Interpretation and classification of FBN1 variants associated with Marfan syndrome: consensus recommendations from the Clinical Genome Resource’s FBN1 variant curation expert panel

被引：0
作者：
A. Drackley [1 ]
C. Somerville [2 ]
P. Arnaud [3 ]
L. M. Baudhuin [4 ]
N. Hanna [5 ]
M. L. Kluge [3 ]
K. Kotzer [4 ]
C. Boileau [5 ]
L. Bronicki [5 ]
B. Callewaert [3 ]
A. Cecchi [2 ]
H. Dietz [6 ]
D. Guo [7 ]
S. Harris [8 ]
O. Jarinova [9 ]
M. Lindsay [10 ]
L. Little [9 ]
B. Loeys [11 ]
G. MacCarrick [2 ]
J. Meester [6 ]
D. Milewicz [11 ]
T. Morisaki [2 ]
H. Morisaki [4 ]
D. Murdock [12 ]
M. Renard [10 ]
J. Richer [4 ]
L. Robert [12 ]
M. Ouzounian [9 ]
L. Van Laer [13 ]
J. De Backer [13 ]
L. Muiño-Mosquera [14 ]
机构：
[1] Department of Pathology & Laboratory Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL
[2] Genetics Diagnostic Laboratory, Children’s Hospital of Eastern Ontario, Ottawa, ON
[3] Genetics Department, Hôpital Bichat, Université Paris Cité, Paris
[4] European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD and MSA Rare Disease, Working Group, Paris
[5] Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
[6] Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON
[7] Centre for Medical Genetics, Ghent University Hospital, Ghent
[8] Department of Biomolecular Medicine, Ghent University, Ghent
[9] Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
[10] McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
[11] Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA
[12] Centre of Medical Genetics, Antwerp University Hospital and University of Antwerp, Antwerp
[13] IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, Minato-Ku, Tokyo
[14] Department of Medical Genetics, Sakakibara Heart Institute, Fuchu, Tokyo
[15] Department of Medical Genetics, Children’s Hospital of Eastern Ontario, Ottawa, ON
[16] Department of Cardiology, Guy’s and St Thomas’ Foundation Trust, London
[17] Division of Cardiac Surgery, University of Toronto, Toronto, ON
[18] Department of Cardiology, Ghent University Hospital, Ghent
[19] Department of Internal Medicine and Paediatrics, Ghent University, Ghent
[20] Division of Paediatric Cardiology, Department of Paediatrics, Ghent University Hospital, Ghent
来源：
Genome Medicine | / 16卷 / 1期
关键词：
ACMG-AMP guidelines; FBN1; Marfan syndrome; Variant curation; Variant interpretation;
D O I：
10.1186/s13073-024-01423-3
中图分类号：
学科分类号：
摘要：
Background: In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) developed standardized variant curation guidelines for Mendelian disorders. Although these guidelines have been widely adopted, they are not gene- or disease-specific. To mitigate classification discrepancies, the Clinical Genome Resource FBN1 variant curation expert panel (VCEP) was established in 2018 to develop adaptations to the ACMG/AMP criteria for FBN1 in association with Marfan syndrome. Methods: The specific recommendations were developed through literature review, surveys, online expert panel discussions, and pilot testing of a set of 60 different variants. Consensus among experts was considered reached if at least 75% of the members agreed with a given rule specification. The final set of rules received approval from the ClinGen Sequence Variant Interpretation Working Group. Results: The developed specifications introduce modifications to 14 of the 28 ACMG/AMP evidence criteria and deem 6 criteria non-applicable. Some of these specifications include refining the minor allele frequency thresholds, creating a FBN1-specific flowchart for PVS1, defining functional domains of the protein, developing a point-based system of counting probands and instances of de novo occurrences, recommending a points-based method of accounting for family segregation data, and clarifying the applicable functional assays that should be considered. To date, this VCEP has curated 120 variants which have been deposited to ClinVar with the 3-star review status. Conclusions: Establishing specific adaptations for FBN1 has provided a framework to foster greater classification concordance among clinical laboratories, ultimately improving clinical care for patients with Marfan syndrome. © The Author(s) 2024.
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