Diagnostic utility of next-generation sequencing-based panel testing in 543 patients with suspected skeletal dysplasia

Orphanet Journal of Rare Diseases

Alicia Scocchia¹  Kimberly Gall¹  Tero-Pekka Alastalo¹  Johanna M. Huusko²  Johanna Sistonen²  Inka Saarinen²  Liisa Pelttari²  Tiia Kangas-Kontio²  Juha Koskenvuo²  Jonna Tallila²  Satu Valo²  Matti Hero³  Melita Irving⁴ 

[1] Blueprint Genetics Inc, Seattle, WA, USA;Blueprint Genetics Oy, Espoo, Finland;Blueprint Genetics Oy, Espoo, Finland;New Children’s Hospital, Pediatric Research Center, Helsinki University Hospital, Helsinki, Finland;Department of Clinical Genetics, Guy’s and St. Thomas’ NHS Trust, London, UK;

关键词: Skeletal dysplasia;    Skeletal disorders;    Next-generation sequencing;    Multi-gene panel;    Molecular diagnostics;    Genetic diagnostics;    Prenatal genetic testing;    Copy number variant analysis;   

DOI  :  10.1186/s13023-021-02025-7

来源: Springer

【 摘 要 】

BackgroundSkeletal dysplasia is typically diagnosed using a combination of radiographic imaging, clinical examinations, and molecular testing. Identifying a molecular diagnosis for an individual with a skeletal dysplasia can lead to improved clinical care, guide future medical management and treatment, and inform assessment of risk for familial recurrence. The molecular diagnostic utility of multi-gene panel testing using next-generation sequencing (NGS) has not yet been characterized for an unselected population of individuals with suspected skeletal dysplasia. In this study, we retrospectively reviewed patient reports to assess the diagnostic yield, reported variant characteristics, impact of copy number variation, and performance in prenatal diagnostics of panel tests for variants in genes associated with skeletal dysplasia and growth disorders.ResultsClinical reports of consecutive patients with a clinical indication of suspected skeletal dysplasia who underwent panel testing were examined. The 543 patients included in the study submitted samples for diagnostic genetic testing with an indication of suspected skeletal dysplasia or growth disorder and received one of three nested panel tests. A molecular diagnosis was established in 42.0% of patients (n = 228/543). Diagnostic variants were identified in 71 genes, nearly half of which (n = 35, 49.3%) contributed uniquely to a molecular diagnosis for a single patient in this cohort. Diagnostic yield was significantly higher among fetal samples (59.0%, n = 52/88) than postnatal samples (38.7%, n = 176/455; z = 3.55, p < 0.001). Diagnostic variants in fetal cases were identified across 18 genes. Thirteen diagnostic CNVs were reported, representing 5.7% of diagnostic findings and ranging in size from 241-bp to whole chromosome aneuploidy. Additionally, 11.4% (36/315) of non-diagnostic patient reports had suspicious variants of unknown significance (VUS), in which additional family studies that provide segregation data and/or functional characterization may result in reclassification to likely pathogenic.ConclusionsThese findings demonstrate the utility of panel testing for individuals with a suspected skeletal dysplasia or growth disorder, with a particularly high diagnostic yield seen in prenatal cases. Pursuing comprehensive panel testing with high-resolution CNV analysis can provide a diagnostic benefit, given the considerable phenotype overlap amongst skeletal dysplasia conditions.

【 授权许可】

CC BY