Multinational Genome-Wide Association Study and Functional Genomics Analysis Implicates Decreased SIRT3 Expression Underlying Intracranial Aneurysm Risk

Hale, Andrew T.; He, Jing; Jones, Jesse

doi:10.1227/neu.0000000000002082

Cited by 2 publications

(1 citation statement)

References 66 publications

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“…7,8 Functional genomics approaches such as single-cell RNA sequencing (scRNA seq) delineate molecular mechanisms underlying diseases with a genetic or shared molecular component. [9][10][11][12][13][14][15][16] Collectively, these approaches may enable (1) detection of potential causative or risk-conferring mutations; (2) elucidation of cellular composition in situ; and (3) identification of convergent molecular mechanisms amenable to pharmacologic or even gene therapy based approaches.…”

Section: Introductionmentioning

confidence: 99%

Endothelial samplingin situenables genetic characterization of vein of Galen Malformation

Hale,

Liu,

Huang

et al. 2023

Preprint

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Background and ObjectivesVein of Galen malformation (VOGM), the result of arteriovenous shunting between choroidal and/or subependymal arteries and the embryologic prosencephalic vein, is among the most severe cerebrovascular disorders of childhood. While endovascular treatment options have improved outcomes, morbidity and mortality remain high. We hypothesized thatin situanalysis of the VOGM lesion using endoluminal tissue sampling (ETS) is feasible and may identify somatic mutations and transcriptional aberrations. A mechanistic understanding of VOGM genetics, pathogenesis, and maintenance will guide future therapeutic efforts.MethodsWe utilized a Mendelian, trio-based study design, collecting germline DNA (cheek swab) from patients and their families for whole exome sequencing (WES).In situVOGM ‘endothelial’ cells (EC), defined as CD31+ and CD45-, were obtained from coils via ETS during routine endovascular treatment. Autologous peripheral femoral ECs were also collected from the access sheath. Single-cell RNA sequencing (scRNA-seq) of both VOGM and femoral ECs was performed to demonstrate feasibility to define the transcriptional architecture. Comparison was also made to a published normative cerebrovascular transcriptome atlas. A subset of VOGM ECs was reserved for future DNA sequencing to assess for somatic and second-hit mutations.ResultsOur cohort contains 6 patients who underwent 10 ETS procedures from arterial and/or venous access during routine VOGM treatment (aged 12 days to ∼6 years). No periprocedural complications attributable to ETS occurred. Six unique coil types were used. ETS captured 98 ± 88 (mean ± SD; range 17-256) experimental ‘endothelial’ cells (CD31+ and CD45-). There was no discernable correlation between cell yield and coil type or route of access. Single cell RNA sequencing demonstrated hierarchical clustering and unique cell populations within the VOGM EC compartment compared to autologous femoral controls when annotated using a publicly available cerebrovascular cell atlas.ConclusionWe report the first successful utilization of ETS for VOGM. ETS appears safe and may supplement investigations aimed at development of a molecular-genetic taxonomic classification scheme for VOGM. Moreover, results may eventually inform the selection of personalized pharmacologic or genetic therapies for VOGM and cerebrovascular disorders more broadly.

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Section: Introductionmentioning

confidence: 99%

Endothelial samplingin situenables genetic characterization of vein of Galen Malformation

Hale,

Liu,

Huang

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

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Endoluminal Biopsy for Vein of Galen Malformation

Hale,

Liu,

Huang

et al. 2024

Neurosurgery

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BACKGROUND AND OBJECTIVES: Vein of Galen malformation (VOGM), the result of arteriovenous shunting between choroidal and/or subependymal arteries and the embryologic prosencephalic vein, is among the most severe cerebrovascular disorders of childhood. We hypothesized that in situ analysis of the VOGM lesion using endoluminal tissue sampling (ETS) is feasible and may advance our understanding of VOGM genetics, pathogenesis, and maintenance. METHODS: We collected germline DNA (cheek swab) from patients and their families for genetic analysis. In situ VOGM “endothelial” cells (ECs), defined as CD31+ and CD45−, were obtained from coils through ETS during routine endovascular treatment. Autologous peripheral femoral ECs were also collected from the access sheath. Single-cell RNA sequencing of both VOGM and peripheral ECs was performed to demonstrate feasibility to define the transcriptional architecture. Comparison was also made with a published normative cerebrovascular transcriptome atlas. A subset of VOGM ECs was reserved for future DNA sequencing to assess for somatic and second-hit mutations. RESULTS: Our cohort contains 6 patients who underwent 10 ETS procedures from arterial and/or venous access during routine VOGM treatment (aged 12 days to ∼6 years). No periprocedural complications attributable to ETS occurred. Six unique coil types were used. ETS captured 98 ± 88 (mean ± SD; range 17-256) experimental ECs (CD31+ and CD45−). There was no discernible correlation between cell yield and coil type or route of access. Single-cell RNA sequencing demonstrated hierarchical clustering and unique cell populations within the VOGM EC compartment compared with peripheral EC controls when annotated using a publicly available cerebrovascular cell atlas. CONCLUSION: ETS may supplement investigations aimed at development of a molecular-genetic taxonomic classification scheme for VOGM. Moreover, results may eventually inform the selection of personalized pharmacologic or genetic therapies for VOGM and cerebrovascular disorders more broadly.

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Multinational Genome-Wide Association Study and Functional Genomics Analysis Implicates Decreased SIRT3 Expression Underlying Intracranial Aneurysm Risk

Cited by 2 publications

References 66 publications

Endothelial samplingin situenables genetic characterization of vein of Galen Malformation

Endothelial samplingin situenables genetic characterization of vein of Galen Malformation

Endoluminal Biopsy for Vein of Galen Malformation

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