Portal de Periódicos da CAPES

Genomic answers for children: Dynamic analyses of >1000 pediatric rare disease genomes

2022; Elsevier BV; Volume: 24; Issue: 6 Linguagem: Inglês

10.1016/j.gim.2022.02.007

1530-0366

Ana S.A. Cohen, Emily Farrow, Ahmed Abdelmoity, Joseph T. Alaimo, Shivarajan Amudhavalli, John T. Anderson, Lalit Bansal, Lauren Bartik, Primo Baybayan, Bradley Belden, Courtney Berrios, Rebecca Biswell, Pawel Buczkowicz, Orion J. Buske, Shreyasee Chakraborty, Warren Cheung, Keith A. Coffman, Ashley M. Cooper, Laura Cross, Tom Curran, Thuy Tien T. Dang, Mary Elfrink, Kendra Engleman, Erin Fecske, Cynthia Fieser, Keely Fitzgerald, Emily Fleming, Randi Gadea, Jennifer Gannon, Rose Gelineau‐Morel, Margaret Gibson, Jeffrey A. Goldstein, Elin Grundberg, Kelsee Halpin, Brian S. Harvey, Bryce A. Heese, Wendy Hein, Suzanne Herd, Susan Hughes, Mohammed Ilyas, Jill D. Jacobson, Janda Jenkins, Jiang Shao, Jeffrey Johnston, Kathryn Keeler, Jonas Korlach, Jennifer Kussmann, Christine Lambert, Caitlin E. Lawson, Jean‐Baptiste Le Pichon, J. Steven Leeder, Vicki C. Little, Daniel Louiselle, Michael Lypka, Brittany McDonald, Neil Miller, Ann Modrcin, Annapoorna Nair, Shelby H. Neal, Christopher M. Oermann, Donna Pacicca, Kailash Pawar, Nyshele Posey, Nigel Price, Laura Puckett, Julio Quezada, Nikita Raje, William J. Rowell, Eric T. Rush, Venkatesh Sampath, Carol Saunders, Caitlin Schwager, Richard M. Schwend, Elizabeth Shaffer, Craig Smail, Sarah Soden, Meghan E. Strenk, Bonnie Sullivan, Brooke Sweeney, Jade Tam‐Williams, Adam M. Walter, Holly Welsh, Aaron M. Wenger, Laurel K. Willig, Yun Yan, Scott T. Younger, Dihong Zhou, Tricia Zion, Isabelle Thiffault, Tomi Pastinen,

Genetics and Neurodevelopmental Disorders

PurposeThis study aimed to provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids program.MethodsExtensive analyses of 960 families with suspected genetic disorders included short-read exome sequencing and short-read genome sequencing (srGS); PacBio HiFi long-read genome sequencing (HiFi-GS); variant calling for single nucleotide variants (SNV), structural variant (SV), and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants, and pedigrees were stored in PhenoTips database, with data sharing through controlled access the database of Genotypes and Phenotypes.ResultsDiagnostic rates ranged from 11% in patients with prior negative genetic testing to 34.5% in naive patients. Incorporating SVs from genome sequencing added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with >4-fold more rare coding SVs compared with srGS. Variants and genes of unknown significance remain the most common finding (58% of nondiagnostic cases).ConclusionComputational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated using HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation and by providing HiFi variant (SNV/SV) resources from >1000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.