Diagnostic yield of rare skeletal dysplasia conditions in the radiogenomics era

BMC Medical Genomics

Amaka C. Offiah¹  Ana Beleza-Meireles²  Jameela Sheikh³  Ataf H. Sabir⁴  Melita Irving⁵  Moira S. Cheung⁶  Alessandra Cocca⁶  Christine M. Hall⁷  Yogen Patel⁸  Alistair D. Calder⁹  Elizabeth Morley^1,10  Shu Yau^1,11  Suzanne Lillis^1,11  Mattias Jansson^1,11 

[1] Academic Unit of Child Health, University of Sheffield, Sheffield, UK;Clinical Genetics Department, University Hospitals Bristol and Weston, Bristol, UK;College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK;Department of Clinical Genetics, Guy’s and St Thomas’ NHS Foundation Trust, London, UK;College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK;Department of Clinical Genetics, Guy’s and St Thomas’ NHS Foundation Trust, London, UK;Division of Genetics and Molecular Medicine, King’s College London School of Medicine, London, UK;Department of Paediatric Endocrinology, Evelina London Children’s Hospital, London, UK;Great Ormond Street Hospital for Children, London, UK;Emeritus Professor of Paediatric Radiology, Institute of Child Health, University of London, London, UK;Neurogenetics, Rare and Inherited Disease Laboratory, North Thames GLH, Barclay House, 37 Queen Square, WC1N 3BH, London, UK;Radiology Department, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK;The Royal Wolverhampton NHS Trust, Wolverhampton, UK;Viapath LLP, Guy’s Hospital, 5th Floor Tower Wing, SE1 9RT, London, UK;

关键词: Mendelian;    Molecular genetic test;    Monogenic;    Next-generation sequencing;    Skeletal dysplasia;    Exome sequencing;    Genome sequencing;    Yield;   

DOI  :  10.1186/s12920-021-00993-0

来源: Springer

【 摘 要 】

BackgroundSkeletal dysplasia (SD) conditions are rare genetic diseases of the skeleton, encompassing a heterogeneous group of over 400 disorders, and represent approximately 5% of all congenital anomalies. Developments in genetic and treatment technologies are leading to unparalleled therapeutic advances; thus, it is more important than ever to molecularly confirm SD conditions. Data on ‘rates-of-molecular yields’ in SD conditions, through exome sequencing approaches, is limited. Figures of 39% and 52.5% have been reported in the USA (n = 54) and South Korea (n = 185) respectively.MethodsWe discuss a single-centre (in the UK) experience of whole-exome sequencing (WES) in a cohort of 15 paediatric patients (aged 5 months to 12 years) with SD disorders previously molecularly unconfirmed. Our cohort included patients with known clinical diagnoses and undiagnosed skeletal syndromes. Extensive phenotyping and expert radiological review by a panel of international SD radiology experts, coupled with a complex bioinformatics pipeline, allowed for both gene-targeted and gene-agnostic approaches.ResultsSignificant variants leading to a likely or confirmed diagnosis were identified in 53.3% (n = 8/15) of patients; 46.7% (n = 7/15) having a definite molecular diagnosis and 6.7% (n = 1/15) having a likely molecular diagnosis. We discuss this in the context of a rare disease in general and specifically SD presentations. Of patients with known diagnoses pre-WES (n = 10), molecular confirmation occurred in 7/10 cases, as opposed to 1/5 where a diagnosis was unknown pre-test. Thus, diagnostic return is greatest where the diagnosis is known pre-test. For WGS (whole genome sequencing, the next iteration of WES), careful case selection (ideally of known diagnoses pre-test) will yield highest returns.ConclusionsOur results highlight the cost-effective use of WES-targeted bioinformatic analysis as a diagnostic tool for SD, particularly patients with presumed SD, where detailed phenotyping is essential. Thorough co-ordinated clinical evaluation between clinical, radiological, and molecular teams is essential for improved yield and clinical care. WES (and WGS) yields will increase with time, allowing faster diagnoses, avoiding needless investigations, ensuring individualised patient care and patient reassurance. Further diagnoses will lead to increased information on natural history/mechanistic details, and likely increased therapies and clinical trials.

【 授权许可】

CC BY