Abstract
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.
Highlights
Skeletal dysplasia (SD) conditions are rare genetic diseases of the skeleton, encompassing a hetero‐ geneous group of over 400 disorders, and represent approximately 5% of all congenital anomalies
We explore the utility of whole-exome sequencing (WES) in a cohort solely composed of SD presentations and consider the diagnostic yield in sub-cohorts, i.e., those with an unknown diagnosis and those with an assured diagnosis
Significant variants 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
Summary
Skeletal dysplasia (SD) conditions are rare genetic diseases of the skeleton, encompassing a hetero‐ geneous group of over 400 disorders, and represent approximately 5% of all congenital anomalies. Rare diseases by definition affect less than 1 in 2,000 (in Europe) or 1 in 1,500 (in the USA). 80% of the 7300 rare diseases have a known genetic cause, and whole-exome sequencing (WES) is commonly the final diagnostic step in such cases with diagnostic yields averaging around 31% (24–68%) [1,2,3]. Yield is highly influenced by recruitment type (e.g., single proband versus trio), bioinformatic pipelines, study year, consanguinity, case complexity and degree of prior genetic evaluation. Yields tend to increase with study year (due to increasing novel genes, conditions, and technological advances) and in cohorts with a high degree of consanguinity [2]. Yield is markedly affected by the extent of prior genetic and metabolic evaluation; WES usage earlier in the diagnostic assessment can lead to higher yields
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