Molecular Diagnostic Yield of Exome Sequencing and Chromosomal Microarray in Short Stature

Abstract

ImportanceCurrently, the diagnostic yield of exome sequencing (ES) and chromosomal microarray analysis (CMA) for short stature cohorts is uncertain. Despite previous studies reporting the widespread use of ES and CMA, a definitive diagnostic yield has not been established.ObjectiveTo investigate the diagnostic yield of ES and CMA in short stature.Data SourcesA systematic literature search was conducted using relevant keywords in 3 databases (PubMed, Embase, and Web of Science) in February 2023.Study SelectionEligible studies for meta-analysis were those that had at least 10 participants with short stature who were diagnosed using either ES or CMA and the number of diagnosed patients was reported. Of 5222 identified studies, 20 were eventually included in the study.Data Extraction and SynthesisTwo independent investigators extracted relevant information from each study, which was then synthesized using proportional meta-analysis to obtain the overall diagnostic yield of ES and CMA.Main Outcomes and MeasuresThe primary outcome measure was to determine the overall diagnostic yield of ES and CMA. A subgroup meta-analysis was also performed to assess if the diagnostic yield varied depending on whether ES was used as a first-tier or last-resort test. Additionally, a meta-regression was carried out to investigate how the diagnostic yield varied over time.ResultsTwenty studies were included, comprising 1350 patients with short stature who underwent ES and 1070 patients who completed CMA. The overall diagnostic yield of ES among the cohorts and CMA among the cohorts was found to be 27.1% (95% CI, 18.1%-37.2%) and 13.6% (95% CI, 9.2%-18.7%), respectively. No statistically significant difference was observed between the first-tier (27.8%; 95% CI, 15.7%-41.8%) and last-resort groups (25.6%; 95% CI, 13.6%-39.6%) (P = .83) or in the percentage of positively diagnosed patients over time. No statistically significant difference was observed between the first-tier (27.8%; 95% CI, 15.7%-41.8%) and last-resort groups (25.6%; 95% CI, 13.6%-39.6%) (P = .83) or in the percentage of positively diagnosed patients over time.Conclusion and RelevanceThis systematic review and meta-analysis provides high-level evidence supporting the diagnostic efficacy of ES and CMA in patients with short stature. The findings serve as a solid reference for clinicians when making informed decisions about recommending these genetic tests.

Exploring the Genetic Causes for Postnatal Growth Failure in Children Born Non-Small for Gestational Age

“…Our study demonstrated the high diagnostic yield (47.2%) in non-SGA SS patients compared to the general detection rate of 27.1% (95% CI, 18.1-37.2%), reported in a metaanalysis of 20 studies of patients with SS [52].…”

Unravelling short stature in pediatrics: the crucial role of genetic perspective

“…In this editorial commentary, I will analyze the recent paper authored by Li et al , delving into the dynamic role of contemporary technologies in deciphering the genetic intricacies associated with short stature ( 1 ). The exploration encompasses an in-depth assessment of their diagnostic performance, challenges encountered, and the significant potential they bear for advancing patient care.…”

“…Short stature, defined as a height that is less than 2 standard deviations (SDs) from the mean for the respective age and gender ( 1 , 2 ). The aetiology of short stature is multifactorial and can result from genetic factors, hormonal factors such as growth hormone, thyroid hormones, and cortisol, and a spectrum of environmental factors (prenatal and postnatal), or a combination of both.…”

“…A significant proportion of short stature cases have an underlying genetic aetiology with more than 250 genes implicated in its pathogenesis such as SHOX , GH1 , IGF1 , IGF1R , GHR or FGFR3 , among others. Therefore, identifying the genetic basis of short stature is critical for establishing accurate diagnoses, informing prognosis, and guiding personalized management strategies ( 1 - 6 ). The utility of ES and CMA in the study of short stature extends beyond diagnosis.…”