Browsing by Subject "variant interpretation"

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    Editorial: Current Challenges in Cardiovascular Molecular Diagnostics
    (Frontiers, 2017-09-01) Novelli, Valeria; Vatta, Matteo; Medical and Molecular Genetics, School of Medicine
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    Novel pathogenic variants in filamin C identified in pediatric restrictive cardiomyopathy
    (Wiley, 2018) Schubert, Jeffrey; Tariq, Muhammad; Geddes, Gabrielle; Kindel, Steven; Miller, Erin M.; Ware, Stephanie M.; Pediatrics, School of Medicine
    Restrictive cardiomyopathy (RCM) is a rare and distinct form of cardiomyopathy characterized by normal ventricular chamber dimensions, normal myocardial wall thickness, and preserved systolic function. The abnormal myocardium, however, demonstrates impaired relaxation. To date, dominant variants causing RCM have been reported in a small number of sarcomeric or cytoskeletal genes, but the genetic causes in a majority of cases remain unexplained, especially in early childhood. Here, we describe two RCM families with childhood onset: one in a large family with a history of autosomal dominant RCM and the other a family with affected monozygotic, dichorionic/diamniotic twins. Exome sequencing found a pathogenic filamin C (FLNC) variant in each: p.Pro2298Leu, which segregates with disease in the large autosomal dominant RCM family, and p.Tyr2563Cys in both affected twins. In vitro expression of both mutant proteins yielded aggregates of FLNC containing actin in C2C12 myoblast cells. Recently, a number of variants in FLNC have been described that cause hypertrophic, dilated, and restrictive cardiomyopathies. Our data presented here provide further evidence for the role of FLNC in pediatric RCM, and suggest the need to include FLNC in genetic testing of cardiomyopathy patients including those with early ages of onset.