Browsing by Author "Geddes, Gabrielle C."
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Item A multi-disciplinary, comprehensive approach to management of children with heterotaxy(BMC, 2022-09-09) Saba, Thomas G.; Geddes, Gabrielle C.; Ware, Stephanie M.; Schidlow, David N.; del Nido, Pedro J.; Rubalcava, Nathan S.; Gadepalli, Samir K.; Stillwell, Terri; Griffiths, Anne; Bennett Murphy, Laura M.; Barber, Andrew T.; Leigh, Margaret W.; Sabin, Necia; Shapiro, Adam J.; Medical and Molecular Genetics, School of MedicineHeterotaxy (HTX) is a rare condition of abnormal thoraco-abdominal organ arrangement across the left-right axis of the body. The pathogenesis of HTX includes a derangement of the complex signaling at the left-right organizer early in embryogenesis involving motile and non-motile cilia. It can be inherited as a single-gene disorder, a phenotypic feature of a known genetic syndrome or without any clear genetic etiology. Most patients with HTX have complex cardiovascular malformations requiring surgical intervention. Surgical risks are relatively high due to several serious comorbidities often seen in patients with HTX. Asplenia or functional hyposplenism significantly increase the risk for sepsis and therefore require antimicrobial prophylaxis and immediate medical attention with fever. Intestinal rotation abnormalities are common among patients with HTX, although volvulus is rare and surgical correction carries substantial risk. While routine screening for intestinal malrotation is not recommended, providers and families should promptly address symptoms concerning for volvulus and biliary atresia, another serious morbidity more common among patients with HTX. Many patients with HTX have chronic lung disease and should be screened for primary ciliary dyskinesia, a condition of respiratory cilia impairment leading to bronchiectasis. Mental health and neurodevelopmental conditions need to be carefully considered among this population of patients living with a substantial medical burden. Optimal care of children with HTX requires a cohesive team of primary care providers and experienced subspecialists collaborating to provide compassionate, standardized and evidence-based care. In this statement, subspecialty experts experienced in HTX care and research collaborated to provide expert- and evidence-based suggestions addressing the numerous medical issues affecting children living with HTX.Item A Multicenter Analysis of Abnormal Chromosomal Microarray Findings in Congenital Heart Disease(American Heart Association, 2023) Landis, Benjamin J.; Helvaty, Lindsey R.; Geddes, Gabrielle C.; Lin, Jiuann-Huey Ivy; Yatsenko, Svetlana A.; Lo, Cecilia W.; Border, William L.; Burns Wechsler, Stephanie; Murali, Chaya N.; Azamian, Mahshid S.; Lalani, Seema R.; Hinton, Robert B.; Garg, Vidu; McBride, Kim L.; Hodge, Jennelle C.; Ware, Stephanie M.; Pediatrics, School of MedicineBackground: Chromosomal microarray analysis (CMA) provides an opportunity to understand genetic causes of congenital heart disease (CHD). The methods for describing cardiac phenotypes in patients with CMA abnormalities have been inconsistent, which may complicate clinical interpretation of abnormal testing results and hinder a more complete understanding of genotype–phenotype relationships. Methods and Results: Patients with CHD and abnormal clinical CMA were accrued from 9 pediatric cardiac centers. Highly detailed cardiac phenotypes were systematically classified and analyzed for their association with CMA abnormality. Hierarchical classification of each patient into 1 CHD category facilitated broad analyses. Inclusive classification allowing multiple CHD types per patient provided sensitive descriptions. In 1363 registry patients, 28% had genomic disorders with well‐recognized CHD association, 67% had clinically reported copy number variants (CNVs) with rare or no prior CHD association, and 5% had regions of homozygosity without CNV. Hierarchical classification identified expected CHD categories in genomic disorders, as well as uncharacteristic CHDs. Inclusive phenotyping provided sensitive descriptions of patients with multiple CHD types, which occurred commonly. Among CNVs with rare or no prior CHD association, submicroscopic CNVs were enriched for more complex types of CHD compared with large CNVs. The submicroscopic CNVs that contained a curated CHD gene were enriched for left ventricular obstruction or septal defects, whereas CNVs containing a single gene were enriched for conotruncal defects. Neuronal‐related pathways were over‐represented in single‐gene CNVs, including top candidate causative genes NRXN3, ADCY2, and HCN1. Conclusions: Intensive cardiac phenotyping in multisite registry data identifies genotype–phenotype associations in CHD patients with abnormal CMA.Item A multicenter cross-sectional study in infants with congenital heart defects demonstrates high diagnostic yield of genetic testing but variable evaluation practices(Elsevier, 2023-04-29) Durbin, Matthew D.; Helvaty, Lindsey R.; Li, Ming; Border, William; Fitzgerald-Butt, Sara; Garg, Vidu; Geddes, Gabrielle C.; Helm, Benjamin M.; Lalani, Seema R.; McBride, Kim L.; McEntire, Alexis; Mitchell, Dana K.; Murali, Chaya N.; Wechsler, Stephanie B.; Landis, Benjamin J.; Ware, Stephanie M.; Pediatrics, School of MedicinePurpose: For patients with congenital heart disease (CHD), the most common birth defect, genetic evaluation is not universally accepted, and current practices are anecdotal. Here, we analyzed genetic evaluation practices across centers, determined diagnostic yield of testing, and identified phenotypic features associated with abnormal results. Methods: This is a multicenter cross-sectional study of 5 large children's hospitals, including 2899 children ≤14 months undergoing surgical repair for CHD from 2013 to 2016, followed by multivariate logistics regression analysis. Results: Genetic testing occurred in 1607 of 2899 patients (55%). Testing rates differed highly between institutions (42%-78%, P < .001). Choice of testing modality also differed across institutions (ie, chromosomal microarray, 26%-67%, P < .001). Genetic testing was abnormal in 702 of 1607 patients (44%), and no major phenotypic feature drove diagnostic yield. Only 849 patients were seen by geneticists (29%), ranging across centers (15%-52%, P < .001). Geneticist consultation associated with increased genetic testing yield (odds ratio: 5.7, 95% CI 4.33-7.58, P < .001). Conclusion: Genetics evaluation in CHD is diagnostically important but underused and highly variable, with high diagnostic rates across patient types, including in infants with presumed isolated CHD. These findings support recommendations for comprehensive testing and standardization of care.Item Clinical exome sequencing efficacy and phenotypic expansions involving anomalous pulmonary venous return(Springer Nature, 2023) Huth, Emily A.; Zhao, Xiaonan; Owen, Nichole; Luna, Pamela N.; Vogel, Ida; Dorf, Inger L. H.; Joss, Shelagh; Clayton-Smith, Jill; Parker, Michael J.; Louw, Jacoba J.; Gewillig, Marc; Breckpot, Jeroen; Kraus, Alison; Sasaki, Erina; Kini, Usha; Burgess, Trent; Tan, Tiong Y.; Armstrong, Ruth; Neas, Katherine; Ferrero, Giovanni B.; Brusco, Alfredo; Kerstjens-Frederikse, Wihelmina S.; Rankin, Julia; Helvaty, Lindsey R.; Landis, Benjamin J.; Geddes, Gabrielle C.; McBride, Kim L.; Ware, Stephanie M.; Shaw, Chad A.; Lalani, Seema R.; Rosenfeld, Jill A.; Scott, Daryl A.; Medical and Molecular Genetics, School of MedicineAnomalous pulmonary venous return (APVR) frequently occurs with other congenital heart defects (CHDs) or extra-cardiac anomalies. While some genetic causes have been identified, the optimal approach to genetic testing in individuals with APVR remains uncertain, and the etiology of most cases of APVR is unclear. Here, we analyzed molecular data from 49 individuals to determine the diagnostic yield of clinical exome sequencing (ES) for non-isolated APVR. A definitive or probable diagnosis was made for 8 of those individuals yielding a diagnostic efficacy rate of 16.3%. We then analyzed molecular data from 62 individuals with APVR accrued from three databases to identify novel APVR genes. Based on data from this analysis, published case reports, mouse models, and/or similarity to known APVR genes as revealed by a machine learning algorithm, we identified 3 genes-EFTUD2, NAA15, and NKX2-1-for which there is sufficient evidence to support phenotypic expansion to include APVR. We also provide evidence that 3 recurrent copy number variants contribute to the development of APVR: proximal 1q21.1 microdeletions involving RBM8A and PDZK1, recurrent BP1-BP2 15q11.2 deletions, and central 22q11.2 deletions involving CRKL. Our results suggest that ES and chromosomal microarray analysis (or genome sequencing) should be considered for individuals with non-isolated APVR for whom a genetic etiology has not been identified, and that genetic testing to identify an independent genetic etiology of APVR is not warranted in individuals with EFTUD2-, NAA15-, and NKX2-1-related disorders.Item 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 MedicineCongenital 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.Item Early ascertainment of genetic diagnoses clarifies impact on medium-term survival following neonatal congenital heart surgery(American Society for Clinical Investigation, 2024-07-30) Landis, Benjamin J.; Helm, Benjamin M.; Durbin, Matthew D.; Helvaty, Lindsey R.; Herrmann, Jeremy L.; Johansen, Michael; Geddes, Gabrielle C.; Ware, Stephanie M.; Pediatrics, School of MedicineItem Genetic Testing Guidelines Impact Care in Newborns with Congenital Heart Defects(Elsevier, 2023) Durbin, Matthew D.; Fairman, Korre; Helvaty, Lindsey R.; Huang, Manyan; Li, Ming; Abreu, Daniel; Geddes, Gabrielle C.; Helm, Benjamin M.; Landis, Benjamin J.; McEntire, Alexis; Mitchell, Dana K.; Ware, Stephanie M.; Pediatrics, School of MedicineObjective: To evaluate genetic evaluation practices in newborns with the most common birth defect, congenital heart defects (CHD), we determined the prevalence and the yield of genetic evaluation across time and across patient subtypes, before and after implementation of institutional genetic testing guidelines. Study design: This was a retrospective, cross-sectional study of 664 hospitalized newborns with CHD using multivariate analyses of genetic evaluation practices across time and patient subtypes. Results: Genetic testing guidelines for hospitalized newborns with CHD were implemented in 2014, and subsequently genetic testing increased (40% in 2013 and 75% in 2018, OR 5.02, 95% CI 2.84-8.88, P < .001) as did medical geneticists' involvement (24% in 2013 and 64% in 2018, P < .001). In 2018, there was an increased use of chromosomal microarray (P < .001), gene panels (P = .016), and exome sequencing (P = .001). The testing yield was high (42%) and consistent across years and patient subtypes analyzed. Increased testing prevalence (P < .001) concomitant with consistent testing yield (P = .139) added an estimated 10 additional genetic diagnoses per year, reflecting a 29% increase. Conclusions: In patients with CHD, yield of genetic testing was high. After implementing guidelines, genetic testing increased significantly and shifted to newer sequence-based methods. Increased use of genetic testing identified more patients with clinically important results with potential to impact patient care.Item Learning to Crawl: Determining the Role of Genetic Abnormalities on Postoperative Outcomes in Congenital Heart Disease(AHA, 2022-10) Landis, Benjamin J.; Helm, Benjamin M.; Herrmann, Jeremy L.; Hoover, Madeline C.; Durbin, Matthew D.; Elmore, Lindsey R.; Huang, Manyan; Johansen, Michael; Li, Ming; Przybylowski, Leon F.; Geddes, Gabrielle C.; Ware, Stephanie M.; Pediatrics, School of MedicineBackground Our cardiac center established a systematic approach for inpatient cardiovascular genetics evaluations of infants with congenital heart disease, including routine chromosomal microarray (CMA) testing. This provides a new opportunity to investigate correlation between genetic abnormalities and postoperative course. Methods and Results Infants who underwent congenital heart disease surgery as neonates (aged ≤28 days) from 2015 to 2020 were identified. Cases with trisomy 21 or 18 were excluded. Diagnostic genetic results or CMA with variant of uncertain significance were considered abnormal. We compared postoperative outcomes following initial congenital heart disease surgery in patients found to have genetic abnormality to those who had negative CMA. Among 355 eligible patients, genetics consultations or CMA were completed in 88%. A genetic abnormality was identified in 73 patients (21%), whereas 221 had negative CMA results. Genetic abnormality was associated with prematurity, extracardiac anomaly, and lower weight at surgery. Operative mortality rate was 9.6% in patients with a genetic abnormality versus 4.1% in patients without an identified genetic abnormality (P=0.080). Mortality was similar when genetic evaluations were diagnostic (9.3%) or identified a variant of uncertain significance on CMA (10.0%). Among 14 patients with 22q11.2 deletion, the 2 mortality cases had additional CMA findings. In patients without extracardiac anomaly, genetic abnormality was independently associated with increased mortality (P=0.019). CMA abnormality was not associated with postoperative length of hospitalization, extracorporeal membrane oxygenation, or >7 days to initial extubation. Conclusions Routine genetic evaluations and CMA may help to stratify mortality risk in severe congenital heart disease with syndromic or nonsyndromic presentations.Item Misdiagnosis of trisomy 13 and trisomy 18 is more common than anticipated(Wiley, 2022) Geddes, Gabrielle C.; Hafezi, Niloufar; Gray, Brian W.; Medical and Molecular Genetics, School of MedicineItem OBGYN providers' lack of knowledge and management of genetic risks due to advanced paternal age underscore the need for updated practice guidance(Springer, 2022) Biddle, Joseph F.; Wetherill, Leah; Geddes, Gabrielle C.; Quirin, Kayla; Rouse, Caroline E.; Hines, Karrie A.; Medical and Molecular Genetics, School of MedicineThe objective of this pilot study was to characterize healthcare professionals' knowledge of advanced paternal age (APA), the associated risks, as well as current clinical practices regarding APA. Our study utilized an online survey that questioned providers who see children with genetic conditions and patients who are or may become pregnant regarding demographic information, APA knowledge, APA guideline familiarity, and their clinical practices. A total of 67 providers responded to the survey. We had responses from 54 physician participants in the specialties of medical genetics (GEN), maternal fetal medicine (MFM), and obstetrics and gynecology (OBGYN). OBGYN, but not MFM, reported significantly lower agreement that current data supports an association between APA and certain genetic diseases compared to GEN. Furthermore, OBGYN were less likely to identify established risks associated with APA and more likely to incorrectly identify unestablished risks compared to GEN and MFM. Regardless of specialty, the majority of physicians were unfamiliar with the most recently published APA guidelines. This study revealed a desire for more information regarding APA risks and management among our participants. Our data suggest that GEN, MFM, and OBGYN would benefit from updated and more visible guidelines regarding APA. Additionally, OBGYN consistently showed knowledge gaps and misconceptions regarding the risks of APA. Targeted educational or guidance materials regarding APA may also be beneficial for OBGYNs.