Amir Hossein Saeidian1, Leila Youssefian2, Jianhe Huang3, Andrew Touati2, Hassan Vahidnezhad2, Luke Kowal4, Matthew Caffet5, Tamara Wurst5, Jagmohan Singh6, Adam E Snook6, Ellen Ryu4, Paolo Fortina7, Sharon F Terry5, Jonathan G Schoenecker8, Jouni Uitto3, Qiaoli Li9. 1. Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA; Department of Dermatology & Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA; Genetics, Genomics & Cancer Biology PhD Program, College of Life Sciences, Thomas Jefferson University, Philadelphia, PA. 2. Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA; Department of Dermatology & Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA. 3. Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA; Department of Dermatology & Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA; PXE International Center of Excellence in Research & Clinical Care, Thomas Jefferson University, Philadelphia, PA. 4. Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA. 5. PXE International, Inc, Washington, DC. 6. Department of Pharmacology & Experimental Therapeutics, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, PA. 7. Department of Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA. 8. Department of Orthopedics and Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN. 9. Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA; Department of Dermatology & Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA; PXE International Center of Excellence in Research & Clinical Care, Thomas Jefferson University, Philadelphia, PA. Electronic address: Qiaoli.Li@Jefferson.edu.
Abstract
PURPOSE: Heritable ectopic mineralization disorders comprise a group of conditions with a broad range of clinical manifestations in nonskeletal connective tissues. We report the genetic findings from a large international cohort of 478 patients afflicted with ectopic mineralization. METHODS: Sequence variations were identified using a next-generation sequencing panel consisting of 29 genes reported in association with ectopic mineralization. The pathogenicity of select splicing and missense variants was analyzed in experimental systems in vitro and in vivo. RESULTS: A total of 872 variants of unknown significance as well as likely pathogenic and pathogenic variants were disclosed in 25 genes. A total of 159 distinct variants were identified in 425 patients in ABCC6, the gene responsible for pseudoxanthoma elasticum, a heritable multisystem ectopic mineralization disorder. The interpretation of variant pathogenicity relying on bioinformatic predictions did not provide a consensus. Our in vitro and in vivo functional assessment of 14 ABCC6 variants highlighted this dilemma and provided unambiguous interpretations to their pathogenicity. CONCLUSION: The results expand the ABCC6 variant repertoire, shed new light on the genetic heterogeneity of heritable ectopic mineralization disorders, and provide evidence that functional characterization in appropriate experimental systems is necessary to determine the pathogenicity of genetic variants.
PURPOSE: Heritable ectopic mineralization disorders comprise a group of conditions with a broad range of clinical manifestations in nonskeletal connective tissues. We report the genetic findings from a large international cohort of 478 patients afflicted with ectopic mineralization. METHODS: Sequence variations were identified using a next-generation sequencing panel consisting of 29 genes reported in association with ectopic mineralization. The pathogenicity of select splicing and missense variants was analyzed in experimental systems in vitro and in vivo. RESULTS: A total of 872 variants of unknown significance as well as likely pathogenic and pathogenic variants were disclosed in 25 genes. A total of 159 distinct variants were identified in 425 patients in ABCC6, the gene responsible for pseudoxanthoma elasticum, a heritable multisystem ectopic mineralization disorder. The interpretation of variant pathogenicity relying on bioinformatic predictions did not provide a consensus. Our in vitro and in vivo functional assessment of 14 ABCC6 variants highlighted this dilemma and provided unambiguous interpretations to their pathogenicity. CONCLUSION: The results expand the ABCC6 variant repertoire, shed new light on the genetic heterogeneity of heritable ectopic mineralization disorders, and provide evidence that functional characterization in appropriate experimental systems is necessary to determine the pathogenicity of genetic variants.
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