Rare Sequence Variation Underlying Suspected Familial Cerebral Small‐Vessel Disease
Background Cerebral small‐vessel disease (cSVD) is the leading monogenic cause of stroke. Despite genetic screening in routine diagnosis, many cases remain without a known causative variant. Using a cohort with suspected familial cSVD and whole‐genome sequencing, we screened for variants in genes as...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-08-01
|
| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.123.035771 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849725333270429696 |
|---|---|
| author | Bernard P. H. Cho Kate Auckland Stefan Gräf Hugh S. Markus |
| author_facet | Bernard P. H. Cho Kate Auckland Stefan Gräf Hugh S. Markus |
| author_sort | Bernard P. H. Cho |
| collection | DOAJ |
| description | Background Cerebral small‐vessel disease (cSVD) is the leading monogenic cause of stroke. Despite genetic screening in routine diagnosis, many cases remain without a known causative variant. Using a cohort with suspected familial cSVD and whole‐genome sequencing, we screened for variants in genes associated with monogenic cSVD and searched for novel variants associated with the disease. Methods and Results Rare variants were identified in whole‐genome sequencing data from the NBR (National Institute for Health Research BioResource Rare Disease) study. Pathogenic variants in known monogenic cSVD genes were identified. Gene‐based burden tests and family analysis were performed to identify novel variants associated with familial cSVD. A total of 257 suspected cSVD cases (mean ± SD age, 56.2 ± 16.1 years), and 13 086 controls with other nonstroke diseases (5874 [44.9%] men) were studied. A total of 8.9% of the cases carried a variant in known cSVD genes. Excluding these known causes, 23.6% of unrelated subjects with cSVD carried predicted deleterious variants in the Genomics England gene panel, but no association was found with cSVD in burden tests. We identified potential associations with cSVD in noncoding genes, including RP4‐568F9.3 (adjusted P = 7.1 × 10−25), RP3‐466I7.1 (adjusted P = 8.9 × 10−16), and ZNF209P (adjusted P = 1.0 × 10−15), and matrisomal genes (adjusted P = 5.1 × 10−6), including FAM20C, INHA, LAMC1, and VWA5B2. Conclusions Predicted deleterious variants in known cSVD genes were present in 23.6% of unrelated cases with cSVD, but none of the genes were associated with the disease. Rare variants in noncoding and matrisomal genes could potentially contribute to cSVD development. These genes could play a role in tissue development and brain endothelial cell function. However, further studies are needed to confirm their pathophysiological roles. |
| format | Article |
| id | doaj-art-4e09a5ea6a134a539d5b1fd8244492ba |
| institution | DOAJ |
| issn | 2047-9980 |
| language | English |
| publishDate | 2024-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj-art-4e09a5ea6a134a539d5b1fd8244492ba2025-08-20T03:10:29ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802024-08-01131510.1161/JAHA.123.035771Rare Sequence Variation Underlying Suspected Familial Cerebral Small‐Vessel DiseaseBernard P. H. Cho0Kate Auckland1Stefan Gräf2Hugh S. Markus3Stroke Research Group Department of Clinical Neurosciences University of Cambridge Cambridge UKDepartment of Medicine University of Cambridge Victor Phillip Dahdaleh Heart and Lung Research Institute Cambridge UKDepartment of Medicine University of Cambridge Victor Phillip Dahdaleh Heart and Lung Research Institute Cambridge UKStroke Research Group Department of Clinical Neurosciences University of Cambridge Cambridge UKBackground Cerebral small‐vessel disease (cSVD) is the leading monogenic cause of stroke. Despite genetic screening in routine diagnosis, many cases remain without a known causative variant. Using a cohort with suspected familial cSVD and whole‐genome sequencing, we screened for variants in genes associated with monogenic cSVD and searched for novel variants associated with the disease. Methods and Results Rare variants were identified in whole‐genome sequencing data from the NBR (National Institute for Health Research BioResource Rare Disease) study. Pathogenic variants in known monogenic cSVD genes were identified. Gene‐based burden tests and family analysis were performed to identify novel variants associated with familial cSVD. A total of 257 suspected cSVD cases (mean ± SD age, 56.2 ± 16.1 years), and 13 086 controls with other nonstroke diseases (5874 [44.9%] men) were studied. A total of 8.9% of the cases carried a variant in known cSVD genes. Excluding these known causes, 23.6% of unrelated subjects with cSVD carried predicted deleterious variants in the Genomics England gene panel, but no association was found with cSVD in burden tests. We identified potential associations with cSVD in noncoding genes, including RP4‐568F9.3 (adjusted P = 7.1 × 10−25), RP3‐466I7.1 (adjusted P = 8.9 × 10−16), and ZNF209P (adjusted P = 1.0 × 10−15), and matrisomal genes (adjusted P = 5.1 × 10−6), including FAM20C, INHA, LAMC1, and VWA5B2. Conclusions Predicted deleterious variants in known cSVD genes were present in 23.6% of unrelated cases with cSVD, but none of the genes were associated with the disease. Rare variants in noncoding and matrisomal genes could potentially contribute to cSVD development. These genes could play a role in tissue development and brain endothelial cell function. However, further studies are needed to confirm their pathophysiological roles.https://www.ahajournals.org/doi/10.1161/JAHA.123.035771burden testfamilial strokeNational Institute for Health Research BioResource Rare Disease studywhole‐genome sequencing |
| spellingShingle | Bernard P. H. Cho Kate Auckland Stefan Gräf Hugh S. Markus Rare Sequence Variation Underlying Suspected Familial Cerebral Small‐Vessel Disease Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease burden test familial stroke National Institute for Health Research BioResource Rare Disease study whole‐genome sequencing |
| title | Rare Sequence Variation Underlying Suspected Familial Cerebral Small‐Vessel Disease |
| title_full | Rare Sequence Variation Underlying Suspected Familial Cerebral Small‐Vessel Disease |
| title_fullStr | Rare Sequence Variation Underlying Suspected Familial Cerebral Small‐Vessel Disease |
| title_full_unstemmed | Rare Sequence Variation Underlying Suspected Familial Cerebral Small‐Vessel Disease |
| title_short | Rare Sequence Variation Underlying Suspected Familial Cerebral Small‐Vessel Disease |
| title_sort | rare sequence variation underlying suspected familial cerebral small vessel disease |
| topic | burden test familial stroke National Institute for Health Research BioResource Rare Disease study whole‐genome sequencing |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.123.035771 |
| work_keys_str_mv | AT bernardphcho raresequencevariationunderlyingsuspectedfamilialcerebralsmallvesseldisease AT kateauckland raresequencevariationunderlyingsuspectedfamilialcerebralsmallvesseldisease AT stefangraf raresequencevariationunderlyingsuspectedfamilialcerebralsmallvesseldisease AT hughsmarkus raresequencevariationunderlyingsuspectedfamilialcerebralsmallvesseldisease |