Expanding the genetic and phenotypic spectrum of ACTA2-related vasculopathies in a Dutch cohort

Lisa M. van den Bersselaar; Judith M.A. Verhagen; Jos A. Bekkers; Marlies Kempers; Arjan C. Houweling; Marieke Baars; Eline Overwater; Yvonne Hilhorst-Hofstee; Daniela Q.C.M. Barge-Schaapveld; Eline Rompen; Ingrid P.C. Krapels; Eelco Dulfer; Marja W. Wessels; Bart L. Loeys; Hence J.M. Verhagen; Alessandra Maugeri; Jolien W. Roos-Hesselink; Hennie T. Brüggenwirth; Ingrid M.B.H. van de Laar

doi:10.1016/j.gim.2022.07.009

Expanding the genetic and phenotypic spectrum of ACTA2-related vasculopathies in a Dutch cohort

Lisa M. van den Bersselaar
, Judith M.A. Verhagen
, Jos A. Bekkers
, Marlies Kempers
, Arjan C. Houweling
, Marieke Baars
, Eline Overwater
, Yvonne Hilhorst-Hofstee
, Daniela Q.C.M. Barge-Schaapveld
, Eline Rompen
, Ingrid P.C. Krapels
, Eelco Dulfer
, Marja W. Wessels
, Bart L. Loeys
, Hence J.M. Verhagen
, Alessandra Maugeri
, Jolien W. Roos-Hesselink
, Hennie T. Brüggenwirth
, Ingrid M.B.H. van de Laar^*

^*Corresponding author for this work

Radboud University Medical Center
Vrije Universiteit Amsterdam
University of Amsterdam
University Medical Centre Groningen
Leiden University Medical Centre
Maastricht University
University of Antwerp

Research output: Contribution to journal › Article › Academic › peer-review

6 Citations (Scopus)

159 Downloads (Pure)

Abstract

PURPOSE: Heterozygous pathogenic/likely pathogenic (P/LP) variants in the ACTA2 gene confer a high risk for thoracic aortic aneurysms and aortic dissections. This retrospective multicenter study elucidates the clinical outcome of ACTA2-related vasculopathies.

METHODS: Index patients and relatives with a P/LP variant in ACTA2 were included. Data were collected through retrospective review of medical records using a standardized questionnaire.

RESULTS: A total of 49 individuals from 28 families participated in our study. In total, 20 different ACTA2 variants were detected. Aortic events occurred in 65% of the cases (78.6% index patients and 47.6% relatives). Male sex and hypertension emerged as significantly associated with aortic events. Of 20 individuals, 5 had an aortic diameter of <45 mm (1.77 inches) at the time of the type A dissection. Mean age at first aortic event was 49.0 ± 12.4 years. Severe surgical complications for type A and type B dissection occurred in 25% and 16.7% of the cases and in-hospital mortality rates were 9.5% and 0%, respectively.

CONCLUSION: P/LP ACTA2 variants are associated with an increased risk for an aortic event and age-related penetrance, which emphasizes the importance of early recognition of the disease. Caregivers should be aware of the risk for aortic dissections, even in individuals with aortic diameters within the normal range.

Original language	English
Pages (from-to)	2112-2122
Number of pages	11
Journal	Genetics in Medicine
Volume	24
Issue number	10
DOIs	https://doi.org/10.1016/j.gim.2022.07.009
Publication status	Published - Oct 2022

Bibliographical note

Acknowledgments
We would like to thank all the research participants and the physicians and genetic counselors and investigators who
have included individuals in this study and collected clinical data. This work was supported by the Dutch Heart Foundation (2014T007).

Publisher Copyright: © 2022 The Authors

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PIIS1098360022008462Final published version, 538 KBLicence: CC BY-NC-ND

Cite this

van den Bersselaar, L. M., Verhagen, J. M. A., Bekkers, J. A., Kempers, M., Houweling, A. C., Baars, M., Overwater, E., Hilhorst-Hofstee, Y., Barge-Schaapveld, D. Q. C. M., Rompen, E., Krapels, I. P. C., Dulfer, E., Wessels, M. W., Loeys, B. L., Verhagen, H. J. M., Maugeri, A., Roos-Hesselink, J. W., Brüggenwirth, H. T., & van de Laar, I. M. B. H. (2022). Expanding the genetic and phenotypic spectrum of ACTA2-related vasculopathies in a Dutch cohort. Genetics in Medicine, 24(10), 2112-2122. https://doi.org/10.1016/j.gim.2022.07.009

@article{f97555705ef041b5bdb1bd3ba057c2f1,

title = "Expanding the genetic and phenotypic spectrum of ACTA2-related vasculopathies in a Dutch cohort",

abstract = "PURPOSE: Heterozygous pathogenic/likely pathogenic (P/LP) variants in the ACTA2 gene confer a high risk for thoracic aortic aneurysms and aortic dissections. This retrospective multicenter study elucidates the clinical outcome of ACTA2-related vasculopathies.METHODS: Index patients and relatives with a P/LP variant in ACTA2 were included. Data were collected through retrospective review of medical records using a standardized questionnaire.RESULTS: A total of 49 individuals from 28 families participated in our study. In total, 20 different ACTA2 variants were detected. Aortic events occurred in 65\% of the cases (78.6\% index patients and 47.6\% relatives). Male sex and hypertension emerged as significantly associated with aortic events. Of 20 individuals, 5 had an aortic diameter of <45 mm (1.77 inches) at the time of the type A dissection. Mean age at first aortic event was 49.0 ± 12.4 years. Severe surgical complications for type A and type B dissection occurred in 25\% and 16.7\% of the cases and in-hospital mortality rates were 9.5\% and 0\%, respectively.CONCLUSION: P/LP ACTA2 variants are associated with an increased risk for an aortic event and age-related penetrance, which emphasizes the importance of early recognition of the disease. Caregivers should be aware of the risk for aortic dissections, even in individuals with aortic diameters within the normal range.",

author = "\{van den Bersselaar\}, \{Lisa M.\} and Verhagen, \{Judith M.A.\} and Bekkers, \{Jos A.\} and Marlies Kempers and Houweling, \{Arjan C.\} and Marieke Baars and Eline Overwater and Yvonne Hilhorst-Hofstee and Barge-Schaapveld, \{Daniela Q.C.M.\} and Eline Rompen and Krapels, \{Ingrid P.C.\} and Eelco Dulfer and Wessels, \{Marja W.\} and Loeys, \{Bart L.\} and Verhagen, \{Hence J.M.\} and Alessandra Maugeri and Roos-Hesselink, \{Jolien W.\} and Br{\"u}ggenwirth, \{Hennie T.\} and \{van de Laar\}, \{Ingrid M.B.H.\}",

note = "Acknowledgments We would like to thank all the research participants and the physicians and genetic counselors and investigators who have included individuals in this study and collected clinical data. This work was supported by the Dutch Heart Foundation (2014T007). Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = oct,

doi = "10.1016/j.gim.2022.07.009",

language = "English",

volume = "24",

pages = "2112--2122",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Elsevier",

number = "10",

}

van den Bersselaar, LM , Verhagen, JMA , Bekkers, JA, Kempers, M, Houweling, AC, Baars, M, Overwater, E, Hilhorst-Hofstee, Y, Barge-Schaapveld, DQCM, Rompen, E, Krapels, IPC, Dulfer, E, Wessels, MW, Loeys, BL, Verhagen, HJM, Maugeri, A, Roos-Hesselink, JW , Brüggenwirth, HT & van de Laar, IMBH 2022, 'Expanding the genetic and phenotypic spectrum of ACTA2-related vasculopathies in a Dutch cohort', Genetics in Medicine, vol. 24, no. 10, pp. 2112-2122. https://doi.org/10.1016/j.gim.2022.07.009

TY - JOUR

T1 - Expanding the genetic and phenotypic spectrum of ACTA2-related vasculopathies in a Dutch cohort

AU - van den Bersselaar, Lisa M.

AU - Verhagen, Judith M.A.

AU - Bekkers, Jos A.

AU - Kempers, Marlies

AU - Houweling, Arjan C.

AU - Baars, Marieke

AU - Overwater, Eline

AU - Hilhorst-Hofstee, Yvonne

AU - Barge-Schaapveld, Daniela Q.C.M.

AU - Rompen, Eline

AU - Krapels, Ingrid P.C.

AU - Dulfer, Eelco

AU - Wessels, Marja W.

AU - Loeys, Bart L.

AU - Verhagen, Hence J.M.

AU - Maugeri, Alessandra

AU - Roos-Hesselink, Jolien W.

AU - Brüggenwirth, Hennie T.

AU - van de Laar, Ingrid M.B.H.

N1 - Acknowledgments We would like to thank all the research participants and the physicians and genetic counselors and investigators who have included individuals in this study and collected clinical data. This work was supported by the Dutch Heart Foundation (2014T007). Publisher Copyright: © 2022 The Authors

PY - 2022/10

Y1 - 2022/10

N2 - PURPOSE: Heterozygous pathogenic/likely pathogenic (P/LP) variants in the ACTA2 gene confer a high risk for thoracic aortic aneurysms and aortic dissections. This retrospective multicenter study elucidates the clinical outcome of ACTA2-related vasculopathies.METHODS: Index patients and relatives with a P/LP variant in ACTA2 were included. Data were collected through retrospective review of medical records using a standardized questionnaire.RESULTS: A total of 49 individuals from 28 families participated in our study. In total, 20 different ACTA2 variants were detected. Aortic events occurred in 65% of the cases (78.6% index patients and 47.6% relatives). Male sex and hypertension emerged as significantly associated with aortic events. Of 20 individuals, 5 had an aortic diameter of <45 mm (1.77 inches) at the time of the type A dissection. Mean age at first aortic event was 49.0 ± 12.4 years. Severe surgical complications for type A and type B dissection occurred in 25% and 16.7% of the cases and in-hospital mortality rates were 9.5% and 0%, respectively.CONCLUSION: P/LP ACTA2 variants are associated with an increased risk for an aortic event and age-related penetrance, which emphasizes the importance of early recognition of the disease. Caregivers should be aware of the risk for aortic dissections, even in individuals with aortic diameters within the normal range.

AB - PURPOSE: Heterozygous pathogenic/likely pathogenic (P/LP) variants in the ACTA2 gene confer a high risk for thoracic aortic aneurysms and aortic dissections. This retrospective multicenter study elucidates the clinical outcome of ACTA2-related vasculopathies.METHODS: Index patients and relatives with a P/LP variant in ACTA2 were included. Data were collected through retrospective review of medical records using a standardized questionnaire.RESULTS: A total of 49 individuals from 28 families participated in our study. In total, 20 different ACTA2 variants were detected. Aortic events occurred in 65% of the cases (78.6% index patients and 47.6% relatives). Male sex and hypertension emerged as significantly associated with aortic events. Of 20 individuals, 5 had an aortic diameter of <45 mm (1.77 inches) at the time of the type A dissection. Mean age at first aortic event was 49.0 ± 12.4 years. Severe surgical complications for type A and type B dissection occurred in 25% and 16.7% of the cases and in-hospital mortality rates were 9.5% and 0%, respectively.CONCLUSION: P/LP ACTA2 variants are associated with an increased risk for an aortic event and age-related penetrance, which emphasizes the importance of early recognition of the disease. Caregivers should be aware of the risk for aortic dissections, even in individuals with aortic diameters within the normal range.

UR - https://www.scopus.com/pages/publications/85137724874

U2 - 10.1016/j.gim.2022.07.009

DO - 10.1016/j.gim.2022.07.009

M3 - Article

C2 - 36053285

AN - SCOPUS:85137724874

SN - 1098-3600

VL - 24

SP - 2112

EP - 2122

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 10

ER -

Expanding the genetic and phenotypic spectrum of ACTA2-related vasculopathies in a Dutch cohort

Abstract

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