<i>COL4A1/2</i>
            CNVs and cerebral small vessel disease

Saskin, Avi; Sillon, Guillaume; Palfreeman, Natalie; Buhaş, Daniela

doi:10.1212/wnl.0000000000005601

Cited by 12 publications

(8 citation statements)

References 7 publications

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“…Interestingly, COL4A1 duplications have also been associated with a similar phenotype. 18,19 Altogether, these data strongly suggest that COL4A1…”

Section: Discussionmentioning

confidence: 57%

“…However, microbleeds (and to a lower degree, intracerebral hemorrhage, as observed in patients F2-10, F2-15, F5-5, and F5-10) may be more frequent in this condition associated with the AluYa5 insertion. Interestingly, COL4A1 duplications have also been associated with a similar phenotype . Altogether, these data strongly suggest that COL4A1 noncoding sequence variations should be searched in unresolved familial CSVD cases with pontine infarcts and leukoencephalopathy.…”

Section: Discussionmentioning

confidence: 73%

See 1 more Smart Citation

An AluYa5 Insertion in the 3′UTR of COL4A1 and Cerebral Small Vessel Disease

Aloui,

Neumann,

Bergametti

et al. 2024

JAMA Netw Open

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ImportanceCerebral small vessel diseases (CSVDs) account for one-fifth of stroke cases. Numerous familial cases remain unresolved after routine screening of known CSVD genes.ObjectiveTo identify novel genes and mechanisms associated with familial CSVD.Design, Setting, and ParticipantsThis 2-stage study involved linkage analysis and a case-control study; linkage analysis and whole exome and genome sequencing were used to identify candidate gene variants in 2 large families with CSVD (9 patients with CSVD). Then, a case-control analysis was conducted on 246 unrelated probands, including probands from these 2 families and 244 additional probands. All probands (clinical onset &lt;age 55 years and ≥1 first-degree relative with CSVD) were referred to the French cerebrovascular referral center between 2013 and 2023. The large-scale gnomAD structural variant database and 467 healthy individuals of French ancestry were used as a control group.Main Outcomes and MeasuresA pathogenic AluYa5 insertion was identified within the COL4A1 3′UTR in the 2 large families with CSVD. Reverse transcriptase–quantitative polymerase chain reaction (RT-qPCR), Western blot, and long-read RNA sequencing were used to investigate outcomes associated with the insertion using patient fibroblasts. Clinical and magnetic resonance imaging features of probands with variants and available relatives were assessed.ResultsAmong 246 probands (141 females [57.3%]; median [IQR] age at referral, 56 [49-64] years), 7 patients of French ancestry carried the insertion. This insertion was absent in 467 healthy French individuals in a control group (odds ratio, ∞; 95% CI, 2.78 to ∞; P = 5 × 10−4) and 10 847 individuals from the gnomAD structural variant database (odds ratio, ∞; 95% CI, 64.77 to ∞; P = 2.42 × 10−12). In these 7 patients’ families, 19 family members with CSVD carried the insertion. RT-qPCR and Western blot showed an upregulation of COL4A1 mRNA (10.6-fold increase; 95% CI, 1.4-fold to 17.1-fold increase) and protein levels (2.8-fold increase; 95% CI, 2.1-fold to 3.5-fold increase) in patient vs control group fibroblasts. Long-read RNA sequencing data showed that the insertion was associated with perturbation in the use of canonical COL4A1 polyadenylation signals (approximately 87% of isoforms transcribed from the wild type allele vs 5% of isoforms transcribed from the allele with the insertion used the 2 distal canonical polyadenylation signals). The main clinical feature of individuals with CSVD was the recurrence of pontine ischemic lesions starting at an early age (17 of 19 patients [89.5%]).Conclusions and relevanceThis study found a novel mechanism associated with COL4A1 upregulation and a highly penetrant adult-onset CSVD. These findings suggest that quantitative alterations of the cerebrovascular matrisome are associated with CSVD pathogenesis, with diagnostic and therapeutic implications.

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“…Interestingly, COL4A1 duplications have also been associated with a similar phenotype. 18,19 Altogether, these data strongly suggest that COL4A1…”

Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 73%

An AluYa5 Insertion in the 3′UTR of COL4A1 and Cerebral Small Vessel Disease

Aloui,

Neumann,

Bergametti

et al. 2024

JAMA Netw Open

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show abstract

“…25 Multiplex ligation-dependent probe amplification (MLPA) is the gold-standard to analyze this CNV. Rare disease-causing variants : A large (749,000 bp) duplication encompassing six protein-coding genes ( COL4A1, COL4A2, RAB20, NAXD, CARS2, ING1 ) genes as well as several non-protein-coding genes was found in a young patient with recurrent lacunar infarcts due to small vessel disease and in eleven affected family members. 16 The CNV was identified during next-generation sequencing analysis and was confirmed by array comparative genome hybridization. Global genomic imbalance : An excess burden of large, gene-disrupting CNVs was found in stroke patients with unfavorable functional outcome after three months, compared to patients with favorable outcome. 26 SNP-microarrays from previous GWAS were re-utilized to study CNV. Variants of unknown significance (VUS) : a large (> 3.1 Mb) duplication encompassing eight protein-coding genes ( SCOC, CLGN, ELMOD2, TBC1D9, RNF150, ZNF330, IL15, INPP4B ) was detected in a 19-year-old boy with ischemic stroke due to spontaneous carotid artery dissection.…”

Section: Cnv In Stroke Patientsmentioning

confidence: 97%

“…Rare disease-causing variants : A large (749,000 bp) duplication encompassing six protein-coding genes ( COL4A1, COL4A2, RAB20, NAXD, CARS2, ING1 ) genes as well as several non-protein-coding genes was found in a young patient with recurrent lacunar infarcts due to small vessel disease and in eleven affected family members. 16 The CNV was identified during next-generation sequencing analysis and was confirmed by array comparative genome hybridization.…”

Section: Cnv In Stroke Patientsmentioning

confidence: 99%

Copy Number Variation and Risk of Stroke

Grond‐Ginsbach

Erhart

Chen

et al. 2018

Stroke

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“…A lthough COL4A1 and COL4A2 duplications have previously been reported in association with cerebral small vessel disease (CSVD), no functional studies have been performed in these patients. [1][2][3] We performed a microarray analysis of a family with CSVD. Furthermore, we analyzed array data of a cohort of 96 unrelated Finnish cerebrovascular disease patients to study the frequency of the duplication discovered in the family.…”

mentioning

confidence: 99%