Browsing by Subject "whole exome sequencing"

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    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 P
    Variants 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.
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    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 P
    BACKGROUND: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.
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    Profiling Blood Cancer Drivers through Large-Scale Genomics
    (2022) Kositsky, Rachel

    There are 140,000 new cases of blood cancers each year in the US and even more worldwide. Understanding the molecular and genomic origins of blood cancers can refine diagnosis, predict survival, and identify appropriate treatment. Large-scale projects profiling cancer genomes prioritized common cancer types, while other blood cancer genomics studies have been completed in an ad-hoc fashion. In this thesis, I will describe advances made to systemic large-scale molecular profiling of blood cancers.

    To identify cancer drivers in both protein-coding and noncoding regions of the genome, I designed two novel capture panels. In my second chapter, I describe bioinformatics approaches I developed to identify accidental sample switches, refine alignment methods, and prioritize genes as potential cancer drivers.

    Translocations are a major class of blood cancer drivers, which occur when two chromosomes break and repair incorrectly by fusing to each other. Previous studies using sequencing data to identify blood cancer-related translocations had only moderate sensitivity for several of the translocations compared to the clinical test. In my third chapter, I describe the development of a new translocation caller that is more sensitive to translocations in hypermutated regions that may have poor alignment to the reference genome, which is common in B-cell lymphomas.

    Many patients with relapsed/refractory large B-cell lymphoma (R/R LBCL) have had success with chimeric antigen receptor T-cell (CAR-T) products approved by the FDA in 2017. However, a significant proportion of patients fail to respond to this highly expensive therapy and suffer from severe side effects while destined for poor survival. In my fourth chapter, I apply the genomic methods described earlier to identify predictors of resistance to CAR-T cell therapy in R/R LBCL. We found that complete response and survival were associated with clinical and molecular factors in the pre-treatment tumor.