Genetic detection of congenital heart disease Rachamadugu, Sumathi I.; Miller, Kristen A.; Lee, Ina H. ...
Gynecology and obstetrics clinical medicine,
09/2022, Letnik:
2, Številka:
3
Journal Article
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Congenital heart disease (CHD) is the most common congenital anomaly and is an important cause of infant morbidity and mortality. Besides the epigenetic and environmental basis of CHD, genetics plays ...a central role in CHD pathogenesis. Traditional genetic testing strategies including conventional chromosome analysis, fluorescence in situ hybridization, and Sanger sequencing have largely focused on syndromic CHD or selected CHD phenotypes that are strongly associated with a particular genotype. The landscape of clinical genetic testing in CHD is rapidly evolving due to technical advances in genetic testing, including the identification of copy number variants by chromosomal microarray and nucleotide level alterations/variants by next-generation sequencing (NGS), which are essential to detect genetic causes of CHD and identify associations between genotypes and longitudinal clinical phenotypes. Whole-exome and whole-genome NGS not only reveal pathogenic variants in CHD genes, but also identify non-coding variants that influence the expression of CHD genes. Given the increasing availability and cost-effectiveness of clinical NGS to provide information on the causes of CHD and to detect incidental findings that are clinically actionable, the guidance of genetic counselors or experienced clinicians is essential. The identification of definitive causal CHD variants influences patient care and helps to inform the risk of recurrence, prenatal genetic counseling, and pre-implantation testing for the family of a CHD infant and adults with repaired/palliated CHD. Prenatally, circulating cell-free DNA screening as a non-invasive approach is available as early as 9 weeks of gestation and can screen for the common aneuploidies, which may underlie CHD. In this review, we present past and recent genetic testing in CHD based on our increased understanding of the pathogenesis of CHD along with current challenges with the interpretation of de novo genetic variants. Identification of a genetic diagnosis can help to predict and potentially improve clinical outcomes in CHD patients.
The clinical use of genomic analysis has expanded rapidly resulting in an increased availability and utility of genomic information in clinical care. We have developed an infrastructure utilizing ...informatics tools and clinical processes to facilitate the use of whole genome sequencing data for population health management across the healthcare system. Our resulting framework scaled well to multiple clinical domains in both pediatric and adult care, although there were domain specific challenges that arose. Our infrastructure was complementary to existing clinical processes and well-received by care providers and patients. Informatics solutions were critical to the successful deployment and scaling of this program. Implementation of genomics at the scale of population health utilizes complicated technologies and processes that for many health systems are not supported by current information systems or in existing clinical workflows. To scale such a system requires a substantial clinical framework backed by informatics tools to facilitate the flow and management of data. Our work represents an early model that has been successful in scaling to 29 different genes with associated genetic conditions in four clinical domains. Work is ongoing to optimize informatics tools; and to identify best practices for translation to smaller healthcare systems.
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