Multigene Sequencing Analysis of Children Born Small for Gestational Age With Isolated Short Stature

Freire, Bruna L; Homma, Thaís Kataoka; Funari, Mariana F A; Lerário, Antônio Marcondes; Vasques, Gabriela A; Malaquias, Alexsandra C.; Arnhold, Ivo J.P.; Jorge, Alexander A L

doi:10.1210/jc.2018-01971

Cited by 66 publications

(65 citation statements)

References 41 publications

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“…This candidate gene approach is feasible for a small number of patients with a high probability of harboring a SHOX defect. However, patients with SHOX defects frequently lack specific phenotype, and the use of NGS is a potential strategy to investigate a large number of patients classified as ISS …”

Section: Discussionmentioning

confidence: 99%

“…However, patients with SHOX defects frequently lack specific phenotype, and the use of NGS is a potential strategy to investigate a large number of patients classified as ISS. 4,5 We evaluated the performance of a targeted panel that can be useful for ISS diagnosis without the need for the previous CONTRA software presented a sensitivity of 87.5% (14/16) in the detection of CNVs. A sensitivity of 68% was described by Li et al for CONTRA for deletions of 50 to 200 bp and of 96.4% for full exon deletions.…”

Section: Discussionmentioning

confidence: 99%

“…The variants were filtered as previously described. 5 CNV analyses were performed using two software packages able to call CNVs for target region based on the normalized depth of coverage: COpy Number Targeted Resequencing Analysis (CONTRA) 7 and Nexus Copy Number (BioDiscovery, Inc.). 8 We also visually inspected SHOX coverage using Integrative Genomics Viewer (IGV) software.…”

Section: Patientsmentioning

confidence: 99%

“…The massively parallel sequencing technologies have increased the diagnostic yields in several genetic disorders. The molecular investigation of children with short stature of unknown cause has followed this same trend, with the simultaneous analysis of multiple genes using exome or targeted panel strategies . Considering this scenario, the study of SHOX is a major challenge because of the large number of copy number variants (CNVs) and the importance of investigating regulatory regions …”

Section: Introductionmentioning

confidence: 99%

“…The molecular investigation of children with short stature of unknown cause has followed this same trend, with the simultaneous analysis of multiple genes using exome or targeted panel strategies. 4,5 Considering this scenario, the study of SHOX is a major challenge because of the large number of copy number variants (CNVs) and the importance of investigating regulatory regions. 6 We designed a targeted panel for next-generation sequencing (NGS) to evaluate a cohort of patients with ISS.…”

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confidence: 99%

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Evaluation of SHOX defects in the era of next‐generation sequencing

et al. 2019

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Short stature homeobox (SHOX) haploinsufficiency is a frequent cause of short stature. Despite advances in sequencing technologies, the identification of SHOX mutations continues to be performed using standard methods, including multiplex ligation‐dependent probe amplification (MLPA) followed by Sanger sequencing. We designed a targeted panel of genes associated with growth impairment, including SHOX genomic and enhancer regions, to improve the resolution of next‐generation sequencing for SHOX analysis. We used two software packages, CONTRA and Nexus Copy Number, in addition to visual analysis to investigate the presence of copy number variants (CNVs). We evaluated 15 patients with previously known SHOX defects, including point mutations, deletions and a duplication, and 77 patients with idiopathic short stature (ISS). The panel was able to confirm all known defects in the validation analysis. During the prospective evaluation, we identified two new partial SHOX deletions (one detected only by visual analysis), including an intragenic deletion not detected by MLPA. Additionally, we were able to determine the breakpoints in four cases. Our results show that the designed panel can be used for the molecular investigation of patients with ISS, and it may even detect CNVs in SHOX and its enhancers, which may be present in a significant fraction of patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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Evaluation of SHOX defects in the era of next‐generation sequencing

et al. 2019

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

Li,

Chen,

Wang

et al. 2023

JAMA Pediatr

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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.

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