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首页> 外文期刊>BMC Medical Genomics >Diagnostic yield of rare skeletal dysplasia conditions in the radiogenomics era
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Diagnostic yield of rare skeletal dysplasia conditions in the radiogenomics era

机译：辐射素内酯时代罕见骨骼发育不良病症的诊断产量

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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. 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. 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. 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.
机译：骨骼发育不良（SD）条件是骨骼的稀有遗传疾病，包括超过400个疾病的异质组，并且代表所有先天性异常的约5％。遗传和治疗技术的发展导致无与伦比的治疗进展;因此，它比以往更重要的是分子确认SD条件。通过exome测序方法的SD条件下的“分子产率”数据有限。在美国（N？= 54）和韩国（n？= 185），已报道39％和52.5％的数字。我们讨论了15名儿科患者（5岁的5月至12日）的群组中的单中心（英国）的全面测序（WES）体验，先前分别未经证实的SD障碍。我们的队列包括已知临床诊断和未确诊的骨骼综合征的患者。国际SD放射学专家小组的广泛表型和专家放射审查，与复杂的生物信息学管道相结合，允许基因靶向和基因无症方法。在53.3％（n？= 8/15）的患者中确定了导致可能或确诊诊断的显着变体; 46.7％（n？=Δ7/15）具有明确的分子诊断和6.7％（n？=β115），具有可能的分子诊断。我们在一般的罕见疾病的背景下讨论了这一点，特别是SD演示文稿。患有已知诊断的患者（n？= 10），分子确认发生在7/10例中，而不是1/5，其中诊断预先测试。因此，诊断返回最大的是诊断所知的预先测试。对于WGS（整个基因组测序，WES的下一次迭代），仔细的情况选择（理想地是已知的诊断预测试）将产生最高的回报。我们的结果突出了随着SD的诊断工具，突出了WES针对性生物信息分析的成本效益，特别是假定SD的患者，其中详细的表型是必不可少的。临床，放射性和分子团队之间的彻底协调临床评估对于提高产量和临床护理至关重要。 WES（和WGS）产量随着时间的推移而增加，允许更快的诊断，避免不必要的调查，确保个体化患者护理和患者的保证。进一步的诊断将导致有关自然历史/机械细节的信息，并且可能增加疗法和临床试验。

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