Targeted gene panel sequencing for the rapid diagnosis of acutely ill infants

• Main Authors: Luca Brunelli, Sabrina M. Jenkins, James M. Gudgeon, Steven B. Bleyl, Christine E. Miller, Tatiana Tvrdik, Shale A. Dames, Betsy Ostrander, Josue A. F. Daboub, Brandon A. Zielinski, Erin K. Zinkhan, Hunter R. Underhill, Theodore Wilson, Joshua L. Bonkowsky, Christian C. Yost, Lorenzo D. Botto, Justin Jenkins, Theodore J. Pysher, Pinar Bayrak‐Toydemir, Rong Mao
• Format: Article
• Language: English
• Published: Wiley 2019-07-01
• Series: Molecular Genetics & Genomic Medicine
• Subjects: genetic diagnosis; neonatology; newborn; precision medicine; rapid sequencing
• Online Access: https://doi.org/10.1002/mgg3.796

Abstract Background Exome/genome sequencing (ES/GS) have been recently used in neonatal and pediatric/cardiac intensive care units (NICU and PICU/CICU) to diagnose and care for acutely ill infants, but the effectiveness of targeted gene panels for these purposes remains unknown. Methods RapSeq, a newly developed panel targeting 4,503 disease‐causing genes, was employed on selected patients in our NICU/PICU/CICU. Twenty trios were sequenced from October 2015 to March 2017. We assessed diagnostic yield, turnaround times, and clinical consequences. Results A diagnosis was made in 10/20 neonates (50%); eight had de novo variants (ASXL1, CHD, FBN1, KMT2D, FANCB, FLNA, PAX3), one was a compound heterozygote for CHAT, and one had a maternally inherited GNAS variant. Preliminary reports were generated by 9.6 days (mean); final reports after Sanger sequencing at 16.3 days (mean). In all positive infants, the diagnosis changed management. In a case with congenital myasthenia, diagnosis and treatment occurred at 17 days versus 7 months in a historical control. Conclusions This study shows that a gene panel that includes the majority of known disease‐causing genes can rapidly identify a diagnosis in a large number of tested infants. Due to simpler deployment and interpretation and lower costs, this approach might represent an alternative to ES/GS in the NICU/PICU/CICU.