Browsing by Subject "Genome sequencing"

Now showing 1 - 5 of 5
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    Clinical Genetic and Genomic Testing in Congenital Heart Disease and Cardiomyopathy
    (MDPI, 2024-04-26) Pidaparti, Mahati; Geddes, Gabrielle C.; Durbin, Matthew D.; Pediatrics, School of Medicine
    Congenital heart disease (CHD) and cardiomyopathies are the leading cause of morbidity and mortality worldwide. These conditions are often caused by genetic factors, and recent research has shown that genetic and genomic testing can provide valuable information for patient care. By identifying genetic causes, healthcare providers can screen for other related health conditions, offer early interventions, estimate prognosis, select appropriate treatments, and assess the risk for family members. Genetic and genomic testing is now the standard of care in patients with CHD and cardiomyopathy. However, rapid advances in technology and greater availability of testing options have led to changes in recommendations for the most appropriate testing method. Several recent studies have investigated the utility of genetic testing in this changing landscape. This review summarizes the literature surrounding the clinical utility of genetic evaluation in patients with CHD and cardiomyopathy.
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    Evaluating first-line genetic testing strategies for inpatients with congenital heart defects
    (Wiley, 2025) Lindstrom, Al; Breman, Amy; Fitzgerald-Butt, Sara; Helvaty, Lindsey R.; Ware, Stephanie M.; Helm, Benjamin M.; Medical and Molecular Genetics, School of Medicine
    Genetic testing strategies used to determine the etiology of congenital heart disease/defects (CHD/CHDs) vary between and within institutions, leading to potentially missed diagnostic opportunities. There has been little investigation comparing the diagnostic utility of gene panels among more comprehensive strategies used in the genetic evaluation of patients with CHD. In this descriptive study, we investigated the diagnostic yields of different genetic testing strategies in a real-world cohort of 263 patients with CHDs with genetic diagnoses. We counterfactually determined the diagnostic yield of a virtual gene panel designed for this study. We compared the diagnostic yield of the gene panel to other testing strategies, including chromosomal microarray (CMA), CMA + the gene panel, and genome sequencing. We assessed diagnostic yield differences according to clinical presentations to determine if phenotypes can inform optimal testing strategies. The virtual gene panel would have identified 51.3% of genetic disorders in this cohort, and 25.9% of genetic disorders would have remained undetected; another 22.8% may have needed additional testing to fully characterize the diagnoses. A combined approach of the virtual gene panel and CMA increased the diagnostic yield compared with panel-only testing or CMA alone (87.8% vs. 51.3% and 63.1%, respectively). The gene panel plus CMA would have increased the diagnostic yield by 24%-35% compared with CMA or panel testing alone in patients with extracardiac anomalies, 19%-41% in syndromic patients, and 0%-70% across CHD classifications. This combined approach also eliminated the potential need for follow-up testing; however, genome sequencing had a higher diagnostic yield across all clinical presentations (99.6%). CHD gene panels and CMA used individually or in combination are suboptimal first-line testing strategies, missing up to 36.5% of genetic disorders in our sample. Given the wide spectrum of phenotypes and genetic etiologies, our results support consideration of standardized genome sequencing for patients with CHDs.
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    Provision and Availability of Genomic Medicine Services in Level IV Neonatal Intensive Care Units
    (Elsevier, 2023) Wojcik, Monica H.; Callahan, Katharine P.; Antoniou, Austin; del Rosario, Maya C.; Brunelli, Luca; ElHassan, Nahed O.; Gogcu, Semsa; Murthy, Karna; Rumpel, Jennifer A.; Wambach, Jennifer A.; Suhrie, Kristen; Fishler, Kristen; Chaudhari, Bimal P.; Pediatrics, School of Medicine
    Purpose: To describe variation in genomic medicine services across level IV neonatal intensive care units (NICUs) in the United States and Canada. Methods: We developed and distributed a novel survey to the 43 level IV NICUs belonging to the Children's Hospitals Neonatal Consortium, requesting a single response per site from a clinician with knowledge of the provision of genomic medicine services. Results: Overall response rate was 74% (32/43). Although chromosomal microarray and exome or genome sequencing (ES or GS) were universally available, access was restricted for 22% (7/32) and 81% (26/32) of centers, respectively. The most common restriction on ES or GS was requiring approval by a specialist (41%, 13/32). Rapid ES/GS was available in 69% of NICUs (22/32). Availability of same-day genetics consultative services was limited (41%, 13/32 sites), and pre- and post-test counseling practices varied widely. Conclusion: We observed large inter-center variation in genomic medicine services across level IV NICUs: most notably, access to rapid, comprehensive genetic testing in time frames relevant to critical care decision making was limited at many level IV Children's Hospitals Neonatal Consortium NICUs despite a significant burden of genetic disease. Further efforts are needed to improve access to neonatal genomic medicine services.
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    Research‐Based Whole Genome Sequencing Identifies Biallelic Loss of Function Variants in DOCK3 Gene Causing DOCK3‐Related Disorder: The End of a Diagnostic Journey for This Family
    (Wiley, 2025) Liaqat, Khurram; Treat, Kayla; Mantcheva, Lili; McLaughlin, Aaron; Breman, Amy; McPheron, Molly; Conboy, Erin; Vetrini, Francesco; Medical and Molecular Genetics, School of Medicine
    The DOCK3 gene (NM_004947.5) is located on chromosome 3p21.2 spanning 53 exons and encodes the dedicator of cytokinesis 3 protein. DOCK3 belongs to the family of guanine nucleotide exchange factors (GEFs) that activate GTPases. DOCK3 is expressed almost exclusively in the central nervous system and has been shown to promote axonal outgrowth. Biallelic disruptions of DOCK3 are implicated in a neurodevelopmental disorder presenting with intellectual disability, hypotonia and ataxia (OMIM: 618292). We report a 9-year-old female with global developmental delay, moderate intellectual disability, wide-based and ataxic gait, hypotonia, benign nocturnal myoclonus, bifid uvula, moderate obstructive sleep apnea, and alternating esotropia. Prior to enrollment in the Undiagnosed Rare Disease Clinic (URDC), the patient's clinical exome testing was negative. The subsequent enrollment in URDC allowed further research investigations through whole genome sequencing (GS) that identified two compound heterozygous variants in the DOCK3 gene, ultimately yielding an unequivocal definitive molecular diagnosis.
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    Systematic evaluation of genome sequencing for the diagnostic assessment of autism spectrum disorder and fetal structural anomalies
    (Elsevier, 2023) Lowther, Chelsea; Valkanas, Elise; Giordano, Jessica L.; Wang, Harold Z.; Currall, Benjamin B.; O'Keefe, Kathryn; Pierce-Hoffman, Emma; Kurtas, Nehir E.; Whelan, Christopher W.; Hao, Stephanie P.; Weisburd, Ben; Jalili, Vahid; Fu, Jack; Wong, Isaac; Collins, Ryan L.; Zhao, Xuefang; Austin-Tse, Christina A.; Evangelista, Emily; Lemire, Gabrielle; Aggarwal, Vimla S.; Lucente, Diane; Gauthier, Laura D.; Tolonen, Charlotte; Sahakian, Nareh; Stevens, Christine; An, Joon-Yong; Dong, Shan; Norton, Mary E.; MacKenzie, Tippi C.; Devlin, Bernie; Gilmore, Kelly; Powell, Bradford C.; Brandt, Alicia; Vetrini, Francesco; DiVito, Michelle; Sanders, Stephan J.; MacArthur, Daniel G.; Hodge, Jennelle C.; O'Donnell-Luria, Anne; Rehm, Heidi L.; Vora, Neeta L.; Levy, Brynn; Brand, Harrison; Wapner, Ronald J.; Talkowski, Michael E.; Medical and Molecular Genetics, School of Medicine
    Short-read genome sequencing (GS) holds the promise of becoming the primary diagnostic approach for the assessment of autism spectrum disorder (ASD) and fetal structural anomalies (FSAs). However, few studies have comprehensively evaluated its performance against current standard-of-care diagnostic tests: karyotype, chromosomal microarray (CMA), and exome sequencing (ES). To assess the clinical utility of GS, we compared its diagnostic yield against these three tests in 1,612 quartet families including an individual with ASD and in 295 prenatal families. Our GS analytic framework identified a diagnostic variant in 7.8% of ASD probands, almost 2-fold more than CMA (4.3%) and 3-fold more than ES (2.7%). However, when we systematically captured copy-number variants (CNVs) from the exome data, the diagnostic yield of ES (7.4%) was brought much closer to, but did not surpass, GS. Similarly, we estimated that GS could achieve an overall diagnostic yield of 46.1% in unselected FSAs, representing a 17.2% increased yield over karyotype, 14.1% over CMA, and 4.1% over ES with CNV calling or 36.1% increase without CNV discovery. Overall, GS provided an added diagnostic yield of 0.4% and 0.8% beyond the combination of all three standard-of-care tests in ASD and FSAs, respectively. This corresponded to nine GS unique diagnostic variants, including sequence variants in exons not captured by ES, structural variants (SVs) inaccessible to existing standard-of-care tests, and SVs where the resolution of GS changed variant classification. Overall, this large-scale evaluation demonstrated that GS significantly outperforms each individual standard-of-care test while also outperforming the combination of all three tests, thus warranting consideration as the first-tier diagnostic approach for the assessment of ASD and FSAs.