308 - SouthSeq: Whole Genome Sequencing for a Diverse Population of Hospitalized Infants

Poster Number: 308
Publication Number: 308.441

Renate D. Savich, University of New Mexico, Albuquerque, NM, United States; Donald R. Latner, HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States; Michelle L. Thompson, HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States; Candice Finnila, HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States; Waldemar A. Carlo, University of Alabama at Birmingham, Birmingham, AL, United States; Susan M. Hiatt, HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States; Brian M. Kirmse, University of Mississippi Medical Center, Jackson, MS, United States; Sara J. Knight, University of Utah School of Medicine, Salt Lake City, UT, United States; Gregory Barsh, HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States; Gregory Cooper, HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States; Bruce R. Korf, University of Alabama School of Medicine, Birmingham, AL, United States

Background: Whole Genome Sequencing (GS) may shorten the diagnostic pathway and guide clinical management in infants with suspected genetic disorders. GS detects a variety of genetic variant types (SNVs, indels, CNVs, aneuploidy) and permits phenotype-independent variant assessment.

Objective: In SouthSeq, we evaluated GS as a first-line diagnostic tool for neonates/infants that are ill or are dysmorphic with suspected but undiagnosed genetic disorders.

Design/Methods: Enrollment occurred in NICUs in Alabama, Mississippi, Louisiana, and Kentucky, with an emphasis on enrollment of babies from groups historically under-represented in biomedical research. Infants were required to be in-patient, under one year of age, and exhibit symptoms (e.g., congenital anomalies, neuro, or metabolic abnormality) suggestive of a genetic disorder. Illumina genome sequencing was performed to a mean depth of ~30X. Variants were annotated, filtered, and analyzed using in-house software and classified using ACMG/AMP guidelines. Variants of interest were Sanger sequenced in proband and in parent samples, to determine inheritance. GS was performed concurrently with standard-of-care clinical genetic testing and medical management.

Results: Enrollment was 640 infants; 45% were female, and 74% represented racially/ethnically diverse and/or medically underserved communities, with 33% being African American (AA). A definitive diagnostic (DD) or likely diagnostic (LD) result was returned for 29% of infants, and an additional 13% had a result of uncertain significance. Of those with a DD/LD result, only 43% were identified via concurrent clinical standard-of-care genetic testing; the remaining infants diagnosed by GS did not receive a genetic diagnosis by conventional genetic testing. There were similar diagnostic rates between AA (31%) and European American (27%) infants. The DD/LD rates varied across phenotypic features, with the highest diagnostic yield among those with craniofacial, ophthalmologic, and/or auditory abnormalities (OR=2.54, p< 0.0001), followed by those with skin and/or hair abnormalities (OR=2.43, p=0.03).Conclusion(s): GS is a valuable first-line diagnostic tool for infants with clinically suspected genetic disorders and is more likely to provide a genetic diagnosis than standard-of-care clinical genetic tests. Although under-representation in genome reference databases increases the analytical workload for AA probands, GS diagnostic yields appear similar. This study highlights the benefit of using GS as a first-line test for ill infants, especially for serious diseases in the newborn.