Browsing by Subject "genetic testing"
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Item Open Access A 14-year-old in heart failure with multiple cardiomyopathy variants illustrates a role for signal-to-noise analysis in gene test re-interpretation.(Clinical case reports, 2019-01) Connell, Patrick S; Jeewa, Aamir; Kearney, Debra L; Tunuguntla, Hari; Denfield, Susan W; Allen, Hugh D; Landstrom, Andrew PVariants of unknown significance in cardiomyopathic disease should be analyzed systematically based on the prevalence of the variant in the population compared to prevalence of disease, evidence that other variants in the gene are pathologic, consistency of prediction software on pathogenicity, and the current clinical consensus.Item Open Access Amino Acid-Level Signal-to-Noise Analysis Aids in Pathogenicity Prediction of Incidentally Identified TTN-Encoded Titin Truncating Variants.(Circulation. Genomic and precision medicine, 2021-02) Connell, Patrick S; Berkman, Amy M; Souder, BriAnna M; Pirozzi, Elisa J; Lovin, Julia J; Rosenfeld, Jill A; Liu, Pengfei; Tunuguntla, Hari; Allen, Hugh D; Denfield, Susan W; Kim, Jeffrey J; Landstrom, Andrew PBackground
TTN, the largest gene in the human body, encodes TTN (titin), a protein that plays key structural, developmental, and regulatory roles in skeletal and cardiac muscle. Variants in TTN, particularly truncating variants (TTNtvs), have been implicated in the pathogenicity of cardiomyopathy. Despite this link, there is also a high burden of TTNtvs in the ostensibly healthy general population. This complicates the diagnostic interpretation of incidentally identified TTNtvs, which are of increasing abundance given expanding clinical exome sequencing.Methods
Incidentally identified TTNtvs were obtained from a large referral database of clinical exome sequencing (Baylor Genetics) and compared with rare population variants from genome aggregation database and cardiomyopathy-associated variants from cohort studies in the literature. A subset of TTNtv-positive children evaluated for cardiomyopathy at Texas Children's Hospital was retrospectively reviewed for clinical features of cardiomyopathy. Amino acid-level signal-to-noise analysis was performed.Results
Pathological hotspots were identified within the A-band and N-terminal I-band that closely correlated with regions of high percent-spliced in of exons. Incidental TTNtvs and population TTNtvs did not localize to these regions. Variants were reclassified based on current American College of Medical Genetics and Genomics criteria with incorporation of signal-to-noise analysis among Texas Children's Hospital cases. Those reclassified as likely pathogenic or pathogenic were more likely to have evidence of cardiomyopathy on echocardiography than those reclassified as variants of unknown significance.Conclusions
Incidentally found TTNtvs are common among clinical exome sequencing referrals. Pathological hotspots within the A-band of TTN may be informative in determining variant pathogenicity when incorporated into current American College of Medical Genetics and Genomics guidelines.Item Open Access Genotype Predicts Outcomes in Fetuses and Neonates With Severe Congenital Long QT Syndrome.(JACC. Clinical electrophysiology, 2020-11) Moore, Jeremy P; Gallotti, Roberto G; Shannon, Kevin M; Bos, J Martijn; Sadeghi, Elham; Strasburger, Janette F; Wakai, Ronald T; Horigome, Hitoshi; Clur, Sally-Ann; Hill, Allison C; Shah, Maully J; Behere, Shashank; Sarquella-Brugada, Georgia; Czosek, Richard; Etheridge, Susan P; Fischbach, Peter; Kannankeril, Prince J; Motonaga, Kara; Landstrom, Andrew P; Williams, Matthew; Patel, Akash; Dagradi, Federica; Tan, Reina B; Stephenson, Elizabeth; Krishna, Mani Ram; Miyake, Christina Y; Lee, Michelle E; Sanatani, Shubhayan; Balaji, Seshadri; Young, Ming-Lon; Siddiqui, Saad; Schwartz, Peter J; Shivkumar, Kalyanam; Ackerman, Michael JObjectives
This study sought to determine the relationship between long QT syndrome (LQTS) subtype (LTQ1, LTQ2, LTQ3) and postnatal cardiac events (CEs).Background
LQTS presenting with 2:1 atrioventricular block or torsades de pointes in the fetus and/or neonate has been associated with risk for major CEs, but overall outcomes and predictors remain unknown.Methods
A retrospective study involving 25 international centers evaluated the course of fetuses/newborns diagnosed with congenital LQTS and either 2:1 atrioventricular block or torsades de pointes. The primary outcomes were age at first CE after dismissal from the newborn hospitalization and death and/or cardiac transplantation during follow-up. CE was defined as aborted cardiac arrest, appropriate shock from implantable cardioverter-defibrillator, or sudden cardiac death.Results
A total of 84 fetuses and/or neonates were identified with LQTS (12 as LQT1, 35 as LQT2, 37 as LQT3). Median gestational age at delivery was 37 weeks (interquartile range: 35 to 39 weeks) and age at hospital discharge was 3 weeks (interquartile range: 2 to 5 weeks). Fetal demise occurred in 2 and pre-discharge death in 1. Over a median of 5.2 years, there were 1 LQT1, 3 LQT2, and 23 LQT3 CEs (13 aborted cardiac arrests, 5 sudden cardiac deaths, and 9 appropriate shocks). One patient with LQT1 and 11 patients with LQT3 died or received cardiac transplant during follow-up. The only multivariate predictor of post-discharge CEs was LQT3 status (LQT3 vs. LQT2: hazard ratio: 8.4; 95% confidence interval: 2.6 to 38.9; p < 0.001), and LQT3, relative to LQT2, genotype predicted death and/or cardiac transplant (p < 0.001).Conclusions
In this large multicenter study, fetuses and/or neonates with LQT3 but not those with LQT1 or LQT2 presenting with severe arrhythmias were at high risk of not only frequent, but lethal CEs.Item Open Access Incidentally identified genetic variants in arrhythmogenic right ventricular cardiomyopathy-associated genes among children undergoing exome sequencing reflect healthy population variation.(Molecular Genetics & Genomic Medicine, 2019-06) Headrick, Andrew T; Rosenfeld, Jill A; Yang, Yaping; Tunuguntla, Hari; Allen, Hugh D; Penny, Daniel J; Kim, Jeffrey J; Landstrom, Andrew PBACKGROUND:With expanding use of clinical whole exome sequencing (WES), genetic variants of uncertain significance are increasingly identified. As pathologic mutations in genes associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) carry a risk of sudden death, determining the diagnostic relevance of incidentally identified variants associated with these genes is critical. METHODS:WES variants from a large, predominantly pediatric cohort (N = 7,066 probands) were obtained for nine ARVC-associated genes (Baylor Miraca). For comparison, a control cohort was derived from the gnomAD database and an ARVC case cohort (N = 1,379 probands) was established from ARVC cases in the literature. Topologic mapping was performed and signal-to-noise analysis was conducted normalizing WES, or case variants, against control variant frequencies. Retrospective chart review was performed of WES cases evaluated clinically (Texas Children's Hospital). RESULTS:Incidentally identified variants occurred in 14% of WES referrals and localized to genes which were rare among ARVC cases yet similar to controls. Amino acid-level signal-to-noise analysis of cases demonstrated "pathologic hotspots" localizing to critical domains of PKP2 and DSG2 while WES variants did not. PKP2 ARM7 and ARM8 domains and DSG2 N-terminal cadherin-repeat domains demonstrated high pathogenicity while normalized WES variant frequency was low. Review of clinical data available on WES referrals demonstrated none with evidence of ARVC among variant-positive individuals. CONCLUSIONS:Incidentally identified variants are common among pediatric WES testing with gene frequencies similar to "background" variants. Incidentally identified variants are unlikely to be pathologic.