Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/28361
Title: Standardized practices for RNA diagnostics using clinically accessible specimens reclassifies 75% of putative splicing variants.
Austin Authors: Bournazos, Adam M;Riley, Lisa G;Bommireddipalli, Shobhana;Ades, Lesley;Akesson, Lauren S;Al-Shinnag, Mohammad;Alexander, Stephen I;Archibald, Alison D;Balasubramaniam, Shanti;Berman, Yemima;Beshay, Victoria;Boggs, Kirsten;Bojadzieva, Jasmina;Brown, Natasha J;Bryen, Samantha J;Buckley, Michael F;Chong, Belinda;Davis, Mark R;Dawes, Ruebena;Delatycki, Martin B ;Donaldson, Liz;Downie, Lilian;Edwards, Caitlin;Edwards, Matthew;Engel, Amanda;Ewans, Lisa J;Faiz, Fathimath;Fennell, Andrew;Field, Michael;Freckmann, Mary-Louise;Gallacher, Lyndon;Gear, Russell;Goel, Himanshu;Goh, Shuxiang;Goodwin, Linda;Hanna, Bernadette;Harraway, James;Higgins, Megan;Ho, Gladys;Hopper, Bruce K;Horton, Ari E;Hunter, Matthew F;Huq, Aamira J;Josephi-Taylor, Sarah;Joshi, Himanshu;Kirk, Edwin;Krzesinski, Emma;Kumar, Kishore R;Lemckert, Frances;Leventer, Richard J;Lindsey-Temple, Suzanna E;Lunke, Sebastian;Ma, Alan;Macaskill, Steven;Mallawaarachchi, Amali;Marty, Melanie;Marum, Justine E;McCarthy, Hugh J;Menezes, Manoj P;McLean, Alison;Milnes, Di;Mohammad, Shekeeb;Mowat, David;Niaz, Aram;Palmer, Elizabeth E;Patel, Chirag;Patel, Shilpan G;Phelan, Dean;Pinner, Jason R;Rajagopalan, Sulekha;Regan, Matthew;Rodgers, Jonathan;Rodrigues, Miriam;Roxburgh, Richard H;Sachdev, Rani;Roscioli, Tony;Samarasekera, Ruvishani;Sandaradura, Sarah A;Savva, Elena;Schindler, Tim;Shah, Margit;Sinnerbrink, Ingrid B;Smith, Janine M;Smith, Richard J;Springer, Amanda;Stark, Zornitza;Strom, Samuel P;Sue, Carolyn M;Tan, Kenneth;Tan, Tiong Y;Tantsis, Esther;Tchan, Michel C;Thompson, Bryony A;Trainer, Alison H;van Spaendonck-Zwarts, Karin;Walsh, Rebecca;Warwick, Linda;White, Stephanie;White, Susan M;Williams, Mark G;Wilson, Meredith J;Wong, Wui Kwan;Wright, Dale C;Yap, Patrick;Yeung, Alison;Young, Helen ;Jones, Kristi J;Bennetts, Bruce;Cooper, Sandra T
Affiliation: Department of Clinical Pathology, University of Melbourne, Parkville, Victoria, Australia
Department of Pathology, The Royal Melbourne Hospital, Parkville, Victoria, Australia
Department of Genomic Medicine, Westmead Hospital, Westmead, New South Wales, Australia
The TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
Monash Newborn, Monash Children's Hospital, Clayton, Victoria, Australia
Department of Clinical Genetics, Nepean Hospital, Kingswood, New South Wales, Australia
Newborn Care, Royal Hospital for Women, Randwick, New South Wales, Australia
, University of New South Wales, Randwick, New South Wales, Australia
Neuroscience Research Australia
School of Women's and Children's Health, Faculty of Medicine and Health, University of New South Wales, Kensington, NSW, Australia
Mater Research Institute, The University of Queensland, South Brisbane, Queensland, Australia
Department of Paediatrics, Monash University, Clayton, Victoria, Australia
Department of Clinical Genetics, Liverpool Hospital, Liverpool, New South Wales, Australia
Monash Genetics, Monash Health, Clayton, Victoria, Australia
Central Clinical School, The University of Sydney, Camperdown, New South Wales, Australia
Department of Medical Genomics, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
Murdoch Children's Research Institute, Parkville, Victoria, Australia
Centre for Clinical Genetics, Sydney Children's Hospital Randwick, Randwick, New South Wales, Australia
Australian Genomics Health Alliance, Parkville, Victoria, Australia
Northern Clinical School, Royal North Shore Hospital, St Leonards, New South Wales, Australia
Department of Clinical Genetics, Royal North Shore Hospital, St Leonards, New South Wales, Australia
Specialty of Genomic Medicine, Faculty of Medicine and Health, The University of Sydney, Westmead, New South Wales, Australia
Western Sydney Genetics Program, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
Genetic Metabolic Disorders Service, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
Department of Pediatric Nephrology, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
The University of Queensland, Herston, Queensland, Australia
Genetic Health Queensland, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
Department of Clinical Genetics, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
Rare Diseases Functional Genomics, Kids Research, Sydney Children's Hospital Network and Children's Medical Research Institute, Westmead, New South Wales, Australia
Department of Clinical Genetics, The Canberra Hospital, Garran, ACT, Australia
Genetics of Learning Disability Service, Hunter Genetics, Waratah, New South Wales, Australia
ACT Genetic Service, ACT Health, The Canberra Hospital, Garran, ACT, Australia
Department of Paediatrics, School of Medicine, Western Sydney University, Penrith South, New South Wales, Australia
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria, Australia
Department of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Westmead, New South Wales, Australia
Clinical Genetics
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Center for Clinical Genetics, Sydney Children's Hospital, Randwick, New South Wales, Australia
. Electronic address: sandra.cooper@sydney.edu.au
The Children's Medical Research Institute, Westmead, New South Wales, Australia
Department of Neurogenetics, Kolling Institute, Faculty of Medicine and Health, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales, Australia
, Australia
Department of Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, Western Australia
NSW Health Pathology, Randwick, New South Wales, Australia
Forster Genetics, Forster, New South Wales, Australia
Sullivan Nicolaides Pathology, Bowen Hills, Queensland, Australia
Intensive Care
Division of Genomics and Epigenetics, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
Department of Neurology, The Royal Children's Hospital, Parkville, Victoria, Australia
Translational Genomics, Kinghorn Centre for Clinical Genomics, Garvan Institute for Medical Research, Darlinghurst, New South Wales, Australia
Monash Cardiovascular Research Centre, Clayton, Victoria, Australia
Monash Heart and Monash Children's Hospital, Monash Health, Clayton, Victoria, Australia
Department of Molecular Genetics, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
The University of Newcastle, Callaghan, New South Wales, Australia
Kids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
The Royal Melbourne Hospital, Parkville, Victoria, Australia
Department of Cytogenetics, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
Department of Genomic Medicine, The Royal Melbourne Hospital, Parkville, Victoria, Australia
Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
Northern Hub, Genetic Health Service NZ, Auckland, New Zealand
School of Medicine, The University of Auckland, Auckland, New Zealand
Department of Neurology, Auckland City Hospital, Auckland, New Zealand
Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
Fulgent Genetics, Temple City, CA..
Issue Date: Jan-2022
Date: 2021-11-30
Publication information: Genetics in Medicine : Official journal of the American College of Medical Genetics 2022; 24(1): 130-145
Abstract: Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as causal variants in genetic disorders. In this study, we devise standardized practices for polymerase chain reaction (PCR)-based RNA diagnostics using clinically accessible specimens (blood, fibroblasts, urothelia, biopsy). A total of 74 families with diverse monogenic conditions (31% prenatal-congenital onset, 47% early childhood, and 22% teenage-adult onset) were triaged into PCR-based RNA testing, with comparative RNA sequencing for 19 cases. Informative RNA assay data were obtained for 96% of cases, enabling variant reclassification for 75% variants that can be used for genetic counseling (71%), to inform clinical care (32%) and prenatal counseling (41%). Variant-associated mis-splicing was highly reproducible for 28 cases with samples from ≥2 affected individuals or heterozygotes and 10 cases with ≥2 biospecimens. PCR amplicons encompassing another segregated heterozygous variant was vital for clinical interpretation of 22 of 79 variants to phase RNA splicing events and discern complete from partial mis-splicing. RNA diagnostics enabled provision of a genetic diagnosis for 64% of recruited cases. PCR-based RNA diagnostics has capacity to analyze 81.3% of clinically significant genes, with long amplicons providing an advantage over RNA sequencing to phase RNA splicing events. The Australasian Consortium for RNA Diagnostics (SpliceACORD) provide clinically-endorsed, standardized protocols and recommendations for interpreting RNA assay data.
URI: https://ahro.austin.org.au/austinjspui/handle/1/28361
DOI: 10.1016/j.gim.2021.09.001
ORCID: 0000-0002-8769-2569
0000-0002-1657-6034
Journal: Genetics in Medicine : Official journal of the American College of Medical Genetics
PubMed URL: 34906502
PubMed URL: https://pubmed.ncbi.nlm.nih.gov/34906502/
Type: Journal Article
Subjects: Genetic diagnosis
Noncoding variant
Pre-mRNA splicing
Putative splice variant
Variant classification
Appears in Collections:Journal articles

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