Browsing by Author "Liu, Pengfei"
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Item Open Access A Genocentric Approach to Discovery of Mendelian Disorders.(American journal of human genetics, 2019-11) Hansen, Adam W; Murugan, Mullai; Li, He; Khayat, Michael M; Wang, Liwen; Rosenfeld, Jill; Andrews, B Kim; Jhangiani, Shalini N; Coban Akdemir, Zeynep H; Sedlazeck, Fritz J; Ashley-Koch, Allison E; Liu, Pengfei; Muzny, Donna M; Task Force for Neonatal Genomics; Davis, Erica E; Katsanis, Nicholas; Sabo, Aniko; Posey, Jennifer E; Yang, Yaping; Wangler, Michael F; Eng, Christine M; Sutton, V Reid; Lupski, James R; Boerwinkle, Eric; Gibbs, Richard AThe advent of inexpensive, clinical exome sequencing (ES) has led to the accumulation of genetic data from thousands of samples from individuals affected with a wide range of diseases, but for whom the underlying genetic and molecular etiology of their clinical phenotype remains unknown. In many cases, detailed phenotypes are unavailable or poorly recorded and there is little family history to guide study. To accelerate discovery, we integrated ES data from 18,696 individuals referred for suspected Mendelian disease, together with relatives, in an Apache Hadoop data lake (Hadoop Architecture Lake of Exomes [HARLEE]) and implemented a genocentric analysis that rapidly identified 154 genes harboring variants suspected to cause Mendelian disorders. The approach did not rely on case-specific phenotypic classifications but was driven by optimization of gene- and variant-level filter parameters utilizing historical Mendelian disease-gene association discovery data. Variants in 19 of the 154 candidate genes were subsequently reported as causative of a Mendelian trait and additional data support the association of all other candidate genes with disease endpoints.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.