Jill L Maron1, Stephen F Kingsmore2, Kristen Wigby2,3, Shimul Chowdhury2, David Dimmock2, Brenda Poindexter4, Kristen Suhrie5,6, Jerry Vockley7, Thomas Diacovo7, Bruce D Gelb8, Annemarie Stroustrup9, Cynthia M Powell10, Andrea Trembath10, Matthew Gallen11, Thomas E Mullen11, Pranoot Tanpaiboon11, Dallas Reed12,13, Anne Kurfiss13, Jonathan M Davis13,14. 1. Mother Infant Research Institute, Tufts Medical Center, Boston, Massachusetts. 2. Rady Children's Institute for Genomic Medicine, San Diego, California. 3. Department of Pediatrics, University of California, San Diego, San Diego. 4. Children's Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, Georgia. 5. Perinatal Institute, Cincinnati Children's Hospital, Cincinnati, Ohio. 6. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio. 7. UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. 8. Mindich Child Health and Development Institute and Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York. 9. Department of Pediatrics, Cohen Children's Medical Center, New Hyde Park, New York, New York. 10. University of North Carolina Children's Research Institute, University of North Carolina Health Children's Hospital, Chapel Hill. 11. Athena Diagnostics/Quest Diagnostics, Marlborough, Massachusetts. 12. Department of Obstetrics and Gynecology, Tufts Medical Center Boston, Boston, Massachusetts. 13. Department of Pediatrics, The Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts. 14. The Tufts Clinical and Translation Science Institute, Tufts University School of Medicine, Boston, Massachusetts.
Abstract
Importance: A targeted genomic sequencing platform focused on diseases presenting in the first year of life may minimize financial and ethical challenges associated with rapid whole-genomic sequencing. Objective: To report interim variants and associated interpretations of an ongoing study comparing rapid whole-genomic sequencing with a novel targeted genomic platform composed of 1722 actionable genes targeting disorders presenting in infancy. Design, Setting, and Participants: The Genomic Medicine in Ill Neonates and Infants (GEMINI) study is a prospective, multicenter clinical trial with projected enrollment of 400 patients. The study is being conducted at 6 US hospitals. Hospitalized infants younger than 1 year of age suspected of having a genetic disorder are eligible. Results of the first 113 patients enrolled are reported here. Patient recruitment began in July 2019, and the interim analysis of enrolled patients occurred from March to June 2020. Interventions: Patient (proband) and parents (trios, when available) were tested simultaneously on both genomic platforms. Each laboratory performed its own phenotypically driven interpretation and was blinded to other results. Main Outcomes and Measures: Variants were classified according to the American College of Medical Genetics and Genomics standards of pathogenic (P), likely pathogenic (LP), or variants of unknown significance (VUS). Chromosomal and structural variations were reported by rapid whole-genomic sequencing. Results: Gestational age of 113 patients ranged from 23 to 40 weeks and postmenstrual age from 27 to 83 weeks. Sixty-seven patients (59%) were male. Diagnostic and/or VUS were returned for 51 patients (45%), while 62 (55%) had negative results. Results were concordant between platforms in 83 patients (73%). Thirty-seven patients (33%) were found to have a P/LP variant by 2 or both platforms and 14 (12%) had a VUS possibly related to phenotype. The median day of life at diagnosis was 22 days (range, 3-313 days). Significant alterations in clinical care occurred in 29 infants (78%) with a P/LP variant. Incidental findings were reported in 7 trios. Of 51 positive cases, 34 (67%) differed in the reported result because of technical limitations of the targeted platform, interpretation of the variant, filtering discrepancies, or multiple causes. Conclusions and Relevance: As comprehensive genetic testing becomes more routine, these data highlight the critically important variant detection capabilities of existing genomic sequencing technologies and the significant limitations that must be better understood.
Importance: A targeted genomic sequencing platform focused on diseases presenting in the first year of life may minimize financial and ethical challenges associated with rapid whole-genomic sequencing. Objective: To report interim variants and associated interpretations of an ongoing study comparing rapid whole-genomic sequencing with a novel targeted genomic platform composed of 1722 actionable genes targeting disorders presenting in infancy. Design, Setting, and Participants: The Genomic Medicine in Ill Neonates and Infants (GEMINI) study is a prospective, multicenter clinical trial with projected enrollment of 400 patients. The study is being conducted at 6 US hospitals. Hospitalized infants younger than 1 year of age suspected of having a genetic disorder are eligible. Results of the first 113 patients enrolled are reported here. Patient recruitment began in July 2019, and the interim analysis of enrolled patients occurred from March to June 2020. Interventions: Patient (proband) and parents (trios, when available) were tested simultaneously on both genomic platforms. Each laboratory performed its own phenotypically driven interpretation and was blinded to other results. Main Outcomes and Measures: Variants were classified according to the American College of Medical Genetics and Genomics standards of pathogenic (P), likely pathogenic (LP), or variants of unknown significance (VUS). Chromosomal and structural variations were reported by rapid whole-genomic sequencing. Results: Gestational age of 113 patients ranged from 23 to 40 weeks and postmenstrual age from 27 to 83 weeks. Sixty-seven patients (59%) were male. Diagnostic and/or VUS were returned for 51 patients (45%), while 62 (55%) had negative results. Results were concordant between platforms in 83 patients (73%). Thirty-seven patients (33%) were found to have a P/LP variant by 2 or both platforms and 14 (12%) had a VUS possibly related to phenotype. The median day of life at diagnosis was 22 days (range, 3-313 days). Significant alterations in clinical care occurred in 29 infants (78%) with a P/LP variant. Incidental findings were reported in 7 trios. Of 51 positive cases, 34 (67%) differed in the reported result because of technical limitations of the targeted platform, interpretation of the variant, filtering discrepancies, or multiple causes. Conclusions and Relevance: As comprehensive genetic testing becomes more routine, these data highlight the critically important variant detection capabilities of existing genomic sequencing technologies and the significant limitations that must be better understood.
Authors: Mallory J Owen; Sebastien Lefebvre; Christian Hansen; Chris M Kunard; David P Dimmock; Laurie D Smith; Gunter Scharer; Rebecca Mardach; Mary J Willis; Annette Feigenbaum; Anna-Kaisa Niemi; Yan Ding; Luca Van Der Kraan; Katarzyna Ellsworth; Lucia Guidugli; Bryan R Lajoie; Timothy K McPhail; Shyamal S Mehtalia; Kevin K Chau; Yong H Kwon; Zhanyang Zhu; Sergey Batalov; Shimul Chowdhury; Seema Rego; James Perry; Mark Speziale; Mark Nespeca; Meredith S Wright; Martin G Reese; Francisco M De La Vega; Joe Azure; Erwin Frise; Charlene Son Rigby; Sandy White; Charlotte A Hobbs; Sheldon Gilmer; Gail Knight; Albert Oriol; Jerica Lenberg; Shareef A Nahas; Kate Perofsky; Kyu Kim; Jeanne Carroll; Nicole G Coufal; Erica Sanford; Kristen Wigby; Jacqueline Weir; Vicki S Thomson; Louise Fraser; Seka S Lazare; Yoon H Shin; Haiying Grunenwald; Richard Lee; David Jones; Duke Tran; Andrew Gross; Patrick Daigle; Anne Case; Marisa Lue; James A Richardson; John Reynders; Thomas Defay; Kevin P Hall; Narayanan Veeraraghavan; Stephen F Kingsmore Journal: Nat Commun Date: 2022-07-26 Impact factor: 17.694
Authors: Monica H Wojcik; Pankaj B Agrawal; Alissa M D'Gama; Maya C Del Rosario; Mairead A Bresnahan; Timothy W Yu Journal: NPJ Genom Med Date: 2022-09-05 Impact factor: 6.083
Authors: Stephen F Kingsmore; Laurie D Smith; Chris M Kunard; Matthew Bainbridge; Sergey Batalov; Wendy Benson; Eric Blincow; Sara Caylor; Christina Chambers; Guillermo Del Angel; David P Dimmock; Yan Ding; Katarzyna Ellsworth; Annette Feigenbaum; Erwin Frise; Robert C Green; Lucia Guidugli; Kevin P Hall; Christian Hansen; Charlotte A Hobbs; Scott D Kahn; Mark Kiel; Lucita Van Der Kraan; Chad Krilow; Yong H Kwon; Lakshminarasimha Madhavrao; Jennie Le; Sebastien Lefebvre; Rebecca Mardach; William R Mowrey; Danny Oh; Mallory J Owen; George Powley; Gunter Scharer; Seth Shelnutt; Mari Tokita; Shyamal S Mehtalia; Albert Oriol; Stavros Papadopoulos; James Perry; Edwin Rosales; Erica Sanford; Steve Schwartz; Duke Tran; Martin G Reese; Meredith Wright; Narayanan Veeraraghavan; Kristen Wigby; Mary J Willis; Aaron R Wolen; Thomas Defay Journal: Am J Hum Genet Date: 2022-08-24 Impact factor: 11.043