Pathogenic Copy Number and Sequence Variants in Children Born SGA With Short Stature Without Imprinting Disorders

Hara-Isono, Kaori; Nakamura, Akie; Fuke, Tomoko; Inoue, Takeshi; Kawashima, Sayaka; Matsubara, Kazuo; Shinzaki, Shinichiro; Yamazawa, Kazuki; Fukami, Maki; Ogata, Tsutomu; Kagami, Masayo

doi:10.1210/clinem/dgac319

Cited by 8 publications

(5 citation statements)

References 58 publications

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“…Our systematic search identified a total of 5222 records with 24 being deemed eligible and included in the systematic review (eTable 3 in Supplement 1). Of these, 20 studies were included in the meta-analysis.…”

Section: Resultsmentioning

confidence: 99%

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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Section: Resultsmentioning

confidence: 99%

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

Li,

Chen,

Wang

et al. 2023

JAMA Pediatr

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“…There have been several reports combining pathogenic gene variants and chromosomal abnormalities in SGA populations: Stalman et al examined 21 SGA and 24 AGA newborns and identified three CNVs, one systematically disturbed methylation pattern, and one sequence variant explaining SGA [ 17 ]. Hara-Isono et al scrutinized 86 SGA children with short stature but without imprinting disorders, and identified 8 (9.3%) and 11 (12.8%) patients with pathogenic CNVs and candidate pathogenic variants, respectively [ 14 ]. Peeters et al evaluated 20 SGA children with short stature treated with growth hormone and identified likely pathogenic variants in 4 children, pathogenic CNVs in 2 probands, and one DNA methylation signature in a child harboring an NSD1-containing microduplication [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive assessment of the genetic characteristics of small for gestational age newborns in NICU: from diagnosis of genetic disorders to prediction of prognosis

Xiao,

Chen,

Chen

et al. 2023

Genome Med

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Background In China, ~1,072,100 small for gestational age (SGA) births occur annually. These SGA newborns are a high-risk population of developmental delay. Our study aimed to evaluate the genetic profile of SGA newborns in the newborn intensive care unit (NICU) and establish a prognosis prediction model by combining clinical and genetic factors. Methods A cohort of 723 SGA and 1317 appropriate for gestational age (AGA) newborns were recruited between June 2018 and June 2020. Clinical exome sequencing was performed for each newborn. The gene-based rare-variant collapsing analyses and the gene burden test were applied to identify the risk genes for SGA and SGA with poor prognosis. The Gradient Boosting Machine framework was used to generate two models to predict the prognosis of SGA. The performance of two models were validated with an independent cohort of 115 SGA newborns without genetic diagnosis from July 2020 to April 2022. All newborns in this study were recruited through the China Neonatal Genomes Project (CNGP) and were hospitalized in NICU, Children’s Hospital of Fudan University, Shanghai, China. Results Among the 723 SGA newborns, 88(12.2%) received genetic diagnosis, including 42(47.7%) with monogenic diseases and 46(52.3%) with chromosomal abnormalities. SGA with genetic diagnosis showed higher rates in severe SGA(54.5% vs. 41.9%, P=0.0025) than SGA without genetic diagnosis. SGA with chromosomal abnormalities showed higher incidences of physical and neurodevelopmental delay compared to those with monogenic diseases (45.7% vs. 19.0%, P=0.012). We filtered out 3 genes (ITGB4, TXNRD2, RRM2B) as potential causative genes for SGA and 1 gene (ADIPOQ) as potential causative gene for SGA with poor prognosis. The model integrating clinical and genetic factors demonstrated a higher area under the receiver operating characteristic curve (AUC) over the model based solely on clinical factors in both the SGA-model generation dataset (AUC=0.9[95% confidence interval 0.84–0.96] vs. AUC=0.74 [0.64–0.84]; P=0.00196) and the independent SGA-validation dataset (AUC=0.76 [0.6–0.93] vs. AUC=0.53[0.29–0.76]; P=0.0117). Conclusion SGA newborns in NICU presented with roughly equal proportions of monogenic and chromosomal abnormalities. Chromosomal disorders were associated with poorer prognosis. The rare-variant collapsing analyses studies have the ability to identify potential causative factors associated with growth and development. The SGA prognosis prediction model integrating genetic and clinical factors outperformed that relying solely on clinical factors. The application of genetic sequencing in hospitalized SGA newborns may improve early genetic diagnosis and prognosis prediction.

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“…In comparison to the SGA SS group, defect of GH-IGF axis or imprinting disorder is main cause for SGA without catch-up growth in addition to the growth plate dysfunction [53,54]. The genes for growth plate dysfunction have been identified in ISS or FSS group (Table 3).…”

Section: Discussionmentioning

confidence: 99%

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

Kim,

Lim,

Kim

et al. 2023

JCM

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The most common causes of short stature (SS) in children are familial short stature (FSS) and idiopathic short stature (ISS). Recently, growth plate dysfunction has been recognized as the genetic cause of FSS or ISS. The aim of this study was to investigate monogenic growth failure in patients with ISS and FSS. Targeted exome sequencing was performed in patients categorized as ISS or FSS and the subsequent response to growth hormone (GH) therapy was analyzed. We found 17 genetic causes involving 12 genes (NPR2, IHH, BBS1, COL1A1, COL2A1, TRPS1, MASP1, SPRED1, PTPTN11, ADNP, NADSYN1, and CERT1) and 2 copy number variants. A genetic cause was found in 45.5% and 35.7% of patients with FSS and ISS, respectively. The genetic yield in patients with syndromic and non-syndromic SS was 90% and 23.1%, respectively. In the 11 genetically confirmed patients, a gain in height from −2.6 to −1.3 standard deviations after 2 years of GH treatment was found. The overall diagnostic yield in this study was 41.7%. We identified several genetic causes involving paracrine signaling, the extracellular matrix, and basic intracellular processes. Identification of the causative gene may provide prognostic evidence for the use of GH therapy in non-SGA children.

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Pathogenic Copy Number and Sequence Variants in Children Born SGA With Short Stature Without Imprinting Disorders

Cited by 8 publications

References 58 publications

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

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

Comprehensive assessment of the genetic characteristics of small for gestational age newborns in NICU: from diagnosis of genetic disorders to prediction of prognosis

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

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