation of protein export from nucleus	1	267.5×	0.009	EMD
positive regulation of neural precursor cell proliferation	1	255.3×	0.009	FLNA
obsolete negative regulation of DNA-binding transcription factor activity	1	244.2×	0.009	FLNA
megakaryocyte development	1	234.1×	0.009	FLNA
receptor clustering	1	208.1×	0.010	FLNA
amyloid fibril formation	1	200.6×	0.010	EMD
regulation of canonical Wnt signaling pathway	1	181.2×	0.011	EMD
protein localization to cell surface	1	165.2×	0.011	FLNA
negative regulation of fibroblast proliferation	1	165.2×	0.011	EMD
establishment of protein localization	1	144.0×	0.012	FLNA
positive regulation of protein import into nucleus	1	140.4×	0.012	FLNA

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
DNASE1L1	0	0
EMD	0	0

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
EMD	1	Binding:1

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

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	1	DNASE1L1
E	Difficult family or no structure, no drug	1	EMD

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DNASE1L1	0	—
EMD	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.