Brain Small Vessel Disease 2 (COL4A2)

Mendelian MONDO:0013773 Pathograph 18 Show in embeddings browser COL4A1/A2-related disorder Familial porencephaly

Brain small vessel disease 2 is the cerebrovascular disorder caused by pathogenic germline variants in COL4A2, which encodes the alpha-2 chain of the alpha1-alpha1-alpha2 type IV collagen heterotrimer of vascular basement membranes. The common form (BSVD2A) is autosomal dominant with reduced penetrance and variable expression: heterozygous glycine substitutions in the triple helix, frameshift and splice variants are associated with porencephaly, congenital hemiplegia, focal epilepsy, leukoencephalopathy, intracerebral hemorrhage in childhood or adult life, cortical malformations such as schizencephaly and polymicrogyria, and occasional cataract, optic nerve hypoplasia, intracranial aneurysm, hematuria and raised creatine kinase. A rare autosomal recessive form (BSVD2B) has been reported in a handful of families with homozygous or compound heterozygous COL4A2 variants and early, severe presentations including fetal hemorrhagic brain injury, intellectual disability, spastic quadriplegia, epilepsy, leukoencephalopathy with calcifications and cortical malformations. Mechanistically, dominant missense alleles cause intracellular retention of both collagen IV chains with reduced secretion, variable endoplasmic-reticulum stress, and basement-membrane defects that predispose small cerebral vessels to hemorrhage. Management is supportive and follows the shared COL4A1/COL4A2 consensus; no mechanism-directed therapy is established.

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1
Mappings
1
Inheritance
7
Pathophys.
21
Phenotypes
18
Pathograph
1
Genes
4
Medical Actions
2
Subtypes
4
Models
1
References
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Mappings

MONDO
MONDO:0980747 brain small vessel disease 2B, autosomal recessive Not Yet Curated
skos:narrowMatch MONDO
MONDO:0980747 is the biallelic COL4A2 disease (OMIM:621414). This entry covers both the dominant (MONDO:0013773) and recessive COL4A2 forms and carries the recessive form as the BSVD2B subtype, so the recessive MONDO concept is narrower than the entry.
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Inheritance

1
Autosomal dominant HP:0000006
The common form is autosomal dominant. Variants are inherited from mildly affected or asymptomatic parents or arise de novo. Penetrance is reduced and expression varies within families, from congenital hemiplegia to an asymptomatic carrier.
Autosomal dominant inheritance Penetrance: INCOMPLETE
Show evidence (3 references)
PMID:22209246 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The c.3455G>A mutation was found in the proband's mother, who showed very mild monoparesis of the left upper extremity, and the maternal elder uncle, who had congenital hemiplegia. The maternal grandfather harboring the mutation is asymptomatic. The c.3110G>A mutation occurred de novo."
One heterozygous variant segregated through three generations with variable expression and an asymptomatic carrier grandfather; a second arose de novo. Both establish heterozygous (dominant) transmission with incomplete penetrance.
PMID:22333902 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"dominant COL4A2 mutations are a novel major risk factor for familial cerebrovascular disease, including porencephaly and small-vessel disease with reduced penetrance and variable phenotype"
Two families with heterozygous COL4A2 variants show dominant transmission with reduced penetrance.
PMID:24001601 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"we report the identification of a novel dominant G702D mutation in the collagen domain of COL4A2 (collagen IV alpha chain 2) in a family displaying porencephaly with reduced penetrance"
A third family with a dominant COL4A2 glycine substitution and reduced penetrance (the unaffected father carries it).
◆

Subtypes

2
Brain small vessel disease 2A, autosomal dominant MONDO:0013773
COL4A2 hgnc:2203 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in COL4A2 (hgnc:2203). hgnc:2203 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
Heterozygous COL4A2 variants, mostly glycine substitutions in the collagenous domain plus frameshift and splice variants, inherited with reduced penetrance or arising de novo. Presentations range from perinatal porencephaly with hemiplegia and focal epilepsy to adult-onset recurrent deep intracerebral hemorrhage with leukoencephalopathy, and include cortical malformations and occasional cataract.
Show evidence (2 references)
PMID:22209246 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Here we report on two individuals with porencephaly caused by a heterozygous missense mutation in COL4A2, which encodes the type IV α2 collagen chain."
Founding report of heterozygous COL4A2 porencephaly.
PMID:26708157 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We describe a family with an autosomal dominant disorder comprising porencephaly, focal epilepsy, and lens opacities, which was negative for mutations in COL4A1."
Three-generation dominant family with a COL4A2 glycine substitution.
Brain small vessel disease 2B, autosomal recessive MONDO:0980747
COL4A2 hgnc:2203 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in COL4A2 (hgnc:2203). hgnc:2203 is a gene from the HUGO Gene Nomenclature Committee. Autosomal recessive inheritance
Biallelic COL4A2 variants with clinically unaffected heterozygous parents. Three families are described in the sources cited here: two affected siblings homozygous for p.Gly1158Arg from a consanguineous Iranian family (PMID:33912663), a second family with leukoencephalopathy and spot-like calcifications (PMID:36603335), and two further cases, an aborted fetus with a homozygous missense variant and a two-year-old girl with compound heterozygous splice and truncating variants (PMID:41499643). Presentations are early and severe: fetal cerebral hemorrhage and calcification, global developmental delay, intellectual disability, absent speech, spastic quadriplegia, focal epilepsy, colpocephaly and porencephaly, and cortical malformations. The fetal homozygous missense variant was classified likely benign by its reporting authors, so causality for that case remains provisional.
Show evidence (4 references)
PMID:33912663 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We describe 2 children from a consanguineous Iranian family with intellectual disability, spastic cerebral palsy, and epilepsy who each harbored the same homozygous mutation in COL4A2."
First recessive COL4A2 family, two affected siblings.
PMID:33912663 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Our results indicate that both dominant and recessive forms of COL4A2 disease exist."
Authors' conclusion establishing a recessive COL4A2 form alongside the dominant one.
PMID:36603335 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We broaden the phenotypic and genotypic spectra of COL4A2-related disease by describing this second family with recessive pathogenic variants and neuroimaging phenotype of leukoencephalopathy with spot-like calcifications."
Second family with recessive COL4A2 variants.
+ 1 more reference
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Pathophysiology

7
Pathogenic COL4A2 Variation
Germline COL4A2 variants alter the alpha-2(IV) chain. Heterozygous glycine substitutions in the Gly-Xaa-Yaa repeats are predicted to disturb alpha1-alpha1-alpha2 heterotrimer assembly; frameshift and splice alleles and biallelic variants are predicted to reduce or destabilize the chain. Patient-specific functional confirmation exists for only a few dominant alleles, and none for the recessive alleles.
COL4A2 hgnc:2203 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COL4A2 (hgnc:2203). hgnc:2203 is a gene from the HUGO Gene Nomenclature Committee.
extracellular matrix structural constituent GO:0005201 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal extracellular matrix structural constituent (GO:0005201). GO:0005201 is a molecular function from the Gene Ontology.
collagen type IV trimer GO:0005587 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves collagen type IV trimer (GO:0005587). GO:0005587 is a cellular component from the Gene Ontology.
Downstream
Intracellular Collagen IV Retention Dominant COL4A2 missense alleles cause both collagen IV chains to accumulate in the endoplasmic reticulum.
Cerebral Arterial Smooth Muscle Calcium Signaling Dysregulation In aged heterozygous Col4a2 G646D mice, pial artery smooth muscle shows remodeled ryanodine receptor clusters with more calcium sparks and BK channel activity.
Show evidence (2 references)
PMID:22209246 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Our study confirmed that abnormalities of the α1α1α2 heterotrimers of type IV collagen cause porencephaly and stresses the importance of screening for COL4A2 as well as for COL4A1."
Heterotrimer abnormality from COL4A2 variants is the proximate molecular lesion.
PMID:41499643 SUPPORT INDIRECT PRIMARY RESULT Computational
"All variants were rare and predicted to affect protein stability and function in silico."
Recessive alleles are predicted, not shown, to destabilize the protein.
Intracellular Collagen IV Retention
Mutant alpha-2(IV) and its alpha-1(IV) partner are retained in the endoplasmic reticulum at the expense of secretion, in patient cells and in Col4a2 mutant mice. Retention was seen in an affected patient's fibroblasts but not in those of his unaffected carrier father, suggesting that retention or its clearance modifies disease expression. Mutant collagen IV is degraded by the proteasome.
fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
Animal models
Col4a2 mutant mice with intracerebral hemorrhage Mouse recapitulates ER retention of COL4A1 and COL4A2.
Downstream
Endoplasmic Reticulum Stress Retention activates the unfolded protein response for some, but not all, COL4A2 variants.
Abnormal Vascular Basement Membrane Impaired secretion reduces collagen IV incorporation into basement membranes.
Show evidence (2 references)
PMID:22209247 SUPPORT DIRECT PRIMARY RESULT Model Organism
"mutations in mouse and human lead to retention of COL4A1 and COL4A2 within the endoplasmic reticulum (ER)"
ER retention in Col4a2 mutant mice; the human arm of the same sentence is the cellular assay cited on the upstream edge.
PMID:24001601 SUPPORT DIRECT PRIMARY RESULT In Vitro
"the absence of ER retention of COL4A2 and ER stress in cells from the unaffected father indicate that accumulation and/or clearance of mutant COL4A2 from the ER may be a critical modifier for disease development"
Patient versus carrier-father fibroblasts tie retention to disease expression.
Endoplasmic Reticulum Stress
Some COL4A2 variants activate the unfolded protein response, with reduced proliferation and increased apoptosis in patient fibroblasts, and a chemical chaperone reduces both retention and stress in vitro. ER stress is not obligatory: fibroblasts carrying the c.3206delC frameshift showed increased apoptosis without signs of ER stress, and only two of three missense variants tested triggered it.
endoplasmic reticulum unfolded protein response GO:0030968 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased endoplasmic reticulum unfolded protein response (GO:0030968). GO:0030968 is a biological process from the Gene Ontology. apoptotic process GO:0006915 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology.
Show evidence (3 references)
PMID:22209247 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Importantly, two of the three putative mutations found in patients trigger ER stress and activate the unfolded protein response."
Variant-dependent UPR activation in cells.
PMID:24001601 SUPPORT DIRECT PRIMARY RESULT In Vitro
"treatment of patient cells with a chemical chaperone decreased intracellular COL4A2 levels, ER stress and apoptosis"
Chaperone rescue in patient fibroblasts.
PMID:22333902 REFUTE DIRECT PRIMARY RESULT In Vitro
"In COL4A2 (3206delC) fibroblasts we detected increased rates of apoptosis and no signs of ER stress."
Frameshift-allele fibroblasts show no ER stress, so this node does not apply to every allele.
Abnormal Vascular Basement Membrane
Basement membranes of COL4A2 patients show fragmentation, duplication and defective collagen IV incorporation, observed so far in skin biopsies. A defective vascular basement membrane is the proposed substrate of small-vessel fragility; direct cerebrovascular ultrastructure from COL4A2 patients is not available in these sources.
basement membrane organization GO:0071711 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased basement membrane organization (GO:0071711). GO:0071711 is a biological process from the Gene Ontology.
blood vessel UBERON:0001981 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in blood vessel (UBERON:0001981). UBERON:0001981 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cerebral Microvascular Fragility Col4a2 mutant mice develop intracerebral hemorrhage. The step from a defective basement membrane to vessel rupture is inferred from the shared collagen IV biology rather than measured in COL4A2 tissue.
Show evidence (2 references)
PMID:22333902 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Fragmentation and duplication of epidermal basement membranes were observed by electron microscopy in a c.3206delC patient skin biopsy, consistent with abnormal collagen IV network."
Ultrastructural basement-membrane abnormality in a patient.
PMID:24001601 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Analysis of dermal biopsies from a patient and his unaffected father, who also carries the mutation, revealed that both display basement membrane (BM) defects."
Basement-membrane defects in both affected and unaffected carriers.
Cerebral Microvascular Fragility
Small cerebral vessels with defective collagen IV basement membranes are prone to rupture before birth, in infancy or in adult life. Perinatal hemorrhage is the proposed cause of porencephalic cavities.
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Col4a2 mutant mice with intracerebral hemorrhage Mouse recapitulates Spontaneous intracerebral hemorrhage.
Downstream
Intracerebral Hemorrhage Fragile small vessels rupture, giving parenchymal hemorrhage.
Porencephaly Perinatal hemorrhage is proposed to leave fluid-filled porencephalic cavities.
Show evidence (1 reference)
PMID:22209247 SUPPORT DIRECT PRIMARY RESULT Model Organism
"Furthermore, we show that Col4a2 mutant mice also have completely penetrant ICH"
Spontaneous intracerebral hemorrhage in Col4a2 mutant mice.
Cerebral Arterial Smooth Muscle Calcium Signaling Dysregulation
In aged (12-month) but not young heterozygous Col4a2 G646D mice, pial artery smooth muscle cells show enlarged ryanodine receptor 2 clusters, more frequent calcium sparks and elevated BK channel activity, reversible by PKA inhibition. This is a mouse finding for one dominant allele.
smooth muscle cell of the brain vasculature CL:0002590 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves smooth muscle cell of the brain vasculature (CL:0002590). CL:0002590 is a cell type from the Cell Ontology.
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum GO:0014808 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased release of sequestered calcium ion into cytosol by sarcoplasmic reticulum (GO:0014808). GO:0014808 is a biological process from the Gene Ontology.
Downstream
Impaired Cerebral Artery Myogenic Tone Increased spark-BK coupling hyperpolarizes smooth muscle and blunts pressure-induced constriction.
Show evidence (1 reference)
PMID:42856351 SUPPORT DIRECT PRIMARY RESULT Model Organism
"was increased, and large-conductance Ca 2+ -activated K + (BK) channel activity was elevated, in cerebral pial artery smooth muscle cells (SMCs) from aged Col4a2 +/G646D mice"
Calcium spark frequency and BK activity are increased in aged mutant smooth muscle.
Impaired Cerebral Artery Myogenic Tone
Pial arteries of aged Col4a2 G646D mice lose pressure-induced myogenic tone, while downstream parenchymal arterioles respond normally. Whether this contributes to hemorrhage or white matter injury in patients is not established.
artery UBERON:0001637 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in artery (UBERON:0001637). UBERON:0001637 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Col4a2 G646D heterozygous mice Mouse measures Age-dependent loss of pressure-induced tone in pial arteries.
Show evidence (1 reference)
PMID:42856351 SUPPORT DIRECT PRIMARY RESULT Model Organism
"Cerebral pial arteries from aged (12-month-old), but not young (3-month-old), Col4a2 +/G646D mice exhibited impaired pressure-induced myogenic tone, whereas downstream parenchymal arterioles retained normal myogenic responsiveness, revealing a segment-selective vascular defect."
Age- and segment-selective loss of myogenic tone.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Brain Small Vessel Disease 2 (COL4A2) Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

21
Blood 1
Intracerebral Hemorrhage HP:0001342 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intracerebral hemorrhage, annotated with Cerebral hemorrhage (HP:0001342). HP:0001342 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:24390199 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We extensively investigated a 29-year-old male patient with recurrent deep intracerebral hemorrhages causing mild motor and sensory hemisyndromes."
Adult recurrent deep hemorrhage in a heterozygous de novo case.
PMID:41499643 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Case #1, an aborted fetus with cerebral calcifications, hemorrhages, periventricular leukomalacia, and cerebellar disruption"
Fetal cerebral hemorrhage in a biallelic case.
PMID:22209247 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We sequence COL4A2 in 96 patients with ICH and identify three rare, nonsynonymous coding variants in four patients that are not present in a cohort of 144 ICH-free individuals."
Rare COL4A2 variants in sporadic ICH; the authors call them putative mutations.
Cardiovascular 1
Intracranial Aneurysm Dilatation of the cerebral artery HP:0004944 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intracranial carotid aneurysm, annotated with Dilatation of the cerebral artery (HP:0004944). HP:0004944 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:24390199 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Brain MRI showed deep intracerebral hemorrhages of different age, diffuse leukoencephalopathy, multiple cerebral microbleeds and small aneurysms of the carotid siphon bilaterally."
Intracranial carotid aneurysms in a heterozygous adult.
PMID:22333902 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Mutation phenotypes varied, including porencephaly, white matter lesions, cerebellar and optic nerve hypoplasia and unruptured carotid aneurysm."
Unruptured carotid aneurysm in a dominant COL4A2 family; the abstract does not say whether it was intracranial.
Eye 3
Cortical Visual Impairment Cerebral visual impairment HP:0100704 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cortical visual impairment, annotated with Cerebral visual impairment (HP:0100704). HP:0100704 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33912663 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The couple's 8 year-old son was bedridden and exhibited cortical visual impairment."
Cortical visual impairment in a homozygous patient.
Cataract HP:0000518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cataract (HP:0000518). HP:0000518 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26708157 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The cataracts identified in this family expand the phenotypic spectrum associated with mutations in COL4A2 and highlight the increasing overlap with phenotypes associated with COL4A1 mutations."
Cataract in a dominant COL4A2 family.
Optic Nerve Hypoplasia HP:0000609 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic nerve hypoplasia (HP:0000609). HP:0000609 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22333902 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Mutation phenotypes varied, including porencephaly, white matter lesions, cerebellar and optic nerve hypoplasia and unruptured carotid aneurysm."
Optic nerve hypoplasia in a dominant family.
Genitourinary 1
Hematuria HP:0000790 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microscopic hematuria, annotated with Hematuria (HP:0000790). HP:0000790 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:24390199 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Laboratory work-up revealed significant microscopic hematuria and elevation of creatine-kinase."
Hematuria in a heterozygous adult.
PMID:33577044 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The first patient is a 65-year-old woman with hematuria and adult-onset seizures."
Hematuria in a heterozygous adult with cortical malformation.
Metabolism 1
Elevated Creatine Kinase Elevated circulating creatine kinase activity HP:0003236 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated creatine kinase, annotated with Elevated circulating creatine kinase activity (HP:0003236). HP:0003236 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24390199 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Laboratory work-up revealed significant microscopic hematuria and elevation of creatine-kinase."
Raised creatine kinase in a heterozygous adult.
Musculoskeletal 2
Cerebral Calcification HP:0002514 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral calcification (HP:0002514). HP:0002514 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41499643 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Case #1, an aborted fetus with cerebral calcifications, hemorrhages, periventricular leukomalacia, and cerebellar disruption"
Cerebral calcifications in a biallelic fetus.
PMID:36603335 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"neuroimaging phenotype of leukoencephalopathy with spot-like calcifications"
Calcifications in a recessive family.
Spastic Quadriplegia Spastic tetraplegia HP:0002510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spastic quadriplegia, annotated with Spastic tetraplegia (HP:0002510). HP:0002510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33912663 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Motor examination revealed spastic quadriplegia with ophthalmoplegia, nystagmus, and skew deviation."
Spastic quadriplegia in the homozygous brother.
Nervous System 12
Porencephaly Porencephalic cyst HP:0002132 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Porencephaly, annotated with Porencephalic cyst (HP:0002132). HP:0002132 is a phenotype from the Human Phenotype Ontology.
Sequelae: Hemiplegia Focal Epilepsy Intellectual Disability
Show evidence (3 references)
PMID:22209246 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Here we report on two individuals with porencephaly caused by a heterozygous missense mutation in COL4A2, which encodes the type IV α2 collagen chain."
Porencephaly in two heterozygous patients.
PMID:22333902 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Mutation phenotypes varied, including porencephaly, white matter lesions, cerebellar and optic nerve hypoplasia and unruptured carotid aneurysm."
Porencephaly among the phenotypes of two dominant families.
PMID:33912663 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Her brain MRI showed irregular lateral ventricle contour with coalescent porencephaly and generalized cortical atrophy"
Porencephaly in a homozygous (recessive) patient.
Hemiplegia HP:0002301 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital hemiplegia, annotated with Hemiplegia (HP:0002301). HP:0002301 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22209246 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"the maternal elder uncle, who had congenital hemiplegia"
Congenital hemiplegia in a heterozygous relative.
Focal Epilepsy Focal-onset seizure HP:0007359 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Focal epilepsy, annotated with Focal-onset seizure (HP:0007359). HP:0007359 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26708157 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We describe a family with an autosomal dominant disorder comprising porencephaly, focal epilepsy, and lens opacities, which was negative for mutations in COL4A1."
Focal epilepsy in a dominant family.
PMID:33912663 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"He had focal epilepsy that began at age 6 months, partially controlled with carbamazepine."
Focal epilepsy in a homozygous patient.
Infantile Spasms HP:0012469 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Infantile spasms (HP:0012469), qualified as infantile onset, range 0.25-0.83y. HP:0012469 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE; 0.25-0.83y
Show evidence (2 references)
PMID:39006838 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"In this study, we retrospectively analyzed eight patients who were initially diagnosed with Col4a2-related infantile epileptic spasm syndrome and discovered elevated proinflammatory cytokine levels in the cerebrospinal fluid."
Eight-patient retrospective series of COL4A2-related infantile epileptic spasm syndrome.
PMID:39006838 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The age of seizure onset ranged from 3 months to 10 months."
Infantile onset in the same series.
Leukoencephalopathy HP:0002352 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukoencephalopathy (HP:0002352). HP:0002352 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:24390199 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Brain MRI showed deep intracerebral hemorrhages of different age, diffuse leukoencephalopathy, multiple cerebral microbleeds and small aneurysms of the carotid siphon bilaterally."
Leukoencephalopathy in a heterozygous adult.
PMID:36603335 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We broaden the phenotypic and genotypic spectra of COL4A2-related disease by describing this second family with recessive pathogenic variants and neuroimaging phenotype of leukoencephalopathy with spot-like calcifications."
Leukoencephalopathy in a recessive family.
Periventricular Leukomalacia HP:0006970 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Periventricular leukomalacia (HP:0006970). HP:0006970 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41499643 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Case #1, an aborted fetus with cerebral calcifications, hemorrhages, periventricular leukomalacia, and cerebellar disruption"
Periventricular leukomalacia in a biallelic fetus.
Schizencephaly HP:0010636 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Schizencephaly (HP:0010636). HP:0010636 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41499643 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Patient #2, a 2-year-old girl with neurodevelopmental impairment, cortical malformations (frontal schizencephaly, polymicrogyria), and reduced white matter volume"
Schizencephaly in a compound heterozygous child.
PMID:33577044 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Brain MRI showed closed lip schizencephaly of right lateral sulcus associated with polymicrogyria of the surrounding cortex and areas of subcortical heterotopia."
Schizencephaly in a heterozygous adult.
Polymicrogyria HP:0002126 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polymicrogyria (HP:0002126). HP:0002126 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41499643 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Patient #2, a 2-year-old girl with neurodevelopmental impairment, cortical malformations (frontal schizencephaly, polymicrogyria), and reduced white matter volume"
Polymicrogyria in a compound heterozygous child.
PMID:33577044 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Brain MRI showed closed lip schizencephaly of right lateral sulcus associated with polymicrogyria of the surrounding cortex and areas of subcortical heterotopia."
Polymicrogyria in a heterozygous adult.
Intellectual Disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33912663 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We describe 2 children from a consanguineous Iranian family with intellectual disability, spastic cerebral palsy, and epilepsy who each harbored the same homozygous mutation in COL4A2."
Intellectual disability in both homozygous siblings.
Global Developmental Delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33912663 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Milestone attainment had been globally delayed."
Global delay in a homozygous patient.
Absent Speech HP:0001344 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent speech (HP:0001344). HP:0001344 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33912663 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"He did not speak or demonstrate communicative intent."
Absent speech in the homozygous brother (his sister also did not speak).
Colpocephaly HP:0030048 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Colpocephaly (HP:0030048). HP:0030048 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33912663 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Brain MRI revealed bilateral colpocephaly and irregular ventricular contours."
Colpocephaly in a homozygous patient.
🧬

Genetic Associations

1
COL4A2
Gene: COL4A2 hgnc:2203 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is COL4A2 (hgnc:2203). hgnc:2203 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:22209246 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Mutations c.3455G>A and c.3110G>A, one in each of the individuals, cause Gly residues in the Gly-Xaa-Yaa repeat to be substituted as p.Gly1152Asp and p.Gly1037Glu, respectively, probably resulting in alterations of the α1α1α2 heterotrimers."
Glycine substitutions in the triple-helical Gly-Xaa-Yaa repeat are the typical dominant variant class.
PMID:22333902 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Genomic sequencing of COL4A2 identified the heterozygous missense G1389R in exon 44 in one family and the c.3206delC change in exon 34 leading to frame shift and premature stop, in the second family."
Missense and frameshift dominant alleles.
PMID:30315939 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"two COL4A2 mutations were found, respectively in one familial case (c.4129G > A, p.(Gly1377Arg)) and one sporadic patient (c.1776+1G > A)"
Glycine-substitution and splice-site COL4A2 variants in schizencephaly/polymicrogyria.
💊

Medical Actions

4
Genetic Counseling and Testing
Action: Genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Behavioral / lifestyle
Genetic testing and counseling for affected individuals and at-risk relatives, as recommended by the COL4A1/COL4A2 expert consensus. Testing must establish zygosity and phase because dominant and recessive COL4A2 forms both exist.
Show evidence (1 reference)
PMID:40616396 SUPPORT DIRECT REVIEW SYNTHESIS Other
"Genetic testing and counseling are advised for individuals showing symptoms of COL4A1/A2-related disorders and for at-risk relatives."
eDelphi expert consensus recommendation covering COL4A2.
Vascular Risk Reduction
Action: Vascular risk reductionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Vascular risk reduction, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
Treating hypertension and avoiding smoking, head trauma and anticoagulants to lower the risk of intracerebral hemorrhage. This guidance comes from the COL4A1 GeneReviews chapter and is extended to COL4A2 disease by analogy; it has not been tested in COL4A2 patients.
Target Phenotypes: Intracerebral hemorrhage HP:0001342 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Intracerebral hemorrhage, annotated with Cerebral hemorrhage (HP:0001342). HP:0001342 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301768 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"Prevention of primary and secondary complications: Avoiding head trauma and anticoagulant exposure may decrease the risk for intracerebral hemorrhage."
COL4A1 guidance extended to COL4A2 because the two chains form one heterotrimer and share the hemorrhage phenotype.
PMID:20301768 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"Agents/circumstances to avoid: Smoking and hypertension because these factors increase the risk for stroke; sustained head pressure or physical activities that may cause head trauma; anticoagulant use."
COL4A1 guidance on circumstances to avoid, extended to COL4A2 by analogy.
Antiseizure Medication
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: carbamazepine CHEBI:3387 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses carbamazepine (CHEBI:3387). CHEBI:3387 is a therapeutic agent from Chemical Entities of Biological Interest. phenobarbital CHEBI:8069 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses phenobarbital (CHEBI:8069). CHEBI:8069 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Focal epilepsy is treated with standard antiseizure drugs. In the first recessive family carbamazepine partially controlled seizures in one sibling and phenobarbital with carbamazepine controlled them in the other; these are single observations, not response rates.
Target Phenotypes: Focal epilepsy HP:0007359 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Focal epilepsy, annotated with Focal-onset seizure (HP:0007359). HP:0007359 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33912663 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Seizures were controlled with phenobarbital and carbamazepine."
Seizure control in a homozygous patient.
Chemical Chaperone (Preclinical)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: 4-phenylbutyrate CHEBI:41500 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses 4-phenylbutyrate, annotated with 4-phenylbutyric acid (CHEBI:41500). CHEBI:41500 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Sodium 4-phenylbutyrate reduced intracellular COL4A2 accumulation, ER stress and apoptosis in fibroblasts from a G702D patient. This is an in vitro result for one allele and is not a clinical treatment; it would not address alleles that act without ER retention.
Mechanism Target:
Intracellular Collagen IV Retention — The chaperone lowers retained collagen IV in patient fibroblasts.
Show evidence (1 reference)
PMID:24001601 SUPPORT DIRECT PRIMARY RESULT In Vitro
"treatment of patient cells with a chemical chaperone decreased intracellular COL4A2 levels, ER stress and apoptosis"
In vitro rescue of retention and stress.
Show evidence (1 reference)
PMID:24001601 SUPPORT DIRECT PRIMARY RESULT In Vitro
"treatment of patient cells with a chemical chaperone decreased intracellular COL4A2 levels, ER stress and apoptosis"
Preclinical patient-cell evidence only.
🔬

Diagnosis

2
COL4A2 molecular genetic testing
Diagnosis rests on a pathogenic COL4A2 variant in a person with compatible cerebrovascular or brain imaging findings, usually found by exome sequencing or a multigene panel that also covers COL4A1. Zygosity and parental phase separate the dominant form (one heterozygous variant, inherited or de novo) from the recessive form (homozygous or compound heterozygous variants with carrier parents), which matters for recurrence risk.
Genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:40616396 SUPPORT DIRECT REVIEW SYNTHESIS Other
"Genetic testing and counseling are advised for individuals showing symptoms of COL4A1/A2-related disorders and for at-risk relatives."
Expert consensus recommendation covering COL4A1 and COL4A2 jointly, so it applies to COL4A2 directly.
PMID:41499643 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Exome sequencing identified a homozygous missense COL4A2 variant in case #1 and compound heterozygous loss-of-function variants (splicing and truncating) in case #2."
Exome sequencing established the biallelic, recessive diagnosis, with zygosity and phase distinguishing it from the dominant form.
Brain MRI and multiorgan evaluation
Neurological imaging characterizes porencephaly, hemorrhage, leukoencephalopathy, calcification and cortical malformation. Ophthalmological imaging and cardiovascular and renal monitoring are recommended by the joint COL4A1/COL4A2 consensus; renal and ocular involvement in COL4A2 disease is known only from isolated reports.
Brain MRI NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:40616396 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Recommended care includes neurological and ophthalmological imaging and monitoring of cardiovascular and renal function."
Consensus recommendation for COL4A1 and COL4A2 disorders together. Graded indirect because most of the multiorgan involvement behind it comes from COL4A1 patients and the abstract does not separate the genes.
🐁

Animal Models

4
Col4a2 ENU missense mice
Random-mutagenesis Col4a1 and Col4a2 missense alleles. Heterozygotes show eye, brain, kidney and vascular stability defects; homozygotes die by mid-gestation. The abstract reports these findings for the Col4a1 and Col4a2 series together.
Species
Mouse
Genotype
Heterozygous ENU-induced Col4a2 missense alleles (first two Col4a2 mutant alleles)
Genes
Col4a2 MGI:88455 Mouse Genome Informatics (MGI) Relation: this experimental model concerns this gene This experimental model concerns Col4a2 (MGI:88455). MGI:88455 is a gene from Mouse Genome Informatics.
Publication
PMID:17179069
Show evidence (1 reference)
PMID:17179069 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"Heterozygous carriers express defects in the eye, the brain, kidney function, vascular stability, and viability. Homozygotes do not survive beyond the second trimester."
Pooled Col4a1/Col4a2 statement; not separable to Col4a2 alleles from the abstract.
Col4a2 mutant mice with intracerebral hemorrhage
Col4a2 mutant mice develop completely penetrant intracerebral hemorrhage with ER retention of both collagen IV chains.
Species
Mouse
Genotype
Col4a2 missense mutant
Publication
PMID:22209247
Pathograph links
Cerebral Microvascular Fragility recapitulates fidelity: moderate Spontaneous intracerebral hemorrhage.
Show evidence (1 reference)
PMID:22209247 SUPPORT DIRECT PRIMARY RESULT Model Organism
"Furthermore, we show that Col4a2 mutant mice also have completely penetrant ICH"
Hemorrhage phenotype in Col4a2 mutant mice.
Intracellular Collagen IV Retention recapitulates fidelity: moderate ER retention of COL4A1 and COL4A2.
Show evidence (1 reference)
PMID:22209247 SUPPORT DIRECT PRIMARY RESULT Model Organism
"mutations in mouse and human lead to retention of COL4A1 and COL4A2 within the endoplasmic reticulum (ER)"
ER retention in mutant mice.
Col4a2 G646D heterozygous mice
Aged heterozygous mice show segment-selective loss of pial artery myogenic tone with ryanodine receptor cluster remodeling in smooth muscle.
Species
Mouse
Genotype
Col4a2 +/G646D
Publication
PMID:42856351
Pathograph links
Impaired Cerebral Artery Myogenic Tone measures fidelity: unknown Age-dependent loss of pressure-induced tone in pial arteries.
Limitations: Mouse arteries from one dominant allele; no human cerebral artery tone measurement exists for COL4A2 disease, so fidelity to patients is unknown.
Show evidence (1 reference)
PMID:42856351 SUPPORT DIRECT PRIMARY RESULT Model Organism
"Cerebral pial arteries from aged (12-month-old), but not young (3-month-old), Col4a2 +/G646D mice exhibited impaired pressure-induced myogenic tone, whereas downstream parenchymal arterioles retained normal myogenic responsiveness, revealing a segment-selective vascular defect."
Direct measurement in the model.
Col4a2 em1(IMPC)Wtsi homozygous embryos
Homozygous embryos survive organogenesis to E14.5 and show brain, cranial nerve, eye, lung, endocrine, skeletal and cardiovascular defects, including cortical surface irregularities and small cortical cysts. Residual Col4a2 expression explains the longer survival than null alleles. A partial model of biallelic COL4A2 loss, relevant to the recessive form.
Species
Mouse
Genotype
Col4a2 em1(IMPC)Wtsi homozygous (hypomorphic, about 11-fold knockdown)
Publication
PMID:31331924
Show evidence (1 reference)
PMID:31331924 SUPPORT DIRECT PRIMARY RESULT Model Organism
"They showed defects in the brain, cranial nerves, visual system, lungs, endocrine glands, skeleton, subepithelial tissues and mild to severe cardiovascular malformations."
Multiorgan developmental defects in homozygous hypomorphic embryos.
{ }

Source YAML

click to show 
name: Brain Small Vessel Disease 2 (COL4A2)
category: Mendelian
creation_date: "2026-10-11T20:20:00Z"
synonyms:
- COL4A2-related brain small vessel disease
- COL4A2-related disorder
- Brain small vessel disease 2A, autosomal dominant
- Brain small vessel disease 2B, autosomal recessive
- BSVD2A
- BSVD2B
- Porencephaly 2
- Autosomal dominant porencephaly type 2
description: >-
  Brain small vessel disease 2 is the cerebrovascular disorder caused by pathogenic germline variants in COL4A2,
  which encodes the alpha-2 chain of the alpha1-alpha1-alpha2 type IV collagen heterotrimer of vascular
  basement membranes. The common form (BSVD2A) is autosomal dominant with reduced penetrance and variable
  expression: heterozygous glycine substitutions in the triple helix, frameshift and splice variants are
  associated with porencephaly, congenital hemiplegia, focal epilepsy, leukoencephalopathy, intracerebral
  hemorrhage in childhood or adult life, cortical malformations such as schizencephaly and polymicrogyria,
  and occasional cataract, optic nerve hypoplasia, intracranial aneurysm, hematuria and raised creatine kinase.
  A rare autosomal recessive form (BSVD2B) has been reported in a handful of families with homozygous or
  compound heterozygous COL4A2 variants and early, severe presentations including fetal hemorrhagic brain
  injury, intellectual disability, spastic quadriplegia, epilepsy, leukoencephalopathy with calcifications
  and cortical malformations. Mechanistically, dominant missense alleles cause intracellular retention of
  both collagen IV chains with reduced secretion, variable endoplasmic-reticulum stress, and basement-membrane
  defects that predispose small cerebral vessels to hemorrhage. Management is supportive and follows the
  shared COL4A1/COL4A2 consensus; no mechanism-directed therapy is established.
disease_term:
  preferred_term: brain small vessel disease 2A, autosomal dominant
  term:
    id: MONDO:0013773
    label: brain small vessel disease 2A, autosomal dominant
parents:
- COL4A1/A2-related disorder
- Familial porencephaly
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0980747
      label: brain small vessel disease 2B, autosomal recessive
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0980747 is the biallelic COL4A2 disease (OMIM:621414). This entry covers both the dominant
      (MONDO:0013773) and recessive COL4A2 forms and carries the recessive form as the BSVD2B subtype,
      so the recessive MONDO concept is narrower than the entry.
references:
- reference: PMID:20301768
  title: COL4A1-Related Disorders.
  tags:
  - GeneReviews
  findings: []
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  description: >-
    The common form is autosomal dominant. Variants are inherited from mildly affected or asymptomatic
    parents or arise de novo. Penetrance is reduced and expression varies within families, from congenital
    hemiplegia to an asymptomatic carrier.
  evidence:
  - reference: PMID:22209246
    reference_title: "De novo and inherited mutations in COL4A2, encoding the type IV collagen α2 chain cause porencephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "The c.3455G>A mutation was found in the proband's mother, who showed very mild monoparesis of the left upper extremity, and the maternal elder uncle, who had congenital hemiplegia. The maternal grandfather harboring the mutation is asymptomatic. The c.3110G>A mutation occurred de novo."
    explanation: >-
      One heterozygous variant segregated through three generations with variable expression and an
      asymptomatic carrier grandfather; a second arose de novo. Both establish heterozygous (dominant)
      transmission with incomplete penetrance.
  - reference: PMID:22333902
    reference_title: COL4A2 mutation associated with familial porencephaly and small-vessel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "dominant COL4A2 mutations are a novel major risk factor for familial cerebrovascular disease, including porencephaly and small-vessel disease with reduced penetrance and variable phenotype"
    explanation: Two families with heterozygous COL4A2 variants show dominant transmission with reduced penetrance.
  - reference: PMID:24001601
    reference_title: Chemical chaperone treatment reduces intracellular accumulation of mutant collagen IV and ameliorates the cellular phenotype of a COL4A2 mutation that causes haemorrhagic stroke.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "we report the identification of a novel dominant G702D mutation in the collagen domain of COL4A2 (collagen IV alpha chain 2) in a family displaying porencephaly with reduced penetrance"
    explanation: A third family with a dominant COL4A2 glycine substitution and reduced penetrance (the unaffected father carries it).
has_subtypes:
- name: BSVD2A
  display_name: Brain small vessel disease 2A, autosomal dominant
  classification: inheritance
  subtype_term:
    preferred_term: brain small vessel disease 2A, autosomal dominant
    term:
      id: MONDO:0013773
      label: brain small vessel disease 2A, autosomal dominant
  description: >-
    Heterozygous COL4A2 variants, mostly glycine substitutions in the collagenous domain plus frameshift and
    splice variants, inherited with reduced penetrance or arising de novo. Presentations range from perinatal
    porencephaly with hemiplegia and focal epilepsy to adult-onset recurrent deep intracerebral hemorrhage
    with leukoencephalopathy, and include cortical malformations and occasional cataract.
  genes:
  - preferred_term: COL4A2
    term:
      id: hgnc:2203
      label: COL4A2
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:22209246
    reference_title: "De novo and inherited mutations in COL4A2, encoding the type IV collagen α2 chain cause porencephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Here we report on two individuals with porencephaly caused by a heterozygous missense mutation in COL4A2, which encodes the type IV α2 collagen chain."
    explanation: Founding report of heterozygous COL4A2 porencephaly.
  - reference: PMID:26708157
    reference_title: A mutation in COL4A2 causes autosomal dominant porencephaly with cataracts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "We describe a family with an autosomal dominant disorder comprising porencephaly, focal epilepsy, and lens opacities, which was negative for mutations in COL4A1."
    explanation: Three-generation dominant family with a COL4A2 glycine substitution.
- name: BSVD2B
  display_name: Brain small vessel disease 2B, autosomal recessive
  classification: inheritance
  subtype_term:
    preferred_term: brain small vessel disease 2B, autosomal recessive
    term:
      id: MONDO:0980747
      label: brain small vessel disease 2B, autosomal recessive
  description: >-
    Biallelic COL4A2 variants with clinically unaffected heterozygous parents. Three families are described
    in the sources cited here: two affected siblings homozygous for p.Gly1158Arg from a consanguineous
    Iranian family (PMID:33912663), a second family with leukoencephalopathy and spot-like calcifications
    (PMID:36603335), and two further cases, an aborted fetus with a homozygous missense variant and a
    two-year-old girl with compound heterozygous splice and truncating variants (PMID:41499643). Presentations
    are early and severe: fetal cerebral hemorrhage and calcification, global developmental delay,
    intellectual disability, absent speech, spastic quadriplegia, focal epilepsy, colpocephaly and porencephaly,
    and cortical malformations. The fetal homozygous missense variant was classified likely benign by its
    reporting authors, so causality for that case remains provisional.
  genes:
  - preferred_term: COL4A2
    term:
      id: hgnc:2203
      label: COL4A2
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    description: >-
      Homozygous or compound heterozygous COL4A2 variants. Parents carrying one allele were neurologically
      healthy in the first family, although they were not imaged, so subclinical small vessel disease in
      carriers is not excluded.
    evidence:
    - reference: PMID:33912663
      reference_title: Recessive COL4A2 Mutation Leads to Intellectual Disability, Epilepsy, and Spastic Cerebral Palsy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: "This revealed a homozygous c.3472G>C (p.G1158R) variant in COL4A2 (NM_001846) segregating with disease status in the family (both parents are neurologically healthy, although neuroimaging was not able to be performed)"
      explanation: Homozygous variant in two affected siblings with healthy heterozygous parents supports recessive inheritance.
  evidence:
  - reference: PMID:33912663
    reference_title: Recessive COL4A2 Mutation Leads to Intellectual Disability, Epilepsy, and Spastic Cerebral Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "We describe 2 children from a consanguineous Iranian family with intellectual disability, spastic cerebral palsy, and epilepsy who each harbored the same homozygous mutation in COL4A2."
    explanation: First recessive COL4A2 family, two affected siblings.
  - reference: PMID:33912663
    reference_title: Recessive COL4A2 Mutation Leads to Intellectual Disability, Epilepsy, and Spastic Cerebral Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Our results indicate that both dominant and recessive forms of COL4A2 disease exist."
    explanation: Authors' conclusion establishing a recessive COL4A2 form alongside the dominant one.
  - reference: PMID:36603335
    reference_title: Leukoencephalopathy with spot-like calcifications caused by recessive COL4A2 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "We broaden the phenotypic and genotypic spectra of COL4A2-related disease by describing this second family with recessive pathogenic variants and neuroimaging phenotype of leukoencephalopathy with spot-like calcifications."
    explanation: Second family with recessive COL4A2 variants.
  - reference: PMID:41499643
    reference_title: Biallelic COL4A2 Variants Associated With Brain Small Vessel Disease and Brain Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Exome sequencing identified a homozygous missense COL4A2 variant in case #1 and compound heterozygous loss-of-function variants (splicing and truncating) in case #2."
    explanation: Two further biallelic cases, one homozygous and one compound heterozygous.
genetic:
- name: COL4A2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: COL4A2
    term:
      id: hgnc:2203
      label: COL4A2
  notes: >-
    Dominant alleles reported in the cited sources include the glycine substitutions p.Gly1152Asp and
    p.Gly1037Glu (porencephaly), p.Gly1389Arg, p.Gly702Asp, p.Gly800Glu (porencephaly with cataract),
    p.Gly991Glu and p.Gly1377Arg (cortical malformations), plus the frameshift c.3206delC and the splice
    variant c.1776+1G>A. Recessive alleles include homozygous p.Gly1158Arg and compound heterozygous splice
    and truncating variants. Rare missense variants found in sporadic intracerebral hemorrhage
    (PMID:22209247) were reported as putative mutations. Copy-number gains spanning COL4A1 and COL4A2 cause
    an adult small vessel disease by a dosage mechanism and are not covered here. ClinGen has no
    gene-disease validity record for COL4A2 in the local cache, so no validity tier is recorded.
  evidence:
  - reference: PMID:22209246
    reference_title: "De novo and inherited mutations in COL4A2, encoding the type IV collagen α2 chain cause porencephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Mutations c.3455G>A and c.3110G>A, one in each of the individuals, cause Gly residues in the Gly-Xaa-Yaa repeat to be substituted as p.Gly1152Asp and p.Gly1037Glu, respectively, probably resulting in alterations of the α1α1α2 heterotrimers."
    explanation: Glycine substitutions in the triple-helical Gly-Xaa-Yaa repeat are the typical dominant variant class.
  - reference: PMID:22333902
    reference_title: COL4A2 mutation associated with familial porencephaly and small-vessel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Genomic sequencing of COL4A2 identified the heterozygous missense G1389R in exon 44 in one family and the c.3206delC change in exon 34 leading to frame shift and premature stop, in the second family."
    explanation: Missense and frameshift dominant alleles.
  - reference: PMID:30315939
    reference_title: Further refinement of COL4A1 and COL4A2 related cortical malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "two COL4A2 mutations were found, respectively in one familial case (c.4129G > A, p.(Gly1377Arg)) and one sporadic patient (c.1776+1G > A)"
    explanation: Glycine-substitution and splice-site COL4A2 variants in schizencephaly/polymicrogyria.
pathophysiology:
- name: Pathogenic COL4A2 Variation
  biological_scale: MOLECULAR
  description: >-
    Germline COL4A2 variants alter the alpha-2(IV) chain. Heterozygous glycine substitutions in the
    Gly-Xaa-Yaa repeats are predicted to disturb alpha1-alpha1-alpha2 heterotrimer assembly; frameshift and
    splice alleles and biallelic variants are predicted to reduce or destabilize the chain. Patient-specific
    functional confirmation exists for only a few dominant alleles, and none for the recessive alleles.
  genes:
  - preferred_term: COL4A2
    term:
      id: hgnc:2203
      label: COL4A2
  cellular_components:
  - preferred_term: collagen type IV trimer
    term:
      id: GO:0005587
      label: collagen type IV trimer
  molecular_functions:
  - preferred_term: extracellular matrix structural constituent
    term:
      id: GO:0005201
      label: extracellular matrix structural constituent
    modifier: ABNORMAL
  evidence:
  - reference: PMID:22209246
    reference_title: "De novo and inherited mutations in COL4A2, encoding the type IV collagen α2 chain cause porencephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Our study confirmed that abnormalities of the α1α1α2 heterotrimers of type IV collagen cause porencephaly and stresses the importance of screening for COL4A2 as well as for COL4A1."
    explanation: Heterotrimer abnormality from COL4A2 variants is the proximate molecular lesion.
  - reference: PMID:41499643
    reference_title: Biallelic COL4A2 Variants Associated With Brain Small Vessel Disease and Brain Malformations.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    snippet: "All variants were rare and predicted to affect protein stability and function in silico."
    explanation: Recessive alleles are predicted, not shown, to destabilize the protein.
  downstream:
  - target: Intracellular Collagen IV Retention
    description: Dominant COL4A2 missense alleles cause both collagen IV chains to accumulate in the endoplasmic reticulum.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22209247
      reference_title: COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: "Using a cellular assay, we show that these putative mutations cause intracellular accumulation of COL4A1 and COL4A2 at the expense of their secretion, which supports their pathogenecity."
      explanation: Cellular assay of patient-derived COL4A2 missense variants.
  - target: Cerebral Arterial Smooth Muscle Calcium Signaling Dysregulation
    description: In aged heterozygous Col4a2 G646D mice, pial artery smooth muscle shows remodeled ryanodine receptor clusters with more calcium sparks and BK channel activity.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42856351
      reference_title: Ryanodine receptor cluster remodeling links COL4A2 mutation to cerebral artery dysfunction.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: "These findings identify age-associated, PKA-dependent, nanoscale remodeling of RyR2 clusters as a previously unknown mechanism underlying cerebral arterial dysfunction in COL4A2-related disease."
      explanation: Mouse model links a heterozygous Col4a2 mutation to smooth-muscle calcium signaling changes; intermediates between the matrix defect and PKA activation are unknown.
- name: Intracellular Collagen IV Retention
  biological_scale: CELLULAR
  description: >-
    Mutant alpha-2(IV) and its alpha-1(IV) partner are retained in the endoplasmic reticulum at the expense of
    secretion, in patient cells and in Col4a2 mutant mice. Retention was seen in an affected patient's
    fibroblasts but not in those of his unaffected carrier father, suggesting that retention or its clearance
    modifies disease expression. Mutant collagen IV is degraded by the proteasome.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:22209247
    reference_title: COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "mutations in mouse and human lead to retention of COL4A1 and COL4A2 within the endoplasmic reticulum (ER)"
    explanation: ER retention in Col4a2 mutant mice; the human arm of the same sentence is the cellular assay cited on the upstream edge.
  - reference: PMID:24001601
    reference_title: Chemical chaperone treatment reduces intracellular accumulation of mutant collagen IV and ameliorates the cellular phenotype of a COL4A2 mutation that causes haemorrhagic stroke.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "the absence of ER retention of COL4A2 and ER stress in cells from the unaffected father indicate that accumulation and/or clearance of mutant COL4A2 from the ER may be a critical modifier for disease development"
    explanation: Patient versus carrier-father fibroblasts tie retention to disease expression.
  downstream:
  - target: Endoplasmic Reticulum Stress
    description: Retention activates the unfolded protein response for some, but not all, COL4A2 variants.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24001601
      reference_title: Chemical chaperone treatment reduces intracellular accumulation of mutant collagen IV and ameliorates the cellular phenotype of a COL4A2 mutation that causes haemorrhagic stroke.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: "This intracellular accumulation led to ER stress, unfolded protein response activation, reduced cell proliferation and increased apoptosis."
      explanation: Patient G702D fibroblasts.
  - target: Abnormal Vascular Basement Membrane
    description: Impaired secretion reduces collagen IV incorporation into basement membranes.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24001601
      reference_title: Chemical chaperone treatment reduces intracellular accumulation of mutant collagen IV and ameliorates the cellular phenotype of a COL4A2 mutation that causes haemorrhagic stroke.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: "defective collagen IV incorporation into the dermal BM was observed in the patient only and was associated with endoplasmic reticulum (ER) retention of COL4A2 in primary dermal fibroblasts"
      explanation: Patient skin shows defective basement-membrane incorporation alongside fibroblast retention; dermal rather than cerebrovascular tissue.
- name: Endoplasmic Reticulum Stress
  biological_scale: CELLULAR
  description: >-
    Some COL4A2 variants activate the unfolded protein response, with reduced proliferation and increased
    apoptosis in patient fibroblasts, and a chemical chaperone reduces both retention and stress in vitro.
    ER stress is not obligatory: fibroblasts carrying the c.3206delC frameshift showed increased apoptosis
    without signs of ER stress, and only two of three missense variants tested triggered it.
  biological_processes:
  - preferred_term: endoplasmic reticulum unfolded protein response
    term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    modifier: INCREASED
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:22209247
    reference_title: COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Importantly, two of the three putative mutations found in patients trigger ER stress and activate the unfolded protein response."
    explanation: Variant-dependent UPR activation in cells.
  - reference: PMID:24001601
    reference_title: Chemical chaperone treatment reduces intracellular accumulation of mutant collagen IV and ameliorates the cellular phenotype of a COL4A2 mutation that causes haemorrhagic stroke.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "treatment of patient cells with a chemical chaperone decreased intracellular COL4A2 levels, ER stress and apoptosis"
    explanation: Chaperone rescue in patient fibroblasts.
  - reference: PMID:22333902
    reference_title: COL4A2 mutation associated with familial porencephaly and small-vessel disease.
    supports: REFUTE
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "In COL4A2 (3206delC) fibroblasts we detected increased rates of apoptosis and no signs of ER stress."
    explanation: Frameshift-allele fibroblasts show no ER stress, so this node does not apply to every allele.
- name: Abnormal Vascular Basement Membrane
  biological_scale: TISSUE
  description: >-
    Basement membranes of COL4A2 patients show fragmentation, duplication and defective collagen IV
    incorporation, observed so far in skin biopsies. A defective vascular basement membrane is the proposed
    substrate of small-vessel fragility; direct cerebrovascular ultrastructure from COL4A2 patients is not
    available in these sources.
  locations:
  - preferred_term: blood vessel
    term:
      id: UBERON:0001981
      label: blood vessel
  biological_processes:
  - preferred_term: basement membrane organization
    term:
      id: GO:0071711
      label: basement membrane organization
    modifier: DECREASED
  evidence:
  - reference: PMID:22333902
    reference_title: COL4A2 mutation associated with familial porencephaly and small-vessel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Fragmentation and duplication of epidermal basement membranes were observed by electron microscopy in a c.3206delC patient skin biopsy, consistent with abnormal collagen IV network."
    explanation: Ultrastructural basement-membrane abnormality in a patient.
  - reference: PMID:24001601
    reference_title: Chemical chaperone treatment reduces intracellular accumulation of mutant collagen IV and ameliorates the cellular phenotype of a COL4A2 mutation that causes haemorrhagic stroke.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Analysis of dermal biopsies from a patient and his unaffected father, who also carries the mutation, revealed that both display basement membrane (BM) defects."
    explanation: Basement-membrane defects in both affected and unaffected carriers.
  downstream:
  - target: Cerebral Microvascular Fragility
    description: >-
      Col4a2 mutant mice develop intracerebral hemorrhage. The step from a defective basement membrane to
      vessel rupture is inferred from the shared collagen IV biology rather than measured in COL4A2 tissue.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22209247
      reference_title: COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: "Furthermore, we show that Col4a2 mutant mice also have completely penetrant ICH"
      explanation: Hemorrhage in Col4a2 mutant mice supports vessel fragility; the basement-membrane intermediate is inferred.
- name: Cerebral Microvascular Fragility
  biological_scale: TISSUE
  description: >-
    Small cerebral vessels with defective collagen IV basement membranes are prone to rupture before birth,
    in infancy or in adult life. Perinatal hemorrhage is the proposed cause of porencephalic cavities.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:22209247
    reference_title: COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Furthermore, we show that Col4a2 mutant mice also have completely penetrant ICH"
    explanation: Spontaneous intracerebral hemorrhage in Col4a2 mutant mice.
  downstream:
  - target: Intracerebral Hemorrhage
    description: Fragile small vessels rupture, giving parenchymal hemorrhage.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24390199
      reference_title: COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: "Brain MRI showed deep intracerebral hemorrhages of different age, diffuse leukoencephalopathy, multiple cerebral microbleeds and small aneurysms of the carotid siphon bilaterally."
      explanation: Recurrent deep hemorrhages and microbleeds in a de novo COL4A2 patient are the clinical expression of small-vessel fragility.
  - target: Porencephaly
    description: Perinatal hemorrhage is proposed to leave fluid-filled porencephalic cavities.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24001601
      reference_title: Chemical chaperone treatment reduces intracellular accumulation of mutant collagen IV and ameliorates the cellular phenotype of a COL4A2 mutation that causes haemorrhagic stroke.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: BACKGROUND
      snippet: "porencephaly is a clinical consequence of perinatal cerebral haemorrhaging"
      explanation: Background statement linking perinatal hemorrhage to porencephaly.
    - reference: PMID:22209246
      reference_title: "De novo and inherited mutations in COL4A2, encoding the type IV collagen α2 chain cause porencephaly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: BACKGROUND
      snippet: "It has been suggested that porencephalic cavities result from focal cerebral degeneration involving hemorrhages."
      explanation: Background statement of the hemorrhage-to-cavity mechanism.
- name: Cerebral Arterial Smooth Muscle Calcium Signaling Dysregulation
  biological_scale: CELLULAR
  description: >-
    In aged (12-month) but not young heterozygous Col4a2 G646D mice, pial artery smooth muscle cells show
    enlarged ryanodine receptor 2 clusters, more frequent calcium sparks and elevated BK channel activity,
    reversible by PKA inhibition. This is a mouse finding for one dominant allele.
  cell_types:
  - preferred_term: smooth muscle cell of the brain vasculature
    term:
      id: CL:0002590
      label: smooth muscle cell of the brain vasculature
  biological_processes:
  - preferred_term: release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
    term:
      id: GO:0014808
      label: release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
    modifier: INCREASED
  evidence:
  - reference: PMID:42856351
    reference_title: Ryanodine receptor cluster remodeling links COL4A2 mutation to cerebral artery dysfunction.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "was increased, and large-conductance Ca 2+ -activated K + (BK) channel activity was elevated, in cerebral pial artery smooth muscle cells (SMCs) from aged Col4a2 +/G646D mice"
    explanation: Calcium spark frequency and BK activity are increased in aged mutant smooth muscle.
  downstream:
  - target: Impaired Cerebral Artery Myogenic Tone
    description: Increased spark-BK coupling hyperpolarizes smooth muscle and blunts pressure-induced constriction.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42856351
      reference_title: Ryanodine receptor cluster remodeling links COL4A2 mutation to cerebral artery dysfunction.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: "PKA inhibition normalized RyR2 cluster organization and BK channel activity in SMCs from aged Col4a2 +/G646D mice"
      explanation: Pharmacologic normalization of the calcium-signaling change; the link to tone is the authors' mechanistic model.
- name: Impaired Cerebral Artery Myogenic Tone
  biological_scale: TISSUE
  description: >-
    Pial arteries of aged Col4a2 G646D mice lose pressure-induced myogenic tone, while downstream parenchymal
    arterioles respond normally. Whether this contributes to hemorrhage or white matter injury in patients is
    not established.
  locations:
  - preferred_term: artery
    term:
      id: UBERON:0001637
      label: artery
  evidence:
  - reference: PMID:42856351
    reference_title: Ryanodine receptor cluster remodeling links COL4A2 mutation to cerebral artery dysfunction.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Cerebral pial arteries from aged (12-month-old), but not young (3-month-old), Col4a2 +/G646D mice exhibited impaired pressure-induced myogenic tone, whereas downstream parenchymal arterioles retained normal myogenic responsiveness, revealing a segment-selective vascular defect."
    explanation: Age- and segment-selective loss of myogenic tone.
phenotypes:
- category: Neurological
  name: Porencephaly
  description: >-
    Fluid-filled cerebral cavities, the founding phenotype of the dominant form, also seen in the recessive
    sibling pair.
  phenotype_term:
    preferred_term: Porencephaly
    term:
      id: HP:0002132
      label: Porencephalic cyst
  evidence:
  - reference: PMID:22209246
    reference_title: "De novo and inherited mutations in COL4A2, encoding the type IV collagen α2 chain cause porencephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Here we report on two individuals with porencephaly caused by a heterozygous missense mutation in COL4A2, which encodes the type IV α2 collagen chain."
    explanation: Porencephaly in two heterozygous patients.
  - reference: PMID:22333902
    reference_title: COL4A2 mutation associated with familial porencephaly and small-vessel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Mutation phenotypes varied, including porencephaly, white matter lesions, cerebellar and optic nerve hypoplasia and unruptured carotid aneurysm."
    explanation: Porencephaly among the phenotypes of two dominant families.
  - reference: PMID:33912663
    reference_title: Recessive COL4A2 Mutation Leads to Intellectual Disability, Epilepsy, and Spastic Cerebral Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Her brain MRI showed irregular lateral ventricle contour with coalescent porencephaly and generalized cortical atrophy"
    explanation: Porencephaly in a homozygous (recessive) patient.
  sequelae:
  - target: Hemiplegia
    description: Porencephalic cavities commonly cause hemiplegia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22209246
      reference_title: "De novo and inherited mutations in COL4A2, encoding the type IV collagen α2 chain cause porencephaly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      quote_role: BACKGROUND
      snippet: "Porencephaly is a neurological disorder characterized by fluid-filled cysts or cavities in the brain that often cause hemiplegia."
      explanation: Background statement of the clinical consequence of porencephaly.
  - target: Focal Epilepsy
    description: Epilepsy is a recognized manifestation of porencephaly; the COL4A2-specific epileptogenic mechanism is unclear.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39006838
      reference_title: Col4a2 Mutations Contribute to Infantile Epileptic Spasm Syndrome and Neuroinflammation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: BACKGROUND
      snippet: "Although epilepsy is recognized as a clinical manifestation of porencephaly, the specific mechanism of Col4a2-related epileptic phenotypes remains unclear."
      explanation: Background statement that porencephaly manifests with epilepsy, with the mechanism unresolved.
  - target: Intellectual Disability
    description: Porencephaly typically manifests with intellectual disability among other deficits.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301768
      reference_title: COL4A1-Related Disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
      snippet: "Porencephaly (fluid-filled cavities in the brain detected by CT or MRI) is typically manifest as infantile hemiparesis, seizures, and intellectual disability"
      explanation: GeneReviews statement about porencephaly in COL4A1 disease; applied here to the shared lesion, not to COL4A2 specifically.
- category: Neurological
  name: Intracerebral Hemorrhage
  description: >-
    Parenchymal hemorrhage occurs before birth (an aborted biallelic fetus) and in adult life (recurrent deep
    hemorrhages in a de novo heterozygous patient). Rare COL4A2 missense variants were also found in sporadic
    intracerebral hemorrhage.
  phenotype_term:
    preferred_term: Intracerebral hemorrhage
    term:
      id: HP:0001342
      label: Cerebral hemorrhage
  evidence:
  - reference: PMID:24390199
    reference_title: COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "We extensively investigated a 29-year-old male patient with recurrent deep intracerebral hemorrhages causing mild motor and sensory hemisyndromes."
    explanation: Adult recurrent deep hemorrhage in a heterozygous de novo case.
  - reference: PMID:41499643
    reference_title: Biallelic COL4A2 Variants Associated With Brain Small Vessel Disease and Brain Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Case #1, an aborted fetus with cerebral calcifications, hemorrhages, periventricular leukomalacia, and cerebellar disruption"
    explanation: Fetal cerebral hemorrhage in a biallelic case.
  - reference: PMID:22209247
    reference_title: COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "We sequence COL4A2 in 96 patients with ICH and identify three rare, nonsynonymous coding variants in four patients that are not present in a cohort of 144 ICH-free individuals."
    explanation: Rare COL4A2 variants in sporadic ICH; the authors call them putative mutations.
- category: Neurological
  name: Hemiplegia
  description: Congenital hemiplegia or milder monoparesis in heterozygous family members.
  subtype: BSVD2A
  phenotype_term:
    preferred_term: Congenital hemiplegia
    term:
      id: HP:0002301
      label: Hemiplegia
  evidence:
  - reference: PMID:22209246
    reference_title: "De novo and inherited mutations in COL4A2, encoding the type IV collagen α2 chain cause porencephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "the maternal elder uncle, who had congenital hemiplegia"
    explanation: Congenital hemiplegia in a heterozygous relative.
- category: Neurological
  name: Focal Epilepsy
  description: Focal epilepsy in a dominant porencephaly-with-cataract family and in both recessive siblings (onset at 6 and 18 months).
  phenotype_term:
    preferred_term: Focal epilepsy
    term:
      id: HP:0007359
      label: Focal-onset seizure
  evidence:
  - reference: PMID:26708157
    reference_title: A mutation in COL4A2 causes autosomal dominant porencephaly with cataracts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "We describe a family with an autosomal dominant disorder comprising porencephaly, focal epilepsy, and lens opacities, which was negative for mutations in COL4A1."
    explanation: Focal epilepsy in a dominant family.
  - reference: PMID:33912663
    reference_title: Recessive COL4A2 Mutation Leads to Intellectual Disability, Epilepsy, and Spastic Cerebral Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "He had focal epilepsy that began at age 6 months, partially controlled with carbamazepine."
    explanation: Focal epilepsy in a homozygous patient.
- category: Neurological
  name: Infantile Spasms
  description: >-
    A retrospective series of eight children with COL4A2-related infantile epileptic spasm syndrome. All
    eight carried heterozygous COL4A2 missense variants (seven de novo; one maternally inherited and of
    uncertain significance), with seizure onset between 3 and 10 months. Cerebrospinal fluid IL-1beta and IL-6 were raised without infection. This is a
    single-center series; the variants were not assessed against the vascular phenotypes of this entry.
  subtype: BSVD2A
  phenotype_term:
    preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
    onset:
      onset_category: INFANTILE
      min_age_years: 0.25
      max_age_years: 0.83
      notes: Seizure onset 3 to 10 months in the eight-patient series (PMID:39006838).
  evidence:
  - reference: PMID:39006838
    reference_title: Col4a2 Mutations Contribute to Infantile Epileptic Spasm Syndrome and Neuroinflammation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "In this study, we retrospectively analyzed eight patients who were initially diagnosed with Col4a2-related infantile epileptic spasm syndrome and discovered elevated proinflammatory cytokine levels in the cerebrospinal fluid."
    explanation: Eight-patient retrospective series of COL4A2-related infantile epileptic spasm syndrome.
  - reference: PMID:39006838
    reference_title: Col4a2 Mutations Contribute to Infantile Epileptic Spasm Syndrome and Neuroinflammation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "The age of seizure onset ranged from 3 months to 10 months."
    explanation: Infantile onset in the same series.
- category: Neurological
  name: Leukoencephalopathy
  description: Diffuse white matter disease in an adult dominant case and leukoencephalopathy with spot-like calcifications in a recessive family.
  phenotype_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  evidence:
  - reference: PMID:24390199
    reference_title: COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Brain MRI showed deep intracerebral hemorrhages of different age, diffuse leukoencephalopathy, multiple cerebral microbleeds and small aneurysms of the carotid siphon bilaterally."
    explanation: Leukoencephalopathy in a heterozygous adult.
  - reference: PMID:36603335
    reference_title: Leukoencephalopathy with spot-like calcifications caused by recessive COL4A2 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "We broaden the phenotypic and genotypic spectra of COL4A2-related disease by describing this second family with recessive pathogenic variants and neuroimaging phenotype of leukoencephalopathy with spot-like calcifications."
    explanation: Leukoencephalopathy in a recessive family.
- category: Neurological
  name: Cerebral Calcification
  description: Spot-like calcifications in a recessive family and cerebral calcifications in a biallelic fetus.
  subtype: BSVD2B
  phenotype_term:
    preferred_term: Cerebral calcification
    term:
      id: HP:0002514
      label: Cerebral calcification
  evidence:
  - reference: PMID:41499643
    reference_title: Biallelic COL4A2 Variants Associated With Brain Small Vessel Disease and Brain Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Case #1, an aborted fetus with cerebral calcifications, hemorrhages, periventricular leukomalacia, and cerebellar disruption"
    explanation: Cerebral calcifications in a biallelic fetus.
  - reference: PMID:36603335
    reference_title: Leukoencephalopathy with spot-like calcifications caused by recessive COL4A2 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "neuroimaging phenotype of leukoencephalopathy with spot-like calcifications"
    explanation: Calcifications in a recessive family.
- category: Neurological
  name: Periventricular Leukomalacia
  subtype: BSVD2B
  phenotype_term:
    preferred_term: Periventricular leukomalacia
    term:
      id: HP:0006970
      label: Periventricular leukomalacia
  evidence:
  - reference: PMID:41499643
    reference_title: Biallelic COL4A2 Variants Associated With Brain Small Vessel Disease and Brain Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Case #1, an aborted fetus with cerebral calcifications, hemorrhages, periventricular leukomalacia, and cerebellar disruption"
    explanation: Periventricular leukomalacia in a biallelic fetus.
- category: Neurological
  name: Schizencephaly
  description: Schizencephaly, usually with polymicrogyria, in dominant families and in a compound heterozygous child.
  phenotype_term:
    preferred_term: Schizencephaly
    term:
      id: HP:0010636
      label: Schizencephaly
  evidence:
  - reference: PMID:41499643
    reference_title: Biallelic COL4A2 Variants Associated With Brain Small Vessel Disease and Brain Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Patient #2, a 2-year-old girl with neurodevelopmental impairment, cortical malformations (frontal schizencephaly, polymicrogyria), and reduced white matter volume"
    explanation: Schizencephaly in a compound heterozygous child.
  - reference: PMID:33577044
    reference_title: Novel COL4A2 mutation causing familial malformations of cortical development.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Brain MRI showed closed lip schizencephaly of right lateral sulcus associated with polymicrogyria of the surrounding cortex and areas of subcortical heterotopia."
    explanation: Schizencephaly in a heterozygous adult.
- category: Neurological
  name: Polymicrogyria
  phenotype_term:
    preferred_term: Polymicrogyria
    term:
      id: HP:0002126
      label: Polymicrogyria
  evidence:
  - reference: PMID:41499643
    reference_title: Biallelic COL4A2 Variants Associated With Brain Small Vessel Disease and Brain Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Patient #2, a 2-year-old girl with neurodevelopmental impairment, cortical malformations (frontal schizencephaly, polymicrogyria), and reduced white matter volume"
    explanation: Polymicrogyria in a compound heterozygous child.
  - reference: PMID:33577044
    reference_title: Novel COL4A2 mutation causing familial malformations of cortical development.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Brain MRI showed closed lip schizencephaly of right lateral sulcus associated with polymicrogyria of the surrounding cortex and areas of subcortical heterotopia."
    explanation: Polymicrogyria in a heterozygous adult.
- category: Neurological
  name: Intellectual Disability
  subtype: BSVD2B
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:33912663
    reference_title: Recessive COL4A2 Mutation Leads to Intellectual Disability, Epilepsy, and Spastic Cerebral Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "We describe 2 children from a consanguineous Iranian family with intellectual disability, spastic cerebral palsy, and epilepsy who each harbored the same homozygous mutation in COL4A2."
    explanation: Intellectual disability in both homozygous siblings.
- category: Neurological
  name: Global Developmental Delay
  subtype: BSVD2B
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:33912663
    reference_title: Recessive COL4A2 Mutation Leads to Intellectual Disability, Epilepsy, and Spastic Cerebral Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Milestone attainment had been globally delayed."
    explanation: Global delay in a homozygous patient.
- category: Neurological
  name: Absent Speech
  subtype: BSVD2B
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:33912663
    reference_title: Recessive COL4A2 Mutation Leads to Intellectual Disability, Epilepsy, and Spastic Cerebral Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "He did not speak or demonstrate communicative intent."
    explanation: Absent speech in the homozygous brother (his sister also did not speak).
- category: Neurological
  name: Spastic Quadriplegia
  subtype: BSVD2B
  phenotype_term:
    preferred_term: Spastic quadriplegia
    term:
      id: HP:0002510
      label: Spastic tetraplegia
  evidence:
  - reference: PMID:33912663
    reference_title: Recessive COL4A2 Mutation Leads to Intellectual Disability, Epilepsy, and Spastic Cerebral Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Motor examination revealed spastic quadriplegia with ophthalmoplegia, nystagmus, and skew deviation."
    explanation: Spastic quadriplegia in the homozygous brother.
- category: Neurological
  name: Cortical Visual Impairment
  subtype: BSVD2B
  phenotype_term:
    preferred_term: Cortical visual impairment
    term:
      id: HP:0100704
      label: Cerebral visual impairment
  evidence:
  - reference: PMID:33912663
    reference_title: Recessive COL4A2 Mutation Leads to Intellectual Disability, Epilepsy, and Spastic Cerebral Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "The couple's 8 year-old son was bedridden and exhibited cortical visual impairment."
    explanation: Cortical visual impairment in a homozygous patient.
- category: Neurological
  name: Colpocephaly
  subtype: BSVD2B
  phenotype_term:
    preferred_term: Colpocephaly
    term:
      id: HP:0030048
      label: Colpocephaly
  evidence:
  - reference: PMID:33912663
    reference_title: Recessive COL4A2 Mutation Leads to Intellectual Disability, Epilepsy, and Spastic Cerebral Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Brain MRI revealed bilateral colpocephaly and irregular ventricular contours."
    explanation: Colpocephaly in a homozygous patient.
- category: Ophthalmological
  name: Cataract
  subtype: BSVD2A
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:26708157
    reference_title: A mutation in COL4A2 causes autosomal dominant porencephaly with cataracts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "The cataracts identified in this family expand the phenotypic spectrum associated with mutations in COL4A2 and highlight the increasing overlap with phenotypes associated with COL4A1 mutations."
    explanation: Cataract in a dominant COL4A2 family.
- category: Ophthalmological
  name: Optic Nerve Hypoplasia
  subtype: BSVD2A
  phenotype_term:
    preferred_term: Optic nerve hypoplasia
    term:
      id: HP:0000609
      label: Optic nerve hypoplasia
  evidence:
  - reference: PMID:22333902
    reference_title: COL4A2 mutation associated with familial porencephaly and small-vessel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Mutation phenotypes varied, including porencephaly, white matter lesions, cerebellar and optic nerve hypoplasia and unruptured carotid aneurysm."
    explanation: Optic nerve hypoplasia in a dominant family.
- category: Cardiovascular
  name: Intracranial Aneurysm
  description: Unruptured carotid aneurysm in one dominant family and bilateral carotid siphon aneurysms in a de novo adult.
  subtype: BSVD2A
  phenotype_term:
    preferred_term: Intracranial carotid aneurysm
    term:
      id: HP:0004944
      label: Dilatation of the cerebral artery
  evidence:
  - reference: PMID:24390199
    reference_title: COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Brain MRI showed deep intracerebral hemorrhages of different age, diffuse leukoencephalopathy, multiple cerebral microbleeds and small aneurysms of the carotid siphon bilaterally."
    explanation: Intracranial carotid aneurysms in a heterozygous adult.
  - reference: PMID:22333902
    reference_title: COL4A2 mutation associated with familial porencephaly and small-vessel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Mutation phenotypes varied, including porencephaly, white matter lesions, cerebellar and optic nerve hypoplasia and unruptured carotid aneurysm."
    explanation: Unruptured carotid aneurysm in a dominant COL4A2 family; the abstract does not say whether it was intracranial.
- category: Renal
  name: Hematuria
  subtype: BSVD2A
  phenotype_term:
    preferred_term: Microscopic hematuria
    term:
      id: HP:0000790
      label: Hematuria
  evidence:
  - reference: PMID:24390199
    reference_title: COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Laboratory work-up revealed significant microscopic hematuria and elevation of creatine-kinase."
    explanation: Hematuria in a heterozygous adult.
  - reference: PMID:33577044
    reference_title: Novel COL4A2 mutation causing familial malformations of cortical development.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "The first patient is a 65-year-old woman with hematuria and adult-onset seizures."
    explanation: Hematuria in a heterozygous adult with cortical malformation.
- category: Musculoskeletal
  name: Elevated Creatine Kinase
  subtype: BSVD2A
  phenotype_term:
    preferred_term: Elevated creatine kinase
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:24390199
    reference_title: COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Laboratory work-up revealed significant microscopic hematuria and elevation of creatine-kinase."
    explanation: Raised creatine kinase in a heterozygous adult.
diagnosis:
- name: COL4A2 molecular genetic testing
  description: >-
    Diagnosis rests on a pathogenic COL4A2 variant in a person with compatible cerebrovascular or brain
    imaging findings, usually found by exome sequencing or a multigene panel that also covers COL4A1.
    Zygosity and parental phase separate the dominant form (one heterozygous variant, inherited or de novo)
    from the recessive form (homozygous or compound heterozygous variants with carrier parents), which
    matters for recurrence risk.
  diagnosis_term:
    preferred_term: Genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:40616396
    reference_title: "COL4A1 and COL4A2-related disorders: Clinical features, diagnostic guidelines, and management."
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "Genetic testing and counseling are advised for individuals showing symptoms of COL4A1/A2-related disorders and for at-risk relatives."
    explanation: Expert consensus recommendation covering COL4A1 and COL4A2 jointly, so it applies to COL4A2 directly.
  - reference: PMID:41499643
    reference_title: Biallelic COL4A2 Variants Associated With Brain Small Vessel Disease and Brain Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Exome sequencing identified a homozygous missense COL4A2 variant in case #1 and compound heterozygous loss-of-function variants (splicing and truncating) in case #2."
    explanation: Exome sequencing established the biallelic, recessive diagnosis, with zygosity and phase distinguishing it from the dominant form.
- name: Brain MRI and multiorgan evaluation
  description: >-
    Neurological imaging characterizes porencephaly, hemorrhage, leukoencephalopathy, calcification and
    cortical malformation. Ophthalmological imaging and cardiovascular and renal monitoring are recommended
    by the joint COL4A1/COL4A2 consensus; renal and ocular involvement in COL4A2 disease is known only from
    isolated reports.
  diagnosis_term:
    preferred_term: Brain MRI
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:40616396
    reference_title: "COL4A1 and COL4A2-related disorders: Clinical features, diagnostic guidelines, and management."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "Recommended care includes neurological and ophthalmological imaging and monitoring of cardiovascular and renal function."
    explanation: >-
      Consensus recommendation for COL4A1 and COL4A2 disorders together. Graded indirect because most of the
      multiorgan involvement behind it comes from COL4A1 patients and the abstract does not separate the genes.
treatments:
- name: Genetic Counseling and Testing
  description: >-
    Genetic testing and counseling for affected individuals and at-risk relatives, as recommended by the
    COL4A1/COL4A2 expert consensus. Testing must establish zygosity and phase because dominant and recessive
    COL4A2 forms both exist.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:40616396
    reference_title: "COL4A1 and COL4A2-related disorders: Clinical features, diagnostic guidelines, and management."
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "Genetic testing and counseling are advised for individuals showing symptoms of COL4A1/A2-related disorders and for at-risk relatives."
    explanation: eDelphi expert consensus recommendation covering COL4A2.
- name: Vascular Risk Reduction
  description: >-
    Treating hypertension and avoiding smoking, head trauma and anticoagulants to lower the risk of
    intracerebral hemorrhage. This guidance comes from the COL4A1 GeneReviews chapter and is extended to
    COL4A2 disease by analogy; it has not been tested in COL4A2 patients.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Vascular risk reduction
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Intracerebral hemorrhage
    term:
      id: HP:0001342
      label: Cerebral hemorrhage
  evidence:
  - reference: PMID:20301768
    reference_title: COL4A1-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "Prevention of primary and secondary complications: Avoiding head trauma and anticoagulant exposure may decrease the risk for intracerebral hemorrhage."
    explanation: COL4A1 guidance extended to COL4A2 because the two chains form one heterotrimer and share the hemorrhage phenotype.
  - reference: PMID:20301768
    reference_title: COL4A1-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "Agents/circumstances to avoid: Smoking and hypertension because these factors increase the risk for stroke; sustained head pressure or physical activities that may cause head trauma; anticoagulant use."
    explanation: COL4A1 guidance on circumstances to avoid, extended to COL4A2 by analogy.
- name: Antiseizure Medication
  description: >-
    Focal epilepsy is treated with standard antiseizure drugs. In the first recessive family carbamazepine
    partially controlled seizures in one sibling and phenobarbital with carbamazepine controlled them in the
    other; these are single observations, not response rates.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: carbamazepine
      term:
        id: CHEBI:3387
        label: carbamazepine
    - preferred_term: phenobarbital
      term:
        id: CHEBI:8069
        label: phenobarbital
  target_phenotypes:
  - preferred_term: Focal epilepsy
    term:
      id: HP:0007359
      label: Focal-onset seizure
  evidence:
  - reference: PMID:33912663
    reference_title: Recessive COL4A2 Mutation Leads to Intellectual Disability, Epilepsy, and Spastic Cerebral Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Seizures were controlled with phenobarbital and carbamazepine."
    explanation: Seizure control in a homozygous patient.
- name: Chemical Chaperone (Preclinical)
  description: >-
    Sodium 4-phenylbutyrate reduced intracellular COL4A2 accumulation, ER stress and apoptosis in fibroblasts
    from a G702D patient. This is an in vitro result for one allele and is not a clinical treatment; it would
    not address alleles that act without ER retention.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: 4-phenylbutyrate
      term:
        id: CHEBI:41500
        label: 4-phenylbutyric acid
  target_mechanisms:
  - target: Intracellular Collagen IV Retention
    description: The chaperone lowers retained collagen IV in patient fibroblasts.
    evidence:
    - reference: PMID:24001601
      reference_title: Chemical chaperone treatment reduces intracellular accumulation of mutant collagen IV and ameliorates the cellular phenotype of a COL4A2 mutation that causes haemorrhagic stroke.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: "treatment of patient cells with a chemical chaperone decreased intracellular COL4A2 levels, ER stress and apoptosis"
      explanation: In vitro rescue of retention and stress.
  evidence:
  - reference: PMID:24001601
    reference_title: Chemical chaperone treatment reduces intracellular accumulation of mutant collagen IV and ameliorates the cellular phenotype of a COL4A2 mutation that causes haemorrhagic stroke.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "treatment of patient cells with a chemical chaperone decreased intracellular COL4A2 levels, ER stress and apoptosis"
    explanation: Preclinical patient-cell evidence only.
animal_models:
- name: Col4a2 ENU missense mice
  species: Mouse
  genotype: Heterozygous ENU-induced Col4a2 missense alleles (first two Col4a2 mutant alleles)
  publication: PMID:17179069
  description: >-
    Random-mutagenesis Col4a1 and Col4a2 missense alleles. Heterozygotes show eye, brain, kidney and vascular
    stability defects; homozygotes die by mid-gestation. The abstract reports these findings for the Col4a1
    and Col4a2 series together.
  genes:
  - preferred_term: Col4a2
    term:
      id: MGI:88455
      label: Col4a2
  evidence:
  - reference: PMID:17179069
    reference_title: "Type IV procollagen missense mutations associated with defects of the eye, vascular stability, the brain, kidney function and embryonic or postnatal viability in the mouse, Mus musculus: an extension of the Col4a1 allelic series and the identification of the first two Col4a2 mutant alleles."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    snippet: "Heterozygous carriers express defects in the eye, the brain, kidney function, vascular stability, and viability. Homozygotes do not survive beyond the second trimester."
    explanation: Pooled Col4a1/Col4a2 statement; not separable to Col4a2 alleles from the abstract.
- name: Col4a2 mutant mice with intracerebral hemorrhage
  species: Mouse
  genotype: Col4a2 missense mutant
  publication: PMID:22209247
  description: Col4a2 mutant mice develop completely penetrant intracerebral hemorrhage with ER retention of both collagen IV chains.
  modeled_mechanisms:
  - target: Cerebral Microvascular Fragility
    description: Spontaneous intracerebral hemorrhage.
    relationship: RECAPITULATES
    fidelity: MODERATE
    evidence:
    - reference: PMID:22209247
      reference_title: COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: "Furthermore, we show that Col4a2 mutant mice also have completely penetrant ICH"
      explanation: Hemorrhage phenotype in Col4a2 mutant mice.
  - target: Intracellular Collagen IV Retention
    description: ER retention of COL4A1 and COL4A2.
    relationship: RECAPITULATES
    fidelity: MODERATE
    evidence:
    - reference: PMID:22209247
      reference_title: COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: "mutations in mouse and human lead to retention of COL4A1 and COL4A2 within the endoplasmic reticulum (ER)"
      explanation: ER retention in mutant mice.
- name: Col4a2 G646D heterozygous mice
  species: Mouse
  genotype: Col4a2 +/G646D
  publication: PMID:42856351
  description: Aged heterozygous mice show segment-selective loss of pial artery myogenic tone with ryanodine receptor cluster remodeling in smooth muscle.
  modeled_mechanisms:
  - target: Impaired Cerebral Artery Myogenic Tone
    description: Age-dependent loss of pressure-induced tone in pial arteries.
    relationship: MEASURES
    fidelity: UNKNOWN
    limitations: >-
      Mouse arteries from one dominant allele; no human cerebral artery tone measurement exists for COL4A2
      disease, so fidelity to patients is unknown.
    evidence:
    - reference: PMID:42856351
      reference_title: Ryanodine receptor cluster remodeling links COL4A2 mutation to cerebral artery dysfunction.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: "Cerebral pial arteries from aged (12-month-old), but not young (3-month-old), Col4a2 +/G646D mice exhibited impaired pressure-induced myogenic tone, whereas downstream parenchymal arterioles retained normal myogenic responsiveness, revealing a segment-selective vascular defect."
      explanation: Direct measurement in the model.
- name: Col4a2 em1(IMPC)Wtsi homozygous embryos
  species: Mouse
  genotype: Col4a2 em1(IMPC)Wtsi homozygous (hypomorphic, about 11-fold knockdown)
  publication: PMID:31331924
  description: >-
    Homozygous embryos survive organogenesis to E14.5 and show brain, cranial nerve, eye, lung, endocrine,
    skeletal and cardiovascular defects, including cortical surface irregularities and small cortical cysts.
    Residual Col4a2 expression explains the longer survival than null alleles. A partial model of biallelic
    COL4A2 loss, relevant to the recessive form.
  evidence:
  - reference: PMID:31331924
    reference_title: "The Col4a2(em1(IMPC)Wtsi) mouse line: lessons from the Deciphering the Mechanisms of Developmental Disorders program."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: "They showed defects in the brain, cranial nerves, visual system, lungs, endocrine glands, skeleton, subepithelial tissues and mild to severe cardiovascular malformations."
    explanation: Multiorgan developmental defects in homozygous hypomorphic embryos.
notes: >-
  This entry deliberately lumps the dominant (BSVD2A, MONDO:0013773) and recessive (BSVD2B, MONDO:0980747)
  COL4A2 diseases as two subtypes of one entry. The recessive form is known from three published families,
  shares the collagen IV pathophysiology, and has no recessive-specific mechanism node in the literature, so
  a separate entry would duplicate the pathograph. COL4A1-related brain small vessel disease is curated
  separately (Brain_Small_Vessel_Disease_1_With_Or_Without_Ocular_Anomalies); most mechanistic detail there
  comes from Col4a1 models and is not copied here, where only COL4A2-specific evidence is cited. The only
  GeneReviews chapter in this area (PMID:20301768, COL4A1-Related Disorders) covers COL4A1 alone and is
  cited only for the general consequences of porencephaly and for vascular risk-reduction advice, both as
  indirect evidence, not as a COL4A2 phenotype baseline; the 2025 eDelphi consensus (PMID:40616396) covers
  both genes. No prevalence estimate specific to COL4A2 disease was found.
📚

References & Deep Research

References

1
PMID:20301768
COL4A1-Related Disorders.
No top-level findings curated for this source.