Diagnostic yield of pediatric and prenatal exome sequencing in a diverse population

Abstract

The diagnostic yield of exome sequencing (ES) has primarily been evaluated in individuals of European ancestry, with less focus on underrepresented minority (URM) and underserved (US) patients. We evaluated the diagnostic yield of ES in a cohort of predominantly US and URM pediatric and prenatal patients suspected to have a genetic disorder. Eligible pediatric patients had multiple congenital anomalies and/or neurocognitive disabilities and prenatal patients had one or more structural anomalies, disorders of fetal growth, or fetal effusions. URM and US patients were prioritized for enrollment and underwent ES at a single academic center. We identified definitive positive or probable positive results in 201/845 (23.8%) patients, with a significantly higher diagnostic rate in pediatric (26.7%) compared to prenatal patients (19.0%) (P = 0.01). For both pediatric and prenatal patients, the diagnostic yield and frequency of inconclusive findings did not differ significantly between URM and non-URM patients or between patients with US status and those without US status. Our results demonstrate a similar diagnostic yield of ES between prenatal and pediatric URM/US patients and non-URM/US patients for positive and inconclusive results. These data support the use of ES to identify clinically relevant variants in patients from diverse populations.

Trust in prenatal exome sequencing for expectant families facing unexplained fetal anomalies

“…Themes were elucidated through initial readings, codes were iteratively created and revised, and each transcript was coded twice to ensure intercoder reliability. 7 An inductive approach was implemented whereby emerging patterns and themes were determined a posteriori. 23,24 Multiple themes were identified and summarized to provide an overall picture of participants' perspectives over time.…”

“…18,27,28 Programs such as the Clinical Sequencing Evidence-Generating Research consortium, which measures the effectiveness of integrating genomic sequencing into clinical care for diverse and medically underserved individuals, are critical for addressing inequities in healthcare and research related to genetics and genomic testing. 7,29,30 Numerous additional barriers to research participation may impact trust, such as health literacy, access to care, and preferred language. While our cohort had varying levels of health literacy, all had access to prenatal care by virtue of being seen at UCSF.…”

“…Results of the original ES studies are reported separately. 5,7 The UCSF Genomic Medicine Laboratory, a Clinical Laboratory Improvement Amendments certified program, performed ES and the results were delivered back to patients. Methods of the ES and variant interpretation have been previously described by our group.…”

“…Methods of the ES and variant interpretation have been previously described by our group. 5,7 In cases of ongoing pregnancies and live births, results of ES were prioritized to inform decision-making and clinical management. In all cases, participants received genetic counseling prior to undergoing ES, as well as after the results returned to explain the findings and their implications.…”

The Role of Genetic Testing for Short Stature Now and in the Future

“…Additionally, future studies will need to evaluate diagnostic yield in diverse populations as most of the individuals evaluated in these studies were of European ancestry. Nevertheless, 1 study suggests that diagnostic yield is similar in patients who are underrepresented in biomedical research and underserved in health care when undergoing ES for multiple congenital anomalies or neurocognitive disabilities and others suggest a higher yield due to referral bias …”