Caspar Grond-Ginsbach1, Tobias Brandt2, Manja Kloss1, Suna Su Aksay1, Philipp Lyrer3, Christopher Traenka3, Philipp Erhart4, Juan Jose Martin5, Ayse Altintas6, Aksel Siva6, Gabriel R de Freitas7, Andreas Thie8, Jochen Machetanz9, Ralf W Baumgartner10, Martin Dichgans11,12, Stefan T Engelter3,13. 1. Department of Neurology, University of Heidelberg, Heidelberg, Germany. 2. Clinics for Neurologic Rehabilitation, Kliniken Schmieder, Heidelberg, Germany. 3. Department of Neurology and Stroke Center, Basel University Hospital, Basel, Switzerland. 4. Department of Vascular and Endovascular Surgery, University Hospital Heidelberg, Germany. 5. Department of Neurology, Sanatorio Allende, Cordoba, Argentina. 6. Neurology Department, Cerrahpasa Medical School, Istanbul University, Turkey. 7. Service of Neurology, Hospital Quinta D'Or/D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil. 8. Klinikum und Seniorenzentrum Itzehoe, Itzehoe, Germany. 9. Städtisches Krankenhaus Dresden-Neustadt, Dresden, Germany. 10. NeuroZentrum, Klinik Hirslanden, Zürich, Switzerland. 11. Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilians Universität, Munich, Germany. 12. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. 13. Neurorehabilitation Unit, University of Basel and University Center for Medicine of Aging and Rehabilitation, Felix Platter Hospital, Basel, Switzerland.
Abstract
BACKGROUND: The cause of cervical artery dissection is not well understood. We test the hypothesis that mutations in genes associated with known arterial connective tissue disorders are enriched in patients with familial cervical artery dissection. PATIENTS AND METHODS: Patient duos from nine pedigrees with familial cervical artery dissection were analyzed by whole exome sequencing. Single nucleotide variants in a panel of 11 candidate genes (ACTA2, MYH11, FBN1, TGFBR1, TGFBR2, TGFB2, COL3A1, COL4A1, SMAD3, MYLK and SLC2A10) were prioritized according to functionality (stop-loss, nonsense, and missense variants with polyphen-2 score ≥0.95). Variants classified as "benign" or "likely benign" in the ClinVar database were excluded from further analysis. For comparison, non-benign stop-loss, nonsense and missense variants with polyphen-2 score ≥0.95 in the same panel of candidate genes were identified in the European non-Finnish population of the ExAC database (n = 33,370). RESULTS: Non-benign Single nucleotide variants in both affected patients were identified in four of the nine cervical artery dissection families (COL3A1; Gly324Ser, FBN1: Arg2554Trp, COL4A1: Pro116Leu, and TGFBR2: Ala292Thr) yielding an allele frequency of 22.2% (4/18). In the comparison group, 1782 variants were present in 33,370 subjects from the ExAC database (allele frequency: 1782/66,740 = 2.7%; p = 0.0008; odds ratio = 14.2; 95% confidence interval = 3.8-52.9). CONCLUSION: Cervical artery dissection families showed enrichment for non-benign variants in genes associated with arterial connective tissue disorders. The observation that findings differed across families indicates genetic heterogeneity of familial cervical artery dissection.
BACKGROUND: The cause of cervical artery dissection is not well understood. We test the hypothesis that mutations in genes associated with known arterial connective tissue disorders are enriched in patients with familial cervical artery dissection. PATIENTS AND METHODS: Patient duos from nine pedigrees with familial cervical artery dissection were analyzed by whole exome sequencing. Single nucleotide variants in a panel of 11 candidate genes (ACTA2, MYH11, FBN1, TGFBR1, TGFBR2, TGFB2, COL3A1, COL4A1, SMAD3, MYLK and SLC2A10) were prioritized according to functionality (stop-loss, nonsense, and missense variants with polyphen-2 score ≥0.95). Variants classified as "benign" or "likely benign" in the ClinVar database were excluded from further analysis. For comparison, non-benign stop-loss, nonsense and missense variants with polyphen-2 score ≥0.95 in the same panel of candidate genes were identified in the European non-Finnish population of the ExAC database (n = 33,370). RESULTS: Non-benign Single nucleotide variants in both affected patients were identified in four of the nine cervical artery dissection families (COL3A1; Gly324Ser, FBN1: Arg2554Trp, COL4A1: Pro116Leu, and TGFBR2: Ala292Thr) yielding an allele frequency of 22.2% (4/18). In the comparison group, 1782 variants were present in 33,370 subjects from the ExAC database (allele frequency: 1782/66,740 = 2.7%; p = 0.0008; odds ratio = 14.2; 95% confidence interval = 3.8-52.9). CONCLUSION: Cervical artery dissection families showed enrichment for non-benign variants in genes associated with arterial connective tissue disorders. The observation that findings differed across families indicates genetic heterogeneity of familial cervical artery dissection.
Authors: T Brandt; E Orberk; R Weber; I Werner; O Busse; B T Müller; F Wigger; A Grau; C Grond-Ginsbach; I Hausser Journal: Neurology Date: 2001-07-10 Impact factor: 9.910
Authors: Juan Jose Martin; Ingrid Hausser; Philippe Lyrer; Otto Busse; Ralf Schwarz; Rolf Schneider; Tobias Brandt; Manja Kloss; Markus Schwaninger; Stefan Engelter; Caspar Grond-Ginsbach Journal: Stroke Date: 2006-10-19 Impact factor: 7.914
Authors: Paolo Comeglio; Philip Johnson; Gavin Arno; Glen Brice; Alison Evans; José Aragon-Martin; Filipe Pereira da Silva; Anatoli Kiotsekoglou; Anne Child Journal: Hum Mutat Date: 2007-09 Impact factor: 4.878
Authors: Philipp Erhart; Laura Gieldon; Marius Ante; Daniel Körfer; Tim Strom; Caspar Grond-Ginsbach; Dittmar Böckler Journal: J Thorac Dis Date: 2020-11 Impact factor: 2.895
Authors: Philipp Erhart; Daniel Körfer; Susanne Dihlmann; Jia-Lu Qiao; Ingrid Hausser; Peter Ringleb; Jörg Männer; Nicola Dikow; Christian P Schaaf; Caspar Grond-Ginsbach; Dittmar Böckler Journal: J Clin Med Date: 2022-06-07 Impact factor: 4.964
Authors: Lukas Mayer-Suess; Florian Frank; Thomas Töll; Christian Boehme; Elke R Gizewski; Gudrun Ratzinger; Gregor Broessner; Stefan Kiechl; Michael Knoflach Journal: Cephalalgia Date: 2022-03-18 Impact factor: 6.075
Authors: Christopher Traenka; Manja Kloss; Tim Strom; Philippe Lyrer; Tobias Brandt; Leo H Bonati; Caspar Grond-Ginsbach; Stefan Engelter Journal: Eur Stroke J Date: 2019-07-12