Diagnostic yield of rare skeletal dysplasia conditions in the radiogenomics era
| Autor: | Melita Irving, Moira Cheung, Ana Beleza-Meireles, Christine Hall, Yogen Patel, S. Lillis, Alessandra Cocca, Shu Yau, Jameela Sheikh, Alistair Calder, Elizabeth Morley, Ataf H. Sabir, Mattias Jansson, Amaka C. Offiah |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Exome sequencing
0301 basic medicine Yield Pediatrics medicine.medical_specialty Monogenic Radiogenomics Context (language use) QH426-470 Mendelian 030105 genetics & heredity Genome sequencing 03 medical and health sciences Genetics medicine Medical diagnosis Internal medicine Genetics (clinical) business.industry medicine.disease RC31-1245 Clinical trial Molecular genetic test 030104 developmental biology Dysplasia Cohort Next-generation sequencing Skeletal dysplasia business Research Article Rare disease |
| Zdroj: | BMC Medical Genomics BMC Medical Genomics, Vol 14, Iss 1, Pp 1-14 (2021) |
| Popis: | Background Skeletal 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. Methods We 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. Results Significant 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. Conclusions Our 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. |
| Databáze: | OpenAIRE |
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