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Exome sequencing in fetuses with short long bones detected by ultrasonography: A retrospective cohort study

Background: Prenatal diagnosis of fetal short long bones (SLBs) was reported to be associated with skeletal dysplasias, chromosomal abnormalities, and genetic syndromes. This study aims to identify the genetic causes for fetal short long bones, and retrospectively evaluate the additional diagnostic...

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Autores principales: Huang, Yanlin, Liu, Chang, Ding, Hongke, Wang, Yunan, Yu, Lihua, Guo, Fangfang, Li, Fake, Shi, Xiaomei, Zhang, Yan, Yin, Aihua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10010437/
https://www.ncbi.nlm.nih.gov/pubmed/36923788
http://dx.doi.org/10.3389/fgene.2023.1032346
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author Huang, Yanlin
Liu, Chang
Ding, Hongke
Wang, Yunan
Yu, Lihua
Guo, Fangfang
Li, Fake
Shi, Xiaomei
Zhang, Yan
Yin, Aihua
author_facet Huang, Yanlin
Liu, Chang
Ding, Hongke
Wang, Yunan
Yu, Lihua
Guo, Fangfang
Li, Fake
Shi, Xiaomei
Zhang, Yan
Yin, Aihua
author_sort Huang, Yanlin
collection PubMed
description Background: Prenatal diagnosis of fetal short long bones (SLBs) was reported to be associated with skeletal dysplasias, chromosomal abnormalities, and genetic syndromes. This study aims to identify the genetic causes for fetal short long bones, and retrospectively evaluate the additional diagnostic yield of exome sequencing (ES) for short long bones following the use of conventional genetic testing. Methods: A cohort of ninety-four fetuses with sonographically identified short long bones was analyzed by trio-exome sequencing between January 2016 and June 2021. Fetuses with abnormal results of karyotype or chromosomal microarray analysis were excluded. Variants were interpreted based on ACMG/AMP guidelines. All diagnostic de novo variants were validated by Sanger sequencing. Results: Of the 94 fetuses, 38 (40.4%) were found to carry causal genetic variants (pathogenic or likely pathogenic) in sixteen genes with 38 variants. Five fetuses (5.3%) had variant(s) of uncertain significance. Thirty-five cases (37.2%) were diagnosed as genetic skeletal dysplasias including 14 different diseases that were classified into 10 groups according to the Nosology and Classification of Genetic Skeletal Disorders. The most common disease in the cohort was achondroplasia (28.9%), followed by osteogenesis imperfecta (18.4%), thanatophoric dysplasia (10.5%), chondrogenesis (7.9%), and 3-M syndrome (5.3%). The diagnostic yield in fetuses with isolated short long bones was lower than the fetuses with non-isolated short long bones, but not reached statistical significance (27.3% vs. 44.4%; p = 0.151). Whereas, the rate in the fetuses with other skeletal abnormalities was significantly higher than those with non-skeletal abnormalities (59.4% vs. 32.5%, p = 0.023), and the diagnostic rate was significantly higher in femur length (FL) below -4SDs group compared with FL 2-4SDs below GA group (72.5% vs. 16.7%; p < 0.001). A long-term follow-up showed that outcomes for fetuses with FL 2-4SDs below GA were significantly better than those with FL below -4SDs. Additionally, fourteen (36.8%) novel short long bones-related variants were identified in the present study. Conclusion: The findings suggest that in fetuses with short long bones routine genetic tests failed to determine the underlying causes, exome sequencing could add clinically relevant information that could assist the clinical management of pregnancies. Novel pathogenic variants identified may broaden the mutation spectrum for the disorders and contributes to clinical consultation and subsequent pregnancy examination.
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spelling pubmed-100104372023-03-14 Exome sequencing in fetuses with short long bones detected by ultrasonography: A retrospective cohort study Huang, Yanlin Liu, Chang Ding, Hongke Wang, Yunan Yu, Lihua Guo, Fangfang Li, Fake Shi, Xiaomei Zhang, Yan Yin, Aihua Front Genet Genetics Background: Prenatal diagnosis of fetal short long bones (SLBs) was reported to be associated with skeletal dysplasias, chromosomal abnormalities, and genetic syndromes. This study aims to identify the genetic causes for fetal short long bones, and retrospectively evaluate the additional diagnostic yield of exome sequencing (ES) for short long bones following the use of conventional genetic testing. Methods: A cohort of ninety-four fetuses with sonographically identified short long bones was analyzed by trio-exome sequencing between January 2016 and June 2021. Fetuses with abnormal results of karyotype or chromosomal microarray analysis were excluded. Variants were interpreted based on ACMG/AMP guidelines. All diagnostic de novo variants were validated by Sanger sequencing. Results: Of the 94 fetuses, 38 (40.4%) were found to carry causal genetic variants (pathogenic or likely pathogenic) in sixteen genes with 38 variants. Five fetuses (5.3%) had variant(s) of uncertain significance. Thirty-five cases (37.2%) were diagnosed as genetic skeletal dysplasias including 14 different diseases that were classified into 10 groups according to the Nosology and Classification of Genetic Skeletal Disorders. The most common disease in the cohort was achondroplasia (28.9%), followed by osteogenesis imperfecta (18.4%), thanatophoric dysplasia (10.5%), chondrogenesis (7.9%), and 3-M syndrome (5.3%). The diagnostic yield in fetuses with isolated short long bones was lower than the fetuses with non-isolated short long bones, but not reached statistical significance (27.3% vs. 44.4%; p = 0.151). Whereas, the rate in the fetuses with other skeletal abnormalities was significantly higher than those with non-skeletal abnormalities (59.4% vs. 32.5%, p = 0.023), and the diagnostic rate was significantly higher in femur length (FL) below -4SDs group compared with FL 2-4SDs below GA group (72.5% vs. 16.7%; p < 0.001). A long-term follow-up showed that outcomes for fetuses with FL 2-4SDs below GA were significantly better than those with FL below -4SDs. Additionally, fourteen (36.8%) novel short long bones-related variants were identified in the present study. Conclusion: The findings suggest that in fetuses with short long bones routine genetic tests failed to determine the underlying causes, exome sequencing could add clinically relevant information that could assist the clinical management of pregnancies. Novel pathogenic variants identified may broaden the mutation spectrum for the disorders and contributes to clinical consultation and subsequent pregnancy examination. Frontiers Media S.A. 2023-02-27 /pmc/articles/PMC10010437/ /pubmed/36923788 http://dx.doi.org/10.3389/fgene.2023.1032346 Text en Copyright © 2023 Huang, Liu, Ding, Wang, Yu, Guo, Li, Shi, Zhang and Yin. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Huang, Yanlin
Liu, Chang
Ding, Hongke
Wang, Yunan
Yu, Lihua
Guo, Fangfang
Li, Fake
Shi, Xiaomei
Zhang, Yan
Yin, Aihua
Exome sequencing in fetuses with short long bones detected by ultrasonography: A retrospective cohort study
title Exome sequencing in fetuses with short long bones detected by ultrasonography: A retrospective cohort study
title_full Exome sequencing in fetuses with short long bones detected by ultrasonography: A retrospective cohort study
title_fullStr Exome sequencing in fetuses with short long bones detected by ultrasonography: A retrospective cohort study
title_full_unstemmed Exome sequencing in fetuses with short long bones detected by ultrasonography: A retrospective cohort study
title_short Exome sequencing in fetuses with short long bones detected by ultrasonography: A retrospective cohort study
title_sort exome sequencing in fetuses with short long bones detected by ultrasonography: a retrospective cohort study
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10010437/
https://www.ncbi.nlm.nih.gov/pubmed/36923788
http://dx.doi.org/10.3389/fgene.2023.1032346
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