Prenatal diagnosis of fetal skeletal dysplasia using targeted next-generation sequencing: an analysis of 30 cases

Liu, Yan; Wang, Li; Yang, Yong; Zhang, Tie-Juan; Liang, Na; Yang, Liang; Li, Sijing; Shan, Dan

doi:10.1186/s13000-019-0853-x

Cited by 44 publications

(39 citation statements)

References 37 publications

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“…Thirty-one studies published prenatal analysis by WES with the diagnostic rates between 6.2% and 80% [4]. Notably, the application of targeted exome sequencing in prenatal diagnosis of skeletal dysplasia is outstanding as several researches have reported high detection rates from 75% to 83.3% [5][6][7][8]. De nitive molecular diagnosis can provide accurate results instead of a suspected clinical impression and information about subsequent development of the disease and treatmentregimens, thus parents get consultation and birth defect intervention could be implemented.…”

Section: Introductionmentioning

confidence: 99%

Whole Exome Sequencing Aids The Diagnosis of Fetal Skeletal Dysplasia

Tang

Zhang

Yin

et al. 2020

Preprint

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Background: Skeletal dysplasia is a complex group of bone and cartilage disorders with strong clinical and genetical heterogeneousity. Several types have prenatal phenotypes. And it is difficult to make a molecular diagnosis rapidly due to lacking family history and non-specific and limited clinical symptoms in utero. This study aims to diagnose 16 Chinese fetuses with skeletal dysplasia.Methods: Single nucleotide polymorphism-array (SNP-array) was performed in 12 of 16 samples. If no microdeletions or microreplications related to skeletal dysplasia were detected, whole-exome sequencing (WES) was adopted. And the last four cases only got whole-exome sequencing for analyzing copy number variants and single nucleotide variations at the same time.Results: Among the 16 cases, 12 patients received definitive diagnosis and we detected one deletion in DMD gene by SNP-array and 15 variants of 6 genes including FGFR3, COL1A1, COL1A2, ALPL, HSPG2 and DYNC2H1. 8 variants of COL1A1, COL1A2, ALPL and HSPG2 are novel. And somatic mosaicism in asymptomatic parent with mutations in COL1A1 or COL1A2 was observed.Conclusions: In general, our study expanded the prenatal phenotypes in Duchenne muscular dystrophy (DMD)/ Becker muscular dystrophy (BMD), found 8 novel variants and elucidated that the utilization of whole-exome sequencing improved the diagnosis yield of skeletal dysplasia and provided useful genetic counseling guidance for parents.

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Section: Introductionmentioning

confidence: 99%

Whole Exome Sequencing Aids The Diagnosis of Fetal Skeletal Dysplasia

Tang

Zhang

Yin

et al. 2020

Preprint

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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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“…This encodes the γ subunit of nicotinic receptors. Most studies have indicated an association of the subunit with skeletal muscle disorders [47][48][49][50]. However, King et al [16] found the association of polymorphisms in this gene with nausea in varenicline treatment.…”

Section: Discussionmentioning

confidence: 99%

Profile of the Nicotinic Cholinergic Receptor Alpha 7 Subunit Gene Expression is Associated with Response to Varenicline Treatment

Santos

Tomaz

Scholz

et al. 2020

Genes

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Introduction: Smoking is considered the leading cause of preventable morbidity and mortality worldwide. Studies have sought to identify predictors of response to smoking cessation treatments. The aim of this study was to analyze a possible association of target gene expression for smoking cessation with varenicline. Methods: We included 74 smokers starting treatment with varenicline. Gene expression analysis was performed through the custom RT² Profiler qPCR array assay, including 17 genes. Times for sample collection were before the start of therapy (T0) and two weeks (T2) and four weeks (T4) after the start of treatment. Results: For gene expression analysis, we selected 14 patients who had success and 13 patients resistant to varenicline treatment. Success was considered to be when a patient achieved tobacco abstinence until the fourth week of treatment and resistant was when a patient had not stopped smoking as of the fourth week of treatment. We observed a significant difference for CHRNA7 gene expression: in the resistant group, samples from T2 and T4 had lower expression compared with T0 (fold change: 0.38, P = 0.007; fold change: 0.67, P = 0.004; respectively). Conclusion: This exploratory clinical study, searching for a possible predictor of effectiveness for varenicline, reaffirmed the association of the α7 nAChR subunit for nicotine dependence and smoking therapy effectiveness with varenicline.

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Prenatal diagnosis of fetal skeletal dysplasia using targeted next-generation sequencing: an analysis of 30 cases

Cited by 44 publications

References 37 publications

Whole Exome Sequencing Aids The Diagnosis of Fetal Skeletal Dysplasia

Whole Exome Sequencing Aids The Diagnosis of Fetal Skeletal Dysplasia

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

Profile of the Nicotinic Cholinergic Receptor Alpha 7 Subunit Gene Expression is Associated with Response to Varenicline Treatment

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