Genetic Analysis in Fetal Skeletal Dysplasias by Trio Whole-Exome Sequencing

Yang, Kai; Shen, Ming; Yan, Yousheng; Tan, Ya; Zhang, Jing; Wu, Jue; Yang, Guangming; Li, Shang; Wang, Jing; Ren, Zhuo; Dong, Zhe; Wang, Shan; Zhang, Manli; Tian, Yaping

doi:10.1155/2019/2492590

Cited by 39 publications

(43 citation statements)

References 31 publications

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“…Due to the strong clinical and genetic heterogeneities, searching for the causative mutations of skeletal dysplasia remains a task with big challenges. With the advance of next-generation sequencing (NGS) technology, attempts have been made to implement and apply it to offer a comprehensive strategy in clinical practice (Liu et al, 2019;Yang et al, 2019). In the current study, through integration of WES and molecular analyses, we identified novel pathogenic compound mutations in patients affected with OI: a splicing error-causing mutation (NM_006371.4:c.1153-3C > G) and a large deletion in the CRTAP gene (hg19, chr3:g.32398837_34210906del).…”

Section: Discussionmentioning

confidence: 99%

Novel Compound Heterozygous Mutations in CRTAP Cause Rare Autosomal Recessive Osteogenesis Imperfecta

et al. 2020

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Whole-exome sequencing (WES) has advantages over the traditional molecular test by screening 20,000 genes simultaneously and has become an invaluable tool for genetic diagnosis in clinical practice. Here, we reported a family with a child and a fetus presenting undiagnosed skeletal dysplasia phenotypes, while the parents were asymptomatic. WES was applied to the parents and affected fetus to identify the genetic cause of the phenotypes. We identified novel compound heterozygous mutations consisting of a single-nucleotide variant (SNV) and a large deletion in the CRTAP gene (NM_006371.4:c.1153-3C > G/hg19 chr3:g.32398837_34210906del). Genetic alterations of CRTAP are known to cause osteogenesis imperfecta (OI) in an autosomal recessive manner. Further examination of the proband's elder sibling who was diagnosed as OI after birth found that she shares the inherited compound heterozygous mutations of CRTAP; thus, the findings support the disease-causing role of CRTAP mutations. Through the in vitro molecular test and in silico analysis, the deleterious effects of the splicing-altering SNV in CRTAP (c.1153-3C > G) on gene product were confirmed. Collectively, our WES-based pathogenic variant discovery pipeline identifies the SNVs and copy number variation to delineate the genetic cause on the proband affected with OI. The data not only extend the knowledge of mutation spectrum in patients with skeletal dysplasia but also demonstrate that WES holds great promise for genetic screening of rare diseases in clinical settings.

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Section: Discussionmentioning

confidence: 99%

Novel Compound Heterozygous Mutations in CRTAP Cause Rare Autosomal Recessive Osteogenesis Imperfecta

et al. 2020

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“…After induced abortion, more DNA was extracted from umbilical cord sample and then used for WES detection. DNA fragments hybridization (by IDT’s xGen Exome Research Panel, Integrated DNA Technologies), library quality testing, and WES sequencing (using Novaseq6000 platform, Illumina) were performed as described in our previous study . Sanger sequencing was used to verify the variation of suspected pathogenicity.…”

Section: Methodsmentioning

confidence: 99%

Whole‐exome sequencing identified compound heterozygous variants in ROR2 gene in a fetus with Robinow syndrome

Yang

Zhu

Tan

et al. 2019

Clinical Laboratory Analysis

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Background Autosomal recessive Robinow syndrome (ARRS) is a rare genetic disorder, which affects the development of multiple systems, particularly the bones. Objectives The aim of this study was to investigate the genetic cause of a ARRS fetus and to evaluate the reliability of whole‐exome sequencing (WES) in prenatal diagnosis on cases with indistinguishable multiple malformation. Methods Clinical and ultrasonic evaluations were conducted on the fetus, and multiplatform genetic techniques were used to identify the variation responsible for RS. The pathogenicity of the novel variation was evaluated by in silico methods. Western blotting (WB) and immunohistochemistry (IHC) were performed on fetal tissues after the fetus' stillbirth and postabortal autopsy. Results A compound heterozygous variation consisting c.613C > T and c.904C > T in ROR2 gene was identified. In silico prediction suggested that c.904C > T was a deleterious variant. IHC result demonstrated that ror2 expression level of the proband in osteochondral tissue significantly increased comparing with that of the control sample. Conclusions For the first time in Chinese population, we characterized a novel variation in ROR2 gene causing ARRS. This study extended the mutation spectrum of ARRS and provided a promising strategy for prenatal diagnosis of cases with ambiguous multiple deformities.

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“…Genomic DNA samples were extracted from chorionic villi, amniocytes, fetal tissues or parental blood using a Qiagen DNA Blood Midi/Mini kit (Qiagen GmbH, Hilden, Germany) following the manufacturer's protocol. Then WES was performed according to the published paper 5 . And data was analyzed on the Cruxome system developed by Berry Genomics.…”

Section: Whole Exome Sequencingmentioning

confidence: 99%

Clinical utility of whole exome sequencing in the prenatal diagnosis with fetuses at risk

Zhu¹,

Liu²,

Zhao³

et al. 2020

Preprint

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Purpose: To investigate the clinical utility of whole exome sequencing (WES) in the prenatal diagnosis with fetuses at risk and variation information identified by WES. Methods: WES was conducted for 40 families with clinical informed consent, and the overall diagnosis rate and performance in different subgroups were analyzed. Genetic variants identified by ES were assessed according to the Mendelian model of inheritance. Results: Of the 40 prenatal specimens, there were 28 cases of amniotic fluid, 6 cases of villi and 6 cases of fetal tissues. And the average gestational age was 19.5±4.8 weeks. It revealed that a total of 8 pathogenic / likely pathogenic variants were detected which likely to be associated with the observed fetal anomalies, and the diagnosis rate was 20% (8/40). Among them, the detection rate of fetal ultrasound abnormal group could be up to 60% (6/10). All 8 diagnosed cases had inherited the relevant variants (5 variants were autosomal recessively inherited and 3 were dominantly inherited disorders). Conclusion: The application of whole exome sequencing to prenatal diagnosis can improve the clinical diagnosis rate. WES has the potential to improve the clinical management of pregnancies and provide risk of recurrence in future pregnancies. However, further investigation was needed to maximize clinical usefulness of prenatal WES in the future.

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Genetic Analysis in Fetal Skeletal Dysplasias by Trio Whole-Exome Sequencing

Cited by 39 publications

References 31 publications

Novel Compound Heterozygous Mutations in CRTAP Cause Rare Autosomal Recessive Osteogenesis Imperfecta

Novel Compound Heterozygous Mutations in CRTAP Cause Rare Autosomal Recessive Osteogenesis Imperfecta

Whole‐exome sequencing identified compound heterozygous variants in ROR2 gene in a fetus with Robinow syndrome

Clinical utility of whole exome sequencing in the prenatal diagnosis with fetuses at risk

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