Browsing by Author "Cowan, Jason R."

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    Copy number variation as a genetic basis for heterotaxy and heterotaxy-spectrum congenital heart defects
    (Royal Society, 2016-12-19) Cowan, Jason R.; Tariq, Muhammad; Shaw, Chad; Rao, Mitchell; Belmont, John W.; Lalani, Seema R.; Smolarek, Teresa A.; Ware, Stephanie M.; Pediatrics, School of Medicine
    Genomic disorders and rare copy number abnormalities are identified in 15–25% of patients with syndromic conditions, but their prevalence in individuals with isolated birth defects is less clear. A spectrum of congenital heart defects (CHDs) is seen in heterotaxy, a highly heritable and genetically heterogeneous multiple congenital anomaly syndrome resulting from failure to properly establish left–right (L-R) organ asymmetry during early embryonic development. To identify novel genetic causes of heterotaxy, we analysed copy number variants (CNVs) in 225 patients with heterotaxy and heterotaxy-spectrum CHDs using array-based genotyping methods. Clinically relevant CNVs were identified in approximately 20% of patients and encompassed both known and putative heterotaxy genes. Patients were carefully phenotyped, revealing a significant association of abdominal situs inversus with pathogenic or likely pathogenic CNVs, while d-transposition of the great arteries was more frequently associated with common CNVs. Identified cytogenetic abnormalities ranged from large unbalanced translocations to smaller, kilobase-scale CNVs, including a rare, single exon deletion in ZIC3, a gene known to cause X-linked heterotaxy. Morpholino loss-of-function experiments in Xenopus support a role for one of these novel candidates, the platelet isoform of phosphofructokinase-1 (PFKP) in heterotaxy. Collectively, our results confirm a high CNV yield for array-based testing in patients with heterotaxy, and support use of CNV analysis for identification of novel biological processes relevant to human laterality., This article is part of the themed issue ‘Provocative questions in left–right asymmetry’.
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    Genetics and Genetic Testing in Congenital Heart Disease
    (Elsevier, 2015-06) Cowan, Jason R.; Ware, Stephanie M.; Department of Pediatrics, IU School of Medicine
    Congenital heart defects (CHDs) are structural abnormalities of the heart and great vessels that are present from birth. The presence or absence of extra-cardiac anomalies has historically been used to identify patients with possible monogenic, chromosomal, or teratogenic CHD etiologies. These distinctions remain clinically relevant, particularly with regard to management; however, identification of genetic causes in patients with presumably non-syndromic CHD indicates that isolated CHD can also be genetic in origin. In recent years, the field of cardiac genetics has benefited from a growing understanding of the complex molecular mechanisms underpinning heart development, and the extreme genetic heterogeneity of CHD is increasingly appreciated. Progress has been largely supported by improvements in genetic testing technology derived from worldwide efforts to accurately and economically characterize the full breadth of human genomic variation. The last fifteen years in particular have witnessed emergence and refinement of novel cytogenetic and sequencing technologies, which have proven to be enormously effective tools for both diagnosis and identification of novel CHD-causing genes. These advancements have led to an increasing need for cardiac care providers to be well versed in the molecular genetic origins of CHD and to have working knowledge of the benefits and limitations of available testing methods. In this review, we provide a general overview of key morphologic, molecular, and signaling mechanisms relevant to heart development before summarizing overall progress in the molecular genetic analyses of CHDs and current recommendations for clinical application of genetic testing. Particular emphasis is placed on the utility and limitations of chromosomal microarray analyses (CMAs) and on emerging clinical roles for whole exome sequencing (WES) and other next-generation sequencing (NGS) technologies.