Brain small vessel disease 2B, autosomal recessive: disease-characteristics report
Brain small vessel disease 2B (BSVD2B) is a rare, early-onset disorder associated with biallelic variants in COL4A2, which encodes the α2 chain of basement-membrane collagen IV. Reported presentations range from severe fetal brain injury to childhood developmental impairment, epilepsy and motor disability. The human evidence remains a small set of families and cases; findings from the broader, predominantly heterozygous COL4A2 disease spectrum must not be treated as measured frequencies or proven mechanisms of BSVD2B. BSVD2B is not CARASIL: CARASIL is an HTRA1-related disorder. [35][61][63][16]
Evidence and provenance
Table (click to expand)
| Evidence item | Publication date and URL | What it establishes |
|---|---|---|
| Bakhtiari et al., PMID: 33912663 | April 22, 2021; https://pubmed.ncbi.nlm.nih.gov/33912663/ | Human clinical: two affected siblings with homozygous COL4A2 p.Gly1158Arg, epilepsy and spastic cerebral palsy. The authors concluded: “Our results indicate that both dominant and recessive forms of COL4A2 disease exist.” [91] |
| Nicita et al., PMID: 36603335 | Online December 31, 2022; February 2023 issue; https://pubmed.ncbi.nlm.nih.gov/36603335/ | Human clinical: a second recessive family, described in the abstract as having “leukoencephalopathy with spot-like calcifications.” [61] |
| McNeilly et al., PMID: 39216230 | Online August 30, 2024; https://pubmed.ncbi.nlm.nih.gov/39216230/ | Mouse, human-cell and human-tissue experiments: reduced collagen IV, vascular remodeling and altered endothelial calcium-dependent signaling in broader COL4A1/COL4A2 small-vessel disease—not a direct demonstration in BSVD2B patients. [85] |
| Muhammad et al., PMID: 41499643 | Online August 13, 2025; February 2026 issue; https://pmc.ncbi.nlm.nih.gov/articles/PMC12779229/ | Human clinical and computational: a severely affected fetus and a child with biallelic variants; extends the reported spectrum to fetal hemorrhagic injury and cortical malformations. [63] |
| Tambala et al., PMID: 40616396 | Online July 2, 2025; https://pubmed.ncbi.nlm.nih.gov/40616396/ | Expert consensus: evaluation and management guidance for COL4A1/COL4A2-related disorders collectively; not a BSVD2B-specific therapeutic trial. [199][167] |
These are published, aggregated disease-level observations, not an extract of individual patients’ electronic health records (EHRs). An additional 2026 retrospective EHR cohort concerns childhood-onset COL4A1/COL4A2 disorders generally and does not identify how many of its ten COL4A2 patients had biallelic disease. [35][207]
1. Disease information
Table (click to expand)
| Identifier or name | BSVD2B entry |
|---|---|
| Preferred name; synonym | Brain small vessel disease 2B, autosomal recessive; BSVD2B. [35] |
| Disease ontology | MONDO:0980747. [35][44] |
| OMIM phenotype | 621414; distinguish from COL4A2 gene OMIM 120090. [35][106] |
| NCBI MedGen | C6065929, UID 1896158. [35] |
| Orphanet, ICD-10/ICD-11, MeSH | A BSVD2B-specific identifier was not established from the consulted resources. The subject headings assigned to a relevant paper, such as Cerebrovascular Disorders and Leukoencephalopathies, are not disease-specific BSVD2B identifiers. [21][61] |
| Important distinction | BSVD2A denotes the autosomal-dominant COL4A2 phenotype, OMIM 614483; BSVD2B denotes the biallelic phenotype. [39][35] |
The defining clinical description is neurologic abnormality beginning in infancy or the first years of life—developmental delay, impaired cognition or speech, seizures and sometimes spastic quadriplegia—with variable white-matter, ventricular, atrophic or vascular-injury findings on imaging. The later fetal report shows that COL4A2-associated injury can also be detected before birth. [35][63]
2. Etiology: causes, risks, protection and interactions
Established cause: disease-associated homozygous or compound-heterozygous germline COL4A2 variants, ordinarily inherited one from each parent. The α2(IV) protein contributes to collagen-IV basement membranes; disruption provides a biologically plausible link to fragile or dysfunctional developing cerebral vessels. Variant effects differ, and a predicted effect in one family must not automatically be assigned to every allele. [91][63][106]
Table (click to expand)
| Factor | BSVD2B-specific assessment |
|---|---|
| Genetic risk and family history | Having two relevant COL4A2 alleles is the central risk. Consanguinity helped expose homozygosity in the original Iranian family; a later affected child had two variants inherited from nonconsanguineous parents. [91][63] |
| Age, sex and ancestry | Fetal and childhood presentations are documented in both sexes. Published case geography is not evidence of an ancestry-specific incidence or sex ratio. [91][63] |
| Environmental cause; infection | No toxin, occupation, diet, pathogen or infectious transmission has been established as a cause of BSVD2B. [35][91][63] |
| Plausible aggravating exposures | Hypertension, smoking, anticoagulation and head trauma are concerns in the broader collagen-IV angiopathy literature. Applying risk-reduction guidance to BSVD2B is prudent clinical extrapolation, not a measured gene–environment effect in recessive cases. [167][81] |
| Protective variants or modifiers | No validated BSVD2B-protective allele, modifier gene or epigenetic modifier was identified. Healthy heterozygous parents in reported families support recessive inheritance in those families but do not prove that every carrier is symptom-free. [91][63] |
| Gene–environment interaction | No BSVD2B-specific interaction has been quantified. A structurally vulnerable vessel might be more susceptible to blood-pressure or trauma-related injury; that final proposition is inference. [167][91] |
3. Phenotypes and effects on functioning
Frequency rule: the published recessive cases were ascertained for clinical abnormalities and are too few and heterogeneous for reliable population percentages. “Reported” below means observed in a cited person or family; it does not mean that all affected individuals develop the feature. HPO identifiers are suggested annotation terms, not independently measured frequencies. [91][61][63]
Table (click to expand)
| Phenotype type and finding | Onset, severity, course and frequency evidence | Function or quality-of-life implications; suggested HPO |
|---|---|---|
| Developmental sign: global developmental delay and intellectual impairment | Infancy/early childhood; severe in the original two siblings, variable across later reports; frequency undetermined. [91][63] | Limits learning and independence; HP:0001263, HP:0001249. [91][154] |
| Communication sign: poor, delayed or absent speech | The original siblings did not speak at assessment; later children had delayed or markedly impaired language. Frequency undetermined. [91][63] | Major communication and caregiving impact; HP:0001344, HP:0000750. [195][190] |
| Motor signs: axial hypotonia, spasticity, quadriplegia or asymmetric hemiplegia | Childhood; ranges from inability to sit or walk to asymmetric impairment. The boy in the 2021 family was bedridden at age eight; his sister began independent walking at three. Frequency undetermined. [91][63] | Mobility, positioning and personal-care needs vary substantially; HP:0008936, HP:0001257, HP:0002510, HP:0002301. [160][124][182] |
| Clinical symptom: epilepsy | Focal seizures began at six months and 18 months in the two original siblings; drug-resistant epilepsy was reported in the 2023 child. Not present in every later reported child. [91][63] | Seizure safety, schooling and care burden; HP:0007359 for focal-onset seizures. [131] |
| Imaging signs: colpocephaly, porencephalic cyst and cerebral atrophy | The 2021 boy had bilateral colpocephaly; his sister had porencephaly and generalized cortical atrophy. Imaging patterns are variable, not diagnostic alone. [91] | May accompany motor, visual and cognitive disability; HP:0030048 and HP:0002132 are suitable terms for the first two findings. [187][181] |
| Imaging signs: leukoencephalopathy and intracranial calcifications | Reported in the 2023 recessive family; calcifications and white-matter injury were also described in the later fetal case. Frequency undetermined. [61][63] | Markers of brain injury rather than patient-reported symptoms; HP:0002352, HP:0002514. [130] |
| Imaging signs: fetal hemorrhagic injury, periventricular leukomalacia and cerebellar disruption | Severe prenatal abnormalities reported in one later fetus; not established as universal. [63] | Potentially profound developmental consequences; annotate hemorrhage with HP:0002170 when its anatomical designation fits the finding. [122] |
| Cortical malformations: schizencephaly and polymicrogyria | Reported in a later child with biallelic variants; authors describe an expanded spectrum. [63] | May compound motor and developmental impairment; HP:0010636, HP:0002126. [127][123] |
| Visual or ocular signs: cortical visual impairment, nystagmus, ophthalmoplegia and strabismus | Particular reported patients, not a uniform syndrome. A homozygous COL4A2 variant was also found in a study of optic-nerve hypoplasia, but that finding alone does not define typical BSVD2B. [91][63][120] | Can restrict visual access to learning and mobility; record each observed sign separately rather than assuming eye disease in every case. [91][63] |
No BSVD2B-specific EQ-5D, SF-36 or PROMIS result was identified. The functional descriptions above are clinical interpretations of reported abilities, not questionnaire scores. [91][63]
4. Genetic and molecular information
COL4A2 is at 13q34 (HGNC:2203; NCBI Gene:1284; Ensembl:ENSG00000134871; UniProt:P08572). NM_001846.4 is the reference transcript used in the later variant report. Its product is the collagen-IV α2 chain; α2(IV) assembles with two α1(IV) chains into a basement-membrane heterotrimer. COL4A1 is its assembly partner, not a second established causal gene for BSVD2B. [106][63][136][174]
Table (click to expand)
| Reported COL4A2 variant, NM_001846.4 | Origin, evidence and interpretation |
|---|---|
| c.3472G>C, p.(Gly1158Arg) | Homozygous in the two 2021 siblings; their clinically unaffected parents carried the variant. A glycine substitution in the collagen triple-helix repeat was predicted to destabilize collagen; it was absent from the population databases checked by those authors. No direct assay of this family’s mutant protein was reported. [91] |
| c.535C>T, p.(Arg179Cys) and c.2069G>T, p.(Gly690Val) | Reported in trans in the 2023 child with leukoencephalopathy and spot-like calcifications; both were described as rare or absent in the cited gnomAD assessment. Their combined clinical interpretation must not be assumed to apply to either allele alone. [61][71][63] |
| c.535C>T, p.(Arg179Cys), homozygous | Reported in a fetus with severe abnormalities and inherited from unaffected heterozygous parents. Important classification conflict: the 2025/26 paper itself labels this allele “likely benign” under its ACMG assessment while proposing a possible hypomorphic contribution on computational grounds. Do not enter it as independently proven pathogenic without further assessment. The authors reported gnomAD allele frequency 0.00001449. [63] |
| c.826-1G>T and c.4275dup, p.(Gly1426Argfs*30) | Paternal splice-acceptor and maternal frameshift alleles, respectively, in a child with developmental impairment and cortical malformations. The authors classified each likely pathogenic. Abnormal splicing, truncation or nonsense-mediated decay was predicted, not established by a patient RNA or protein assay. [63] |
| c.4987G>A, p.(Gly1663Ser) | Reported homozygously in a person ascertained for optic-nerve hypoplasia. Treat as a phenotypic-boundary observation, not proof that optic-nerve hypoplasia is frequent in BSVD2B. [63][120] |
These are reported germline findings, not somatic cancer mutations. No BSVD2B-defining aneuploidy, translocation, reproducible disease-specific methylation signature or validated modifier gene was established in these reports. Gene-level structural changes or variants elsewhere in the collagen-IV spectrum should not be silently assigned to this recessive subtype. [91][63]
5. Environmental information
No infectious agent, toxin, radiation exposure, occupational cause or BSVD2B-specific dietary association has been demonstrated. For patients with a confirmed collagen-IV angiopathy, general expert guidance favors avoiding smoking and preventable head injury and managing hypertension; these are complication-risk precautions extrapolated from the wider COL4A1/COL4A2 spectrum, not methods that prevent inheritance of BSVD2B. Vaccination has no disease-specific preventive role beyond routine care. [35][167][81]
6. Mechanism and pathophysiology
Ordered causal chain — observed evidence and inference explicitly separated
- Biallelic germline COL4A2 variation leads to altered α2(IV) production, structure or availability. A glycine substitution is predicted to disturb triple-helix assembly in the original family; predicted splice and frameshift consequences differ. Patient-variant-specific functional confirmation is limited. [91][63]
- Altered α2(IV) leads to impaired assembly, secretion or composition of the α1–α1–α2 collagen-IV basement-membrane network. Intracellular retention and reduced secretion were demonstrated for other COL4A2 mutations in cellular experiments; applying the exact magnitude of that effect to each BSVD2B allele is inferred. [174][106]
- Defective collagen-IV homeostasis branches: (a) reduced or abnormal vascular basement membrane leads to altered vessel support and mechanics; (b) retained mutant collagen can lead to endoplasmic-reticulum stress and an unfolded-protein response. Both branches have evidence in broader collagen-IV models, but their relative contribution in biallelic human BSVD2B is unresolved. [174][85]
- On the vascular branch, lower collagen IV leads to altered endothelial calcium and calcium-sensitive potassium-channel activity, leading to increased endothelium-dependent hyperpolarization and smooth-muscle-mediated dilation. This sequence was tested in heterozygous mouse and human-cell models in 2024; transfer to recessive patients is inferred. [85]
- Vessel dysfunction or fragility can lead to hemorrhagic injury and disturbed developing-brain tissue integrity. The causal connection is supported by model work and by the coexistence of vascular-appearing lesions and malformations in reported humans; the exact sequence that produces an individual child’s cortical malformation is inferred, not demonstrated. [174][63]
- Fetal or early-life brain injury leads to variable white-matter and cortical abnormalities, which result in developmental, motor, speech, visual and seizure manifestations. The abnormalities and manifestations are human observations; their precise patient-level mediation remains uncertain. [91][61][63]
Upstream versus downstream: collagen folding, secretion and extracellular-matrix organization are upstream; endothelial signaling, vessel remodeling and injury are intermediate; structural brain abnormalities and neurologic disability are downstream. The main cells implicated by experiments are brain microvascular endothelial cells and vascular smooth-muscle cells; relevant suggested annotations are CL:2000044 and CL:0002590. Suitable process/component suggestions include GO:0030198 (extracellular matrix organization), GO:0001525 (angiogenesis, a contextual process rather than a demonstrated BSVD2B-specific cascade) and GO:0005604 (basement membrane). Annotate the endoplasmic reticulum only for the experimentally supported protein-retention branch; do not annotate a proven Wnt, mTOR, immune or metabolic pathway for BSVD2B from these cases. [85][174][125][134][111]
Research limits: the 2025/26 fetal variant assessment used protein-structure predictions, not a demonstrated tissue mechanism. No validated BSVD2B-specific single-cell, spatial-transcriptomic, proteomic, metabolomic, lipidomic, epigenomic or CRISPR-screen signature was established by the cited case studies. The 2024 vascular study is mechanistically valuable comparative evidence, not a BSVD2B molecular profile. [63][85]
7. Anatomical structures affected
Table (click to expand)
| Level | Reported or implicated location; suggested ontology |
|---|---|
| Primary organ and system | Brain, particularly developing cerebral white matter, cortex and small-vessel environment; nervous and cerebrovascular systems. Suggested UBERON:0000955 (brain). [91][61][63][121] |
| Particular brain sites | Periventricular white matter and lateral ventricles; reported lesions also include frontal cortex, an occipital region and cerebellum in individual cases. Do not annotate all sites as obligatory. [91][63] |
| Tissue and cells | Vascular basement membrane is the mechanistic tissue of interest; endothelial and vascular smooth-muscle cells are implicated experimentally. Cortical and white-matter injuries are observed downstream. [85][174][63] |
| Subcellular and extracellular sites | Extracellular basement membrane; intracellular endoplasmic reticulum in experimental collagen-retention mechanisms. [174][85] |
| Other organs | Eye findings occur in some reported people. Renal and cardiovascular surveillance is recommended across COL4A1/COL4A2 disorders, not because these are established frequent BSVD2B manifestations. [91][63][167] |
| Lateralization | Both bilateral and asymmetric abnormalities are reported: bilateral colpocephaly in one sibling, right-predominant motor impairment in another, and unilateral cortical abnormalities in a later child. [91][63] |
8. Temporal development
The reported spectrum begins prenatally or during infancy/early childhood. Seizures began at six and 18 months in the original siblings; fetal imaging identified severe injury in a later report. Disability can persist through childhood and adulthood—the original sister was assessed at age 20—but a standard sequence of early, intermediate and end stages or a reliable annual progression rate has not been established. Epilepsy can be episodic even when developmental and structural impairments persist. Spontaneous remission of BSVD2B, a disease-specific intervention window and a prospective natural-history curve are not documented. [91][63]
9. Inheritance and population
Inheritance is autosomal recessive for the phenotype defined here. For two confirmed carriers of the relevant disease-causing alleles, the usual Mendelian risk for each pregnancy is 25% affected, 50% carrier and 25% inheriting neither familial allele; interpretation remains variant-specific, particularly when pathogenicity is disputed. Unaffected heterozygous parents are documented, but the separate dominant COL4A2 disease spectrum means “carrier” should not be interpreted as a universal guarantee of no clinical effect. [91][63][39]
No credible BSVD2B-specific prevalence, annual incidence, population carrier frequency, sex ratio, founder effect or geographic risk estimate was identified. The first affected sibling pair came from a consanguineous Iranian family; the later child with two different alleles had nonconsanguineous parents. Penetrance, anticipation and germline mosaicism have not been quantified for this recessive phenotype. [91][63]
Do not reuse broader-cohort percentages: a 2026 single-center EHR study included 10 childhood-onset COL4A2 patients and reported median presentation at 0.5 years, but did not establish which had biallelic variants. Its ages and symptom percentages therefore are not BSVD2B epidemiology. [207]
10. Diagnostics
Table (click to expand)
| Diagnostic component | Appropriate use and limitation |
|---|---|
| Clinical recognition | Consider COL4A2 testing in unexplained early developmental/motor impairment with epilepsy and characteristic white-matter, ventricular, hemorrhagic or cortical imaging findings; lack of one particular imaging sign does not exclude it. [91][61][63][167] |
| Neuroimaging | Brain MRI, including sequences sensitive to hemorrhage and white-matter injury, characterizes porencephaly, ventricular shape, leukoencephalopathy and cortical malformations. CT can help characterize calcifications. Broader-spectrum consensus recommends head-and-neck MRI/MRA at diagnosis to assess vessels. [91][61][63][167] |
| Molecular confirmation | Sequence COL4A2 and determine zygosity and parental phase. A small-vessel-disease, epilepsy or leukodystrophy panel containing COL4A1 and COL4A2, or WES, is reasonable for a broad presentation; WGS may help when a panel/exome is negative despite strong suspicion, including assessment of intronic variation. The original family was identified by WES. [91][167] |
| Variant interpretation | Assess segregation, population frequency, predicted effect and current ACMG/AMP classification; seek functional evidence when needed. Do not resolve the p.Arg179Cys classification conflict merely by finding it in an affected fetus. [63][91] |
| Other examinations | EEG evaluates suspected seizures; ophthalmologic assessment, blood pressure, urinalysis, kidney evaluation and selected cardiovascular testing follow broader collagen-IV consensus, with scope individualized. CK and coagulation studies may assist evaluation or differential diagnosis, not molecular confirmation. [91][167] |
| Usually non-primary tests | Routine karyotyping, FISH, mitochondrial or repeat-expansion testing do not confirm this sequence-level diagnosis. Chromosomal microarray may investigate an alternative explanation or relevant copy-number change when clinically indicated; no BSVD2B-specific yield is established. No validated liquid-biopsy or omics diagnostic signature is available. [91][63][167] |
There is no standalone standardized BSVD2B clinical score. Differential diagnosis includes dominant COL4A2 disease, COL4A1-related disease and other causes of early brain injury or malformation; distinguishing the recessive subtype requires careful allele interpretation and phase, not MRI appearance alone. Related hemorrhagic or white-matter presentations warrant a broader genetic and acquired-cause evaluation. [39][91][61][167]
11. Outcome and prognosis
Individual outcomes span severe prenatal injury, a bedridden child, and a sister who achieved walking but had absent speech and motor disability at age 20. Focal seizures were partly controlled in the brother and controlled in the sister with reported medicines. These observations demonstrate substantial variable morbidity, not a calculable prognosis. No defensible BSVD2B-specific five-year survival, mortality rate, life expectancy, validated quality-of-life score or prognostic biomarker is available. Structural damage may require long-term habilitation; an individual recovery probability cannot be inferred from the case series. [91][63]
12. Treatment and current implementation
There is no established disease-modifying treatment for BSVD2B. Management addresses seizures, developmental and motor needs, and avoidable vascular risks; care plans should be individualized with pediatric neurology, genetics and relevant rehabilitation specialists. The 2025 consensus provides guidance for the broader collagen-IV disorder group, not BSVD2B treatment-response rates. Suggested NCIT intervention annotations below are labels to map against the current NCIT release; no unverified NCIT identifier is asserted. [91][167]
Table (click to expand)
| Intervention; suggested NCIT term | Evidence, use and limits |
|---|---|
| Antiseizure medication; Anticonvulsant Therapy | In the original family, carbamazepine partly controlled one child’s focal seizures; phenobarbital plus carbamazepine controlled the sister’s seizures. These are two case observations, not a response-rate estimate or genotype-guided regimen. The 2023 child was reported to have drug-resistant epilepsy. [91][63] |
| Physical, occupational and speech-language therapy; corresponding Physical Therapy, Occupational Therapy and Speech-Language Therapy terms | Appropriate supportive/habilitative planning for documented mobility and communication disability; BSVD2B-specific trial outcomes are unavailable. [91][63] |
| Blood-pressure and vascular-risk management; Blood Pressure Monitoring | Broader COL4A1/COL4A2 consensus advises monitoring and avoiding hypertension. Antiplatelets and anticoagulants are generally not recommended solely for primary or secondary prevention in this disorder group; compelling alternative indications require individualized specialist assessment. [167] |
| Sodium 4-phenylbutyrate; Investigational Drug Treatment | Chemical-chaperone work reduced hemorrhage in Col4a1 mutant mice. This is not evidence of BSVD2B clinical efficacy: another mouse study warned that improved endoplasmic-reticulum stress did not necessarily repair mechanically defective basement membrane. It should not be presented as standard BSVD2B treatment. [139][140] |
| Gene, cell, RNA or targeted channel therapy; relevant experimental-intervention terms only if a study is identified | No established BSVD2B-specific efficacy, approved therapy, treatment-response rate or pharmacogenomic rule was found. The 2024 endothelial-signaling work identifies potential targets, not an administered clinical treatment. [85][167] |
A registered observational, non-drug study of COL4A1/COL4A2-related conditions, NCT07374913 (https://clinicaltrials.gov/study/NCT07374913), collects multisystem assessments and exploratory MMP2/MMP9 measurements; it is not a BSVD2B therapeutic trial or validation of those enzymes as prognostic biomarkers. A hereditary small-vessel-disease registry, NCT06512376 (https://clinicaltrials.gov/study/NCT06512376), also lists COL4A1/2 among eligible genes. [168][171]
13. Prevention and counseling
Table (click to expand)
| Prevention level | BSVD2B-appropriate interpretation |
|---|---|
| Primary prevention of affected births | Offer molecular diagnosis, family-specific carrier testing and genetic counseling; discuss reproductive options, including prenatal or preimplantation testing where appropriate and available. Lifestyle change cannot remove inherited biallelic variants. [91][63][167] |
| Secondary prevention and early detection | Cascade-test relatives when familial alleles are sufficiently classified; assess an at-risk child clinically and consider imaging according to specialist advice. There is no established universal newborn-screening program for BSVD2B. [167][91] |
| Tertiary prevention | Treat epilepsy and functional complications; manage blood pressure, avoid smoking and high-risk head trauma, and review antithrombotic decisions individually. These vascular precautions derive from wider collagen-IV guidance rather than a controlled BSVD2B prevention study. [167][91] |
| Immunization, antimicrobial or environmental prophylaxis | No disease-specific vaccine, antimicrobial prophylaxis, sanitation measure or toxin-removal program prevents BSVD2B. [35][91] |
14. Other species and naturally occurring disease
BSVD2B is a human disease designation ( Homo sapiens, NCBI Taxon:9606*). The orthologous mouse gene is Col4a2 ( Mus musculus*, Taxon:10090; NCBI Gene:12827; MGI:88455). The zebrafish col4a2 ortholog is catalogued as associated with the disease term, but that ontology association does not establish naturally occurring BSVD2B in fish. No spontaneous veterinary breed-specific counterpart, VBO breed identifier, zoonotic transmission or cross-species infection applies on the available evidence. [106][201][32]
15. Model organisms and research applications
Table (click to expand)
| Model and evidence type | Recapitulation, application and limitation |
|---|---|
| ENU-induced Col4a2 missense mice; animal model, PMID:17179069 | Heterozygotes showed eye, brain, kidney, vascular-stability and viability abnormalities; reported homozygotes did not survive beyond the second trimester. Useful for collagen-IV development and vascular integrity, but not a surviving, genotype-matched model of every human BSVD2B allele. [130][42] |
| Col4a2 mutant mouse and human cell assays; animal/in vitro, PMID:22209247 | Other COL4A2 mutations produced intracellular α1/α2 collagen accumulation and impaired secretion; some activated endoplasmic-reticulum stress. Supports a plausible pathway, not direct functional proof for p.Gly1158Arg or each newer recessive allele. [174][91] |
| Heterozygous Col4a2 knockout mice, mutant human brain endothelial cells and human vascular tissue; animal/in vitro/human tissue, PMID:39216230 | Tests collagen-IV abundance, vessel-wall mechanics and calcium-dependent endothelial signaling. Heterozygous knockouts and sporadic-disease tissue cannot supply recessive-patient phenotype frequencies. [85] |
| Computational structural assessment of p.Arg179Cys; computational, PMID:41499643 | Generates a testable protein-stability hypothesis, but does not substitute for an RNA, secretion, basement-membrane or disease-causality assay—especially given the paper’s reported likely-benign classification of that allele. [63] |
Knowledge-base curation priority: retain MONDO:0980747 ↔ OMIM:621414 ↔ biallelic COL4A2 as the disease-level association. Attach each phenotype to its specific patient/publication, each variant to its phase and reported classification, and each mechanistic claim to its human, animal, in-vitro or computational evidence type. Leave prevalence, penetrance, survival, BSVD2B-specific treatment efficacy and most phenotype frequencies unquantified rather than importing estimates from dominant or mixed-inheritance cohorts. [35][91][63][207]
Reference Validation
Checked with linkml-reference-validator 0.3.0.
Table (click to expand)
| Outcome | Count |
|---|---|
| References checked | 20 |
| Resolved | 20 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 20 |
| On topic | 2 |
| Off topic | 2 |
References that may not be about this subject
These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:
DOI:10.3389/frdem.2023.1146055(1 mention) - The emerging role of the HTRA1 protease in brain microvascular disease- shared terms: disease, brain
PMC:PMC11285548(1 mention) - The emerging role of the HTRA1 protease in brain microvascular disease.- shared terms: disease, brain
Weighed against this report's own most characteristic terms: bsvd2b, col4a2, bsvd2b-specific, variant, injury, child, established, recessive, clinical, collagen-iv, family, developmental, biallelic, allele, disease, brain, assessment, seizure, affected, epilepsy.
All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.
Term Validation
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
Table (click to expand)
| Outcome | Count |
|---|---|
| Terms checked | 33 |
| Resolved | 25 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 8 |
Prefixes with no resolver
Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: Gene, UniProt, Taxon, MGI, OMIM.
25 of 33 terms resolved to a current term; the rest could not be looked up either way.