heterotopia, periventricular, X-linked dominant

Summary

heterotopia, periventricular, X-linked dominant (MONDO:0010233) is a disease caused by FLNA (GenCC Definitive), with 8 cohort genes.

At a glance

• Causal gene: FLNA (GenCC Definitive)
• Cohort genes: 8
• ClinVar variants: 3,233

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	heterotopia, periventricular, X-linked dominant
Mondo ID	MONDO:0010233
OMIM	300049
SNOMED CT	448227009
UMLS	C1848213
MedGen	376309
GARD	0007371
Is cancer (heuristic)	no

Also known as: bilateral periventricular nodular heterotopia · BPNH · heterotopia familial nodular · heterotopia periventricular X-linked dominant · heterotopia, periventricular, 1, X-linked dominant · heterotopia, periventricular, Ehlers-Danlos variant · heterotopia, periventricular, X-linked dominant · NHBP · nodular heterotopia bilateral periventricular · periventricular nodular heterotopia 4 · PVNH1 · X-linked periventricular heterotopia

Data availability: 3,233 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › periventricular nodular heterotopia › heterotopia, periventricular, X-linked dominant

Related subtypes (7): periventricular heterotopia with microcephaly, autosomal recessive, heterotopia, periventricular, associated with chromosome 5P anomalies, chromosome 5Q14.3 deletion syndrome, distal, periventricular nodular heterotopia 6, periventricular nodular heterotopia 7, periventricular nodular heterotopia 9, periventricular nodular heterotopia 8

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

600 retrieved; paginated sample, class counts are floors:

200 uncertain significance, 186 likely benign, 109 conflicting classifications of pathogenicity, 37 pathogenic, 35 benign, 21 benign/likely benign, 7 pathogenic/likely pathogenic, 5 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1455467	NC_000023.10:g.(?153599231)(153609567_?)del	EMD	Pathogenic	criteria provided, single submitter
1012290	NM_001110556.2(FLNA):c.5796del (p.Asp1931_Tyr1932insTer)	FLNA	Pathogenic	no assertion criteria provided
1012298	NM_001110556.2(FLNA):c.2527dup (p.Ala843fs)	FLNA	Pathogenic	criteria provided, multiple submitters, no conflicts
1066948	NM_001110556.2(FLNA):c.1066-1G>A	FLNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069630	NM_001110556.2(FLNA):c.334_335insGAGAACGTGTCGG (p.Glu112fs)	FLNA	Pathogenic	criteria provided, single submitter
1070215	NM_001110556.2(FLNA):c.812del (p.Pro271fs)	FLNA	Pathogenic	criteria provided, single submitter
1070361	NM_001110556.2(FLNA):c.2947dup (p.Val983fs)	FLNA	Pathogenic	criteria provided, single submitter
1071106	NM_001110556.2(FLNA):c.6677dup (p.Gln2227fs)	FLNA	Pathogenic	criteria provided, single submitter
1071650	NM_001110556.2(FLNA):c.829_835del (p.Arg276_Pro277insTer)	FLNA	Pathogenic	criteria provided, single submitter
1072111	NM_001110556.2(FLNA):c.577C>T (p.Gln193Ter)	FLNA	Pathogenic	criteria provided, single submitter
1072754	NM_001110556.2(FLNA):c.6329_6330del (p.Glu2110fs)	FLNA	Pathogenic	criteria provided, single submitter
1073243	NM_001110556.2(FLNA):c.5146del (p.Gln1716fs)	FLNA	Pathogenic	criteria provided, single submitter
1075551	NM_001110556.2(FLNA):c.2965C>T (p.Gln989Ter)	FLNA	Pathogenic	criteria provided, single submitter
1075693	NM_001110556.2(FLNA):c.4138dup (p.Thr1380fs)	FLNA	Pathogenic	criteria provided, single submitter
11747	NM_001110556.2(FLNA):c.544C>T (p.Gln182Ter)	FLNA	Pathogenic	criteria provided, single submitter
11748	NM_001110556.2(FLNA):c.720+2T>C	FLNA	Pathogenic	no assertion criteria provided
11750	NM_001110556.2(FLNA):c.373+1G>A	FLNA	Pathogenic	no assertion criteria provided
11751	NM_001110556.2(FLNA):c.287_291del (p.Arg96fs)	FLNA	Pathogenic	no assertion criteria provided
11753	NM_001110556.2(FLNA):c.6915C>G (p.Tyr2305Ter)	FLNA	Pathogenic	no assertion criteria provided
11754	NM_001110556.2(FLNA):c.245A>T (p.Glu82Val)	FLNA	Pathogenic	criteria provided, single submitter
11755	NM_001110556.2(FLNA):c.620C>T (p.Pro207Leu)	FLNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11756	NM_001110556.2(FLNA):c.760G>A (p.Glu254Lys)	FLNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11758	NM_001110556.2(FLNA):c.3562G>A (p.Ala1188Thr)	FLNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11759	NM_001110556.2(FLNA):c.3596C>T (p.Ser1199Leu)	FLNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11761	NM_001110556.2(FLNA):c.3557C>T (p.Ser1186Leu)	FLNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11763	NM_001110556.2(FLNA):c.2762del (p.Arg921fs)	FLNA	Pathogenic	no assertion criteria provided
11764	NM_001110556.2(FLNA):c.4147del (p.Ala1383fs)	FLNA	Pathogenic	no assertion criteria provided
11765	NM_001110556.2(FLNA):c.116C>G (p.Ala39Gly)	FLNA	Pathogenic	no assertion criteria provided
11767	NM_001110556.2(FLNA):c.383C>T (p.Ala128Val)	FLNA	Pathogenic	no assertion criteria provided
11775	NM_001110556.2(FLNA):c.5217G>A (p.Thr1739=)	FLNA	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 30 · Orphanet: 24 · 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	heterotopia, periventricular, X-linked dominant	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
VWF	Orphanet:166078	Von Willebrand disease type 1
VWF	Orphanet:166084	Von Willebrand disease type 2A
VWF	Orphanet:166087	Von Willebrand disease type 2B
VWF	Orphanet:166090	Von Willebrand disease type 2M
VWF	Orphanet:166093	Von Willebrand disease type 2N
VWF	Orphanet:166096	Von Willebrand disease type 3
EMD	Orphanet:98863	X-linked Emery-Dreifuss muscular dystrophy
HCFC1	Orphanet:369962	Methylmalonic acidemia with homocystinuria, type cblX
HCFC1	Orphanet:777	X-linked non-syndromic intellectual disability
ABCD1	Orphanet:139396	X-linked cerebral adrenoleukodystrophy
ABCD1	Orphanet:139399	Adrenomyeloneuropathy
ABCD1	Orphanet:369942	CADDS
ABCD1	Orphanet:388	Hirschsprung disease

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FLNA	HGNC:3754	ENSG00000196924	P21333	Filamin-A	gencc,clinvar
VWF	HGNC:12726	ENSG00000110799	P04275	von Willebrand factor	clinvar
OPN1MW2	HGNC:26952	ENSG00000166160	P0DN77	Medium-wave-sensitive opsin 2	clinvar
DNASE1L1	HGNC:2957	ENSG00000013563	P49184	Deoxyribonuclease-1-like 1	clinvar
EMD	HGNC:3331	ENSG00000102119	P50402	Emerin	clinvar
HCFC1	HGNC:4839	ENSG00000172534	P51610	Host cell factor 1	clinvar
ABCD1	HGNC:61	ENSG00000101986	P33897	ATP-binding cassette sub-family D member 1	clinvar
ARHGAP4	HGNC:674	ENSG00000089820	P98171	Rho GTPase-activating protein 4	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.
VWF	von Willebrand factor	Important in the maintenance of hemostasis, it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V.
OPN1MW2	Medium-wave-sensitive opsin 2	Visual pigments are the light-absorbing molecules that mediate vision.
EMD	Emerin	Stabilizes and promotes the formation of a nuclear actin cortical network.
HCFC1	Host cell factor 1	Transcriptional coregulator.
ABCD1	ATP-binding cassette sub-family D member 1	ATP-dependent transporter of the ATP-binding cassette (ABC) family involved in the transport of very long chain fatty acid (VLCFA)-CoA from the cytosol to the peroxisome lumen.
ARHGAP4	Rho GTPase-activating protein 4	Inhibitory effect on stress fiber organization.

Protein-family classification

Druggable: 5 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.62

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	2	7.3×	0.172
Phosphatase	1	10.5×	0.197
Transporter	1	9.7×	0.197
GPCR	1	3.0×	0.434
Scaffold/PPI	1	2.2×	0.455
Other/Unknown	2	0.5×	0.984

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FLNA	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
VWF	Other/Unknown	no		VWF_dom, VWF_type-D, VWF_A
OPN1MW2	GPCR	yes		GPCR_Rhodpsn, Opsin_red/grn, Opsin
DNASE1L1	Phosphatase	yes		Endo/exonuclease/phosphatase, DNase_I, Deoxyribonuclease-1_AS
EMD	Other/Unknown	no		LEM_dom, LEM/LEM-like_dom_sf, LEM_emerin
HCFC1	Antibody/Immunoglobulin	yes		FN3_dom, Ig-like_fold, Kelch-typ_b-propeller
ABCD1	Transporter	yes	7.6.2.4	ABC_transporter-like_ATP-bd, AAA+_ATPase, FA_transporter
ARHGAP4	Scaffold/PPI	no		RhoGAP_dom, FCH_dom, SH3_domain

Expression context

Cohort genes with no expression data: 0.

7 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	1
moderate (6-20)	0
broad (>20)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
popliteal artery	2
tendon of biceps brachii	2
right coronary artery	1
tibial artery	1
apex of heart	1
urethra	1
colonic epithelium	1
primordial germ cell in gonad	1
ventricular zone	1
gastrocnemius	1
gluteal muscle	1
hindlimb stylopod muscle	1
left ovary	1
left uterine tube	1
parotid gland	1
skeletal muscle tissue of rectus abdominis	1
ileal mucosa	1
left adrenal gland	1
left adrenal gland cortex	1
granulocyte	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
VWF	289	broad	marker	urethra, tendon of biceps brachii, apex of heart
OPN1MW2	4		yes	primordial germ cell in gonad, colonic epithelium, ventricular zone
DNASE1L1	283	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, gluteal muscle
EMD	284	ubiquitous	marker	left ovary, left uterine tube, popliteal artery
HCFC1	274	ubiquitous	marker	tendon of biceps brachii, parotid gland, skeletal muscle tissue of rectus abdominis
ABCD1	201	ubiquitous	marker	ileal mucosa, left adrenal gland cortex, left adrenal gland
ARHGAP4	229	broad	marker	granulocyte, spleen, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FLNA	5,321
VWF	5,204
EMD	3,503
HCFC1	2,637
ABCD1	1,181
ARHGAP4	1,088
DNASE1L1	1,012
OPN1MW2	346

Structural data

PDB: 6 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VWF	P04275	48
FLNA	P21333	26
ABCD1	P33897	14
HCFC1	P51610	11
EMD	P50402	6
ARHGAP4	P98171	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNASE1L1	P49184	90.83
OPN1MW2	P0DN77	82.82

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 61. Enrichment computed across 8 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
GP1b-IX-V activation signalling	2	271.9×	0.001	FLNA, VWF
Defective ABCD1 causes ALD	1	815.7×	0.020	ABCD1
Defective F8 binding to von Willebrand factor	1	815.7×	0.020	VWF
Defective F8 cleavage by thrombin	1	543.8×	0.020	VWF
Defective VWF binding to collagen type I	1	543.8×	0.020	VWF
Enhanced cleavage of VWF variant by ADAMTS13	1	407.9×	0.020	VWF
Defective VWF cleavage by ADAMTS13 variant	1	407.9×	0.020	VWF
Platelet degranulation	2	25.1×	0.020	FLNA, VWF
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1	271.9×	0.024	ABCD1
Enhanced binding of GP1BA variant to VWF multimer:collagen	1	233.1×	0.024	VWF
Defective binding of VWF variant to GPIb:IX:V	1	233.1×	0.024	VWF
OAS antiviral response	1	181.3×	0.026	FLNA
RAC1 GTPase cycle	2	17.4×	0.026	EMD, ARHGAP4
Linoleic acid (LA) metabolism	1	163.1×	0.027	ABCD1
Beta-oxidation of very long chain fatty acids	1	125.5×	0.028	ABCD1
p130Cas linkage to MAPK signaling for integrins	1	108.8×	0.028	VWF
Depolymerization of the Nuclear Lamina	1	108.8×	0.028	EMD
alpha-linolenic acid (ALA) metabolism	1	102.0×	0.028	ABCD1
GRB2:SOS provides linkage to MAPK signaling for Integrins	1	102.0×	0.028	VWF
Peroxisomal lipid metabolism	1	96.0×	0.028	ABCD1
Cell-extracellular matrix interactions	1	96.0×	0.028	FLNA
Platelet Adhesion to exposed collagen	1	96.0×	0.028	VWF
Amplification and propagation of coagulation cascade	1	90.6×	0.028	VWF
ABC transporters in lipid homeostasis	1	85.9×	0.028	ABCD1
Initiation of Nuclear Envelope (NE) Reformation	1	85.9×	0.028	EMD
RHO GTPases activate PAKs	1	77.7×	0.030	FLNA
Class I peroxisomal membrane protein import	1	74.2×	0.030	ABCD1
Insertion of tail-anchored proteins into the endoplasmic reticulum membrane	1	68.0×	0.030	EMD
Initiation of coagulation cascade	1	68.0×	0.030	VWF
Nuclear Envelope Breakdown	1	65.3×	0.030	EMD

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 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	2106.5×	0.016	FLNA
regulation of membrane repolarization during cardiac muscle cell action potential	1	2106.5×	0.016	FLNA
peroxisomal membrane transport	1	1053.2×	0.016	ABCD1
very long-chain fatty-acyl-CoA catabolic process	1	1053.2×	0.016	ABCD1
release from viral latency	1	702.2×	0.016	HCFC1
tubulin deacetylation	1	702.2×	0.016	FLNA
positive regulation of unsaturated fatty acid biosynthetic process	1	702.2×	0.016	ABCD1
formation of radial glial scaffolds	1	526.6×	0.016	FLNA
sterol homeostasis	1	526.6×	0.016	ABCD1
adenylate cyclase-inhibiting dopamine receptor signaling pathway	1	421.3×	0.016	FLNA
long-chain fatty acid import into peroxisome	1	421.3×	0.016	ABCD1
establishment of Sertoli cell barrier	1	421.3×	0.016	FLNA
absorption of visible light	1	351.1×	0.016	OPN1MW2
regulation of fatty acid beta-oxidation	1	351.1×	0.016	ABCD1
long-chain fatty acid catabolic process	1	351.1×	0.016	ABCD1
myelin maintenance	1	351.1×	0.016	ABCD1
regulation of mitochondrial depolarization	1	351.1×	0.016	ABCD1
protein localization to bicellular tight junction	1	351.1×	0.016	FLNA
negative regulation of transcription by RNA polymerase I	1	300.9×	0.016	FLNA
fatty acid elongation	1	300.9×	0.016	ABCD1
very long-chain fatty acid catabolic process	1	300.9×	0.016	ABCD1
nuclear membrane organization	1	300.9×	0.016	EMD
blood coagulation, intrinsic pathway	1	263.3×	0.018	FLNA
hemostasis	1	210.7×	0.021	VWF
negative regulation of fibroblast migration	1	191.5×	0.021	ARHGAP4
positive regulation of fatty acid beta-oxidation	1	191.5×	0.021	ABCD1
fatty acid derivative biosynthetic process	1	191.5×	0.021	ABCD1
positive regulation of platelet activation	1	162.0×	0.021	FLNA
regulation of cellular response to oxidative stress	1	162.0×	0.021	ABCD1
positive regulation of integrin-mediated signaling pathway	1	162.0×	0.021	FLNA

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 2 · Undrugged: 6

Druggability breadth: 4 of 8 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
FLNA	1	2
HCFC1	1	2
VWF	0	0
OPN1MW2	0	0
DNASE1L1	0	0
EMD	0	0
ABCD1	0	0
ARHGAP4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	FLNA, HCFC1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
VWF	17	Binding:17
HCFC1	8	Binding:8
FLNA	7	Binding:7
EMD	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ABCD1	7.6.2.4	ABC-type fatty-acyl-CoA transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; 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, HCFC1

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	2	FLNA, HCFC1
C	Druggable family + PDB, no drug	1	ABCD1
D	Druggable family + AlphaFold only, no drug	2	OPN1MW2, DNASE1L1
E	Difficult family or no structure, no drug	3	VWF, EMD, ARHGAP4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
VWF	17	—
OPN1MW2	0	—
DNASE1L1	0	—
EMD	1	—
ABCD1	0	—
ARHGAP4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.