Browsing by Author "Morris, Shaine A."

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    Design and implementation of multicenter pediatric and congenital studies with cardiovascular magnetic resonance: Big data in smaller bodies
    (Elsevier, 2024) DiLorenzo, Michael P.; Lee, Simon; Rathod, Rahul H.; Raimondi, Francesca; Farooqi, Kanwal M.; Jain, Supriya S.; Samyn, Margaret M.; Johnson, Tiffanie R.; Olivieri, Laura J.; Fogel, Mark A.; Lai, Wyman W.; Renella, Pierangelo; Powell, Andrew J.; Buddhe, Sujatha; Stafford, Caitlin; Johnson, Jason N.; Helbing, Willem A.; Pushparajah, Kuberan; Voges, Inga; Muthurangu, Vivek; Miles, Kimberley G.; Greil, Gerald; McMahon, Colin J.; Slesnick, Timothy C.; Fonseca, Brian M.; Morris, Shaine A.; Soslow, Jonathan H.; Grosse-Wortmann, Lars; Beroukhim, Rebecca S.; Grotenhuis, Heynric B.; Pediatrics, School of Medicine
    Cardiovascular magnetic resonance (CMR) has become the reference standard for quantitative and qualitative assessment of ventricular function, blood flow, and myocardial tissue characterization. There is a preponderance of large CMR studies and registries in adults; However, similarly powered studies are lacking for the pediatric and congenital heart disease (PCHD) population. To date, most CMR studies in children are limited to small single or multicenter studies, thereby limiting the conclusions that can be drawn. Within the PCHD CMR community, a collaborative effort has been successfully employed to recognize knowledge gaps with the aim to embolden the development and initiation of high-quality, large-scale multicenter research. In this publication, we highlight the underlying challenges and provide a practical guide toward the development of larger, multicenter initiatives focusing on PCHD populations, which can serve as a model for future multicenter efforts.
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    Non-coding cause of congenital heart defects: Abnormal RNA splicing with multiple isoforms as a mechanism for heterotaxy
    (Elsevier, 2024) Wells, John R.; Padua, Maria B.; Haaning, Allison M.; Smith, Amanda M.; Morris, Shaine A.; Tariq, Muhammad; Ware, Stephanie M.; Medical and Molecular Genetics, School of Medicine
    Heterotaxy is a disorder characterized by severe congenital heart defects (CHDs) and abnormal left-right patterning in other thoracic or abdominal organs. Clinical and research-based genetic testing has previously focused on evaluation of coding variants to identify causes of CHDs, leaving non-coding causes of CHDs largely unknown. Variants in the transcription factor zinc finger of the cerebellum 3 (ZIC3) cause X-linked heterotaxy. We identified an X-linked heterotaxy pedigree without a coding variant in ZIC3. Whole-genome sequencing revealed a deep intronic variant (ZIC3 c.1224+3286A>G) predicted to alter RNA splicing. An in vitro minigene splicing assay confirmed the variant acts as a cryptic splice acceptor. CRISPR-Cas9 served to introduce the ZIC3 c.1224+3286A>G variant into human embryonic stem cells demonstrating pseudoexon inclusion caused by the variant. Surprisingly, Sanger sequencing of the resulting ZIC3 c.1224+3286A>G amplicons revealed several isoforms, many of which bypass the normal coding sequence of the third exon of ZIC3, causing a disruption of a DNA-binding domain and a nuclear localization signal. Short- and long-read mRNA sequencing confirmed these initial results and identified additional splicing patterns. Assessment of four isoforms determined abnormal functions in vitro and in vivo while treatment with a splice-blocking morpholino partially rescued ZIC3. These results demonstrate that pseudoexon inclusion in ZIC3 can cause heterotaxy and provide functional validation of non-coding disease causation. Our results suggest the importance of non-coding variants in heterotaxy and the need for improved methods to identify and classify non-coding variation that may contribute to CHDs.
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    Variants in ADRB1 and CYP2C9: Association with Response to Atenolol and Losartan in Marfan Syndrome
    (Elsevier, 2020-07) Van Driest, Sara L.; Sleeper, Lynn A.; Gelb, Bruce D.; Morris, Shaine A.; Dietz, Harry C.; Forbus, Geoffrey A.; Goldmuntz, Elizabeth; Hoskoppal, Arvind; James, Jeanne; Lee, Teresa M.; Levine, Jami C.; Li, Jennifer S.; Loeys, Bart L.; Markham, Larry W.; Meester, Josephina A.N.; Mital, Seema; Mosley, Jonathan D.; Olson, Aaron K.; Renard, Marjolijn; Shaffer, Christian M.; Sharkey, Angela; Young, Luciana; Lacro, Ronald V.; Roden, Dan M.; Pediatrics, School of Medicine
    Objective: To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial. Study design: In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models. Results: Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time × Genotype interaction P = .005, mean annual z-score change ± SE -0.20 ± 0.03 vs -0.09 ± 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P = .002; -0.20 ± 0.02 vs -0.07 ± 0.02; P < .001). There were no differences in atenolol response by rs1801252 genotype or in losartan response by CYP2C9 metabolizer status. Conclusions: In this exploratory study, ADRB1-rs1801253 was associated with atenolol response in children and young adults with Marfan syndrome. If these findings are confirmed in future studies, ADRB1 genotyping has the potential to guide therapy by identifying those who are likely to have greater therapeutic response to atenolol than losartan.