Identification of Pathological FBN1 Variants Is Not Straightforward
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See Article by Muiño-Mosquera et al
The ability to identify DNA variants that are pathogenic forms the basis for unbiased characterization of inherited diseases. Improved access to genetic testing and the increasing clinical use of whole exome and whole genome sequencing have identified variants of uncertain pathogenicity often associated with an indefinite disease phenotype. In 2015, the American College of Medical Genetics and Genomics and the Association for Molecular Biology published guidelines to assist in pathogenicity classification of variants in Mendelian diseases.1 However, the application of the 28 criteria is complex and can still be subjective. Difficulties in determining the pathogenicity of sequenced FBN1 (fibrillin-1) variants associated with the Marfan syndrome is a good example of the general problem.
In this issue of Circulation: Genomic and Precision Medicine, Muiño-Mosquera et al2 propose a modification of the American College of Medical Genetics and Genomics and the Association for Molecular Biology guidelines for ascertainment of the significance of FBN1 mutations in patients with clinical signs of Marfan syndrome using nonsubjective criteria and show that their modified criteria result in changes in diagnostic determinations of some patients thought to have a clinical diagnosis of Marfan syndrome. The American College of Medical Genetics and Genomics …