Browsing by Subject "exome sequencing"

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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.
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    SCYL1 disease and liver transplantation diagnosed by reanalysis of exome sequencing and deletion/duplication analysis of SCYL1
    (Wiley, 2021-04) McNiven, Vanda; Gattini, Daniela; Siddiqui, Iram; Pelletier, Stephane; Brill, Herbert; Avitzur, Yaron; Mercimek-Andrews, Saadet; Medical and Molecular Genetics, School of Medicine
    SCYL1 disease results from biallelic pathogenic variants in SCYL1. We report two new patients with severe hepatic phenotype requiring liver transplantation. Patient charts reviewed. DNA samples and skin fibroblasts were utilized. Literature was reviewed. 13-year-old boy and 9-year-old girl siblings had acute liver insufficiency and underwent living related donor liver transplantation in infancy with no genetic diagnosis. Both had tremor, global developmental delay, and cognitive dysfunction during their follow-up in the medical genetic clinic for diagnostic investigations after their liver transplantation. Exome sequencing identified a likely pathogenic variant (c.399delC; p.Asn133Lysfs*136) in SCYL1. Deletion/duplication analysis of SCYL1 identified deletions of exons 7–8 in Patient 1. Both variants were confirmed in Patient 2 and the diagnosis of SCYL1 disease was confirmed in both patients at the age of 13 and 9 years, respectively. SCYL1 protein was not expressed in both patients' fibroblast using western blot analysis. Sixteen patients with SCYL1 disease reported in the literature. Liver phenotype (n = 16), neurological phenotype (n = 13) and skeletal phenotype (n = 11) were present. Both siblings required liver transplantation in infancy and had variable phenotypes. Exome sequencing may miss the diagnosis and phenotyping of patients can help to diagnose patients.