Whole Exome Sequencing Aids the Diagnosis of Fetal Skeletal Dysplasia

Tang, Hui; Zhang, Qin; Xiang, Jingjing; Yin, Long; Wang, Jing; Wang, Ting

doi:10.3389/fgene.2021.599863

Cited by 11 publications

(13 citation statements)

References 41 publications

(48 reference statements)

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“…Prenatal ES identified well-described genetic causes in 38 out of 94 cases (40.4%), and VUS in 5 cases, rendering a total diagnostic yield of 45.74%. Compared with our findings, three recent cohort studies reported a significantly higher diagnostic rate by prenatal ES, which was 80% (12 out of 15), 85% (11 out of 13), and 70% (21 out of 30), respectively (Liu et al, 2019;Peng et al, 2021;Tang et al, 2021). Many aspects could affect the detection rate of ES, such as the selected criteria of the study, the number of cases, proband-only or trio ES, and so on (Tang et al, 2021).…”

Section: Follow-up Assessmentscontrasting

confidence: 81%

“…In the last decade, next-generation sequencing (NGS) has revolutionized the genetic testing of diseases with high genetic and allelic heterogeneity, such as skeletal dysplasias, allowing hundreds of genes to be screened simultaneously. Based on the statements released by the International Society for Prenatal Diagnosis (ISPD), the Society for Maternal Fetal Medicine (SMFM), the Perinatal Quality Foundation (PQF), and the American College of Medical Genetics and Genomics (ACMG), NGS can be used with ultrasound anomalies when standard diagnostic genetic testing, such as CMA, failed to yield a definitive diagnosis (Lord et al, 2019;Tang et al, 2021). In addition, SLBs are mainly attributed to monogenic disorders, such as skeletal dysplasias (Mortier et al, 2019), and therefore NGS may be of importance in their prenatal evaluation.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, SLBs are mainly attributed to monogenic disorders, such as skeletal dysplasias (Mortier et al, 2019), and therefore NGS may be of importance in their prenatal evaluation. Especially, if a specific diagnosis is suspected or when FL is > 4 SDs below the mean, targeted capture sequencing or whole exome sequencing should be performed (Liu et al, 2019;Tang et al, 2021). Definitive molecular diagnosis can provide information about prognosis of the disease and treatment regimens, as well as the estimation of the likelihood of recurrence.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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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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Section: Follow-up Assessmentscontrasting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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“…For the quantitative analysis, 40 articles [121, were secondarily excluded. Of these, three papers focused on fetal demises or stillbirths [256][257][258], three papers focused on information postmortem [242,250,254], three were case reports [238,246,252], five focused on a single specific phenotype [240,241,248,261,274], three presented inhomogeneity in inclusion criteria and chromosomal anomalies/CNV assessment [239,251,262], six included both fetuses and postnatal cases [244,249,253,259,260,269], three focused on candidate genes [243,247,263], three focused on recurrent phenotypes or previously described cohorts [245,255,272], five were excluded for the lack of inclusion or eligibility criteria [264,265,268,271,276], two were excluded for the higher a priori risk for consanguinity and recurrence [266,270], one because parents were tested for recessive disorders [267], two because they focused on gene panels [273,275], and one due to the postnatal diagnosis [121].…”

Section: Exome Sequencingmentioning

confidence: 99%

Molecular Approaches in Fetal Malformations, Dynamic Anomalies and Soft Markers: Diagnostic Rates and Challenges—Systematic Review of the Literature and Meta-Analysis

et al. 2022

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Fetal malformations occur in 2–3% of pregnancies. They require invasive procedures for cytogenetics and molecular testing. “Structural anomalies” include non-transient anatomic alterations. “Soft markers” are often transient minor ultrasound findings. Anomalies not fitting these definitions are categorized as “dynamic”. This meta-analysis aims to evaluate the diagnostic yield and the rates of variants of uncertain significance (VUSs) in fetuses undergoing molecular testing (chromosomal microarray (CMA), exome sequencing (ES), genome sequencing (WGS)) due to ultrasound findings. The CMA diagnostic yield was 2.15% in single soft markers (vs. 0.79% baseline risk), 3.44% in multiple soft markers, 3.66% in single structural anomalies and 8.57% in multiple structural anomalies. Rates for specific subcategories vary significantly. ES showed a diagnostic rate of 19.47%, reaching 27.47% in multiple structural anomalies. WGS data did not allow meta-analysis. In fetal structural anomalies, CMA is a first-tier test, but should be integrated with karyotype and parental segregations. In this class of fetuses, ES presents a very high incremental yield, with a significant VUSs burden, so we encourage its use in selected cases. Soft markers present heterogeneous CMA results from each other, some of them with risks comparable to structural anomalies, and would benefit from molecular analysis. The diagnostic rate of multiple soft markers poses a solid indication to CMA.

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“…The spectrum of the diagnoses that do not belong to the FDH is quite similar to that previously reported in literature. 20,[31][32][33][34] Some skeletal dysplasias, such as achondroplasia, are often diagnosed later in pregnancy. 35 Therefore, in these skeletal dysplasias, prenatal diagnostic methods are rarely of use in the management of pregnancy.…”

Section: Casementioning

confidence: 99%

Genetic spectrum of prenatally diagnosed skeletal dysplasias in a Finnish patient cohort

et al. 2022

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Objective: This retrospective cohort study aims to describe the genetic spectrum of fetal skeletal dysplasias detected in a Finnish patient cohort and the diagnostic yield of various analysis methods used. Method:A total of 121 pregnancies with prenatally suspected or diagnosed skeletal dysplasia were analyzed between 2013 and 2020. Clinical details and findings from genetic testing were collected.Results: Abnormal ultrasound triggered further testing in most cases. However, there were several cases with increased nuchal translucency and/or abnormal risk ratio in the first trimester combined screening as the initial finding. Further genetic testing was performed in 84/121 (69.4%) cases. A genetic diagnosis was confirmed in 36/84 (42.9%) cases. Half of the identified cases could be attributed to a founder mutation specific to the Finnish Disease Heritage, whereas the other half consisted of a variety of other genetic defects. Conclusion:In our patient cohort, the overall genetic spectrum of prenatally diagnosed skeletal dysplasias was wide. However, the impact of Finnish founder mutations was considerable, suggesting that the genetic spectrum of skeletal dysplasias may differ significantly between populations. This should be taken into consideration during the diagnostic process especially as initial ultrasound findings may be unspecific and the interpretation of ultrasound features is usually difficult. Key points What's already known about this topic?� Prenatal diagnosis of skeletal dysplasia is challenging and broader diagnostic methods have increased the diagnostic yield. In addition to well-described ultrasound findings, increased nuchal translucency and/or abnormal first trimester combined screening could indicate skeletal disease.Katri Rajala and Ellamaija Kasanen contributed equally to this work and should be considered as joint first authors.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Whole Exome Sequencing Aids the Diagnosis of Fetal Skeletal Dysplasia

Cited by 11 publications

References 41 publications

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

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

Molecular Approaches in Fetal Malformations, Dynamic Anomalies and Soft Markers: Diagnostic Rates and Challenges—Systematic Review of the Literature and Meta-Analysis

Genetic spectrum of prenatally diagnosed skeletal dysplasias in a Finnish patient cohort

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