The Promise of Whole-exome Sequencing for Prenatal Genetic Diagnosis

2020 ◽  
Vol 17 (1) ◽  
pp. 25-31
Author(s):  
Jiun Kang
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Disorders ◽  
Genetic Diagnosis ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Prognostic Information ◽  
Prenatal Genetic Diagnosis ◽  
Whole Exome ◽  
Nextgeneration Sequencing

Prenatal genetic diagnosis provides information for pregnancy and perinatal decision- making and management. Cytogenetic testing methods, including chromosomal microarray analysis and gene panels, have evolved to become a part of routine laboratory testing, providing valuable diagnostic and prognostic information for prenatal diagnoses. Despite this progress, however, cytogenetic analyses are limited by their resolution and diagnosis is only possible in around 40% of the dysmorphic fetuses. The advent of nextgeneration sequencing (NGS), whole-genome sequencing or whole-exome sequencing has revolutionized prenatal diagnosis and fetal medicine. These technologies have improved the identification of genetic disorders in fetuses with structural abnormalities and provide valuable diagnostic and prognostic information for the detection of genomic defects. Here, the potential future of prenatal genetic diagnosis, including a move toward NGS technologies, is discussed.

scholarly journals Mosaic duplication of 8q24.1q24.3 detected by chromosomal microarray but not karyotyping in two unrelated fetuses with cardiac defects

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Shaobin Lin ◽  
Shufang Huang ◽  
Xueling Ou ◽  
Heng Gu ◽  
Yonghua Wang ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Copy Number ◽  
Genetic Disorders ◽  
Genetic Diagnosis ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Cardiac Defects ◽  
Prenatal Genetic Diagnosis ◽  
Tumor Tissues ◽  
Number Variation

Abstract Background Discordance between traditional cytogenetic and molecular cytogenetic tests is rare but not uncommon. The explanation of discordance between two genetic methods is difficult but especially important for genetic counseling, particularly for prenatal genetic diagnosis. Case presentation Two unrelated fetuses were diagnosed with cardiac defects by prenatal ultrasound examination, and invasive cordocentesis was performed to obtain cord blood samples for prenatal genetic diagnosis. For both fetuses, chromosomal microarray analysis (CMA) detected a novel approximately 27-Mb mosaic duplication with a high copy number of approximately six to seven copies on chromosome 8q24.1q24.3 that was not identified by karyotyping. To exclude artificial errors and validate laboratory detection results, multiple procedures including copy number variation sequencing, fluorescence in situ hybridization, and short tandem repeat and single-nucleotide polymorphism genotype comparison were performed, confirming the discordant results between CMA and karyotyping. The potential causes of discordance between CMA and karyotyping using fetal blood lymphocytes are discussed; we suggest that extrachromosomal DNA or cell-free DNA fragmentation originating from certain tumor tissues with 8q24.1q24.3 duplication might deserve further investigation. Conclusions This study may be helpful for prenatal evaluation and genetic counseling for subsequent patients with similar mosaic 8q24.1q24.3 duplications. Additionally, more cases and further research are needed to understand whether mosaic 8q24.1q24.3 duplication is associated with certain genetic disorders and to investigate the causes of discordance between molecular and morphological methods.

scholarly journals The Added Value of Whole-Exome Sequencing for Anomalous Fetuses With Detailed Prenatal Ultrasound and Postnatal Phenotype

2021 ◽  
Vol 12 ◽  
Author(s):  
Miao He ◽  
Liu Du ◽  
Hongning Xie ◽  
Lihe Zhang ◽  
Yujun Gu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Variants ◽  
Genetic Diagnosis ◽  
Normal Karyotype ◽  
Copy Number Variations ◽  
Prenatal Ultrasound ◽  
Added Value ◽  
Chromosomal Microarray Analysis ◽  
Whole Exome

ObjectivesThe objective of the study was to explore the added value of whole-exome sequencing (WES) in abnormal fetuses with detailed prenatal ultrasound and postnatal phenotype with normal karyotype and chromosomal microarray analysis (CMA).MethodsParents of fetuses with structural abnormalities by prenatal ultrasound who consented to provide fetal samples were prospectively recruited from January 2017 to December 2019. With aneuploidies or cases with copy number variations (CNVs) excluded, WES was performed for cases with normal karyotype and CMA results. Detailed prenatal ultrasound and postnatal imaging or pathology features were recommended for further interpretation of genetic variants.ResultsWES was performed for 94 eligible fetuses, DNA samples of which were extracted from 53 parent–fetus trios and 41 proband-only fetal tissues. A diagnostic genetic variant was identified in 37 (39.4%) of 94 fetuses, and 34 (64.2%) were detected in 53 trios, which was significantly greater than 3 (7.3%) in 41 proband-only cases (p < 0.001). In 34 trios with diagnostic genetic variants, 23 (67.6%) were de novo and 11 (32.4%) were inherited with two homozygous and nine heterozygous variants. Fourteen (14.9%) of 94 fetuses had a variant of uncertain significance (VUS). Among 94 cases, six affected pregnancies continued and 88 terminated, and 57 of 88 terminated cases underwent postmortem examinations. With accurate phenotypes demonstrated by prenatal ultrasound and postnatal autopsies, the clinical phenotypes were correlated in 33 (89.2%) of 37 cases with specific genotypes, with the highest matching ratio in skeletal diseases (20/33, 60.6%).ConclusionWES has added value in the genetic diagnosis of abnormal fetuses with normal karyotypes and CMA, particularly in skeletal diseases. Using WES in various anomalous fetuses can broaden the understanding of prenatal phenotypes and genetic variants.

scholarly journals Whole Exome Sequencing Facilitated the Identification of a Mosaic Small Supernumerary Marker Chromosome (sSMC)

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Huan-xia Xing ◽  
Peng-bin Li ◽  
Li-min Cui ◽  
Jian-ye Jiang ◽  
Ning-ning Hu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Extended Family ◽  
Phenotypic Variability ◽  
Marker Chromosome ◽  
Chromosome 8 ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Chromosomal Anomalies ◽  
Whole Exome

Small supernumerary marker chromosomes (sSMCs) are a group of rare chromosomal anomalies, which pose challenges in the clinical practice of prenatal diagnosis and genetic counseling. This study enrolled an extended family with an underage male patient displaying infantile seizures, intellectual disability, and retarded speech and psychomotor function. A series of multiplatform genetic detections was conducted to explore the diagnostic variation. Whole exome sequencing (WES) and chromosomal microarray analysis (CMA) indicated a mosaic sSMC derived from the pericentromeric region of chromosome 8 in the patient, which was confirmed using cytogenetic methods. The proband and his mother, who carried this mosaic variant, exhibited strong phenotypic variability. We also ruled out the pathogenicity of a KDM5C variant by extended validation. Our results emphasized the capacity of WES to detect mosaic SMCs and the importance of mosaic ratios in the appearance and severity of symptomatic phenotypes.

scholarly journals Towards a Change in the Diagnostic Algorithm of Autism Spectrum Disorders: Evidence Supporting Whole Exome Sequencing as a First-Tier Test

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 560
Author(s):  
Ana Arteche-López ◽  
Maria José Gómez Rodríguez ◽  
Maria Teresa Sánchez Calvin ◽  
Juan Francisco Quesada-Espinosa ◽  
Jose Miguel Lezana Rosales ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Genetic Diagnosis ◽  
Diagnostic Algorithm ◽  
Autism Spectrum ◽  
Chromosomal Microarray ◽  
De Novo Mutations ◽  
Whole Exome

Autism spectrum disorder (ASD) is a prevalent and extremely heterogeneous neurodevelopmental disorder (NDD) with a strong genetic component. In recent years, the clinical relevance of de novo mutations to the aetiology of ASD has been demonstrated. Current guidelines recommend chromosomal microarray (CMA) and a FMR1 testing as first-tier tests, but there is increasing evidence that support the use of NGS for the diagnosis of NDDs. Specifically in ASD, it has not been extensively evaluated and, thus, we performed and compared the clinical utility of CMA, FMR1 testing, and/or whole exome sequencing (WES) in a cohort of 343 ASD patients. We achieved a global diagnostic rate of 12.8% (44/343), the majority of them being characterised by WES (33/44; 75%) compared to CMA (9/44; 20.4%) or FMR1 testing (2/44; 4.5%). Taking into account the age at which genetic testing was carried out, we identified a causal genetic alteration in 22.5% (37/164) of patients over 5 years old, but only in 3.9% (7/179) of patients under this age. Our data evidence the higher diagnostic power of WES compared to CMA in the study of ASD and support the implementation of WES as a first-tier test for the genetic diagnosis of this disorder, when there is no suspicion of fragile X syndrome.

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

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Kai Yang ◽  
Ming Shen ◽  
Yousheng Yan ◽  
Ya Tan ◽  
Jing Zhang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Autosomal Recessive ◽  
Clinical Manifestations ◽  
Autosomal Recessive Inheritance ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Skeletal Dysplasias ◽  
Whole Exome ◽  
Quantitative Fluorescence

Skeletal dysplasias (SDs) comprise a series of severe congenital disorders that have strong clinical heterogeneity and usually attribute to diverse genetic variations. The pathogenesis of more than half of SDs remains unclear. Additionally, the clinical manifestations of fetal SDs are ambiguous, which poses a big challenge for accurate diagnosis. In this study, eight unrelated families with fetal SD were recruited and subjected to sequential tests including chromosomal karyotyping, chromosomal microarray analysis (CMA), and trio whole-exome sequencing (WES). Sanger sequencing and quantitative fluorescence PCR (QF-PCR) were performed as affirmative experiments. In six families, a total of six pathogenic/likely pathogenic variations were identified in four genes including SLC26A2, FGFR3, FLNB, and TMEM38B. These variations caused disorders following autosomal dominant or autosomal recessive inheritance patterns, respectively. The results provided reliable evidence for the subsequent genetic counseling and reproductive options to these families. With its advantage in variation calling and interpreting, trio WES is a promising strategy for the investigation of fetal SDs in cases with normal karyotyping and CMA results. It has considerable prospects to be utilized in prenatal diagnosis.

scholarly journals A Novel Non-frameshift ADA Deletion Detected by Whole Exome Sequencing in an Iranian Family with Severe Combined Immunodeficiency

2020 ◽  
Author(s):  
Taravat Talebi ◽  
Alirezai Biglari ◽  
Mohammad Shahroeei ◽  
Majid Changi-Ashtiani ◽  
Hossein Dinmohammadi ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Novel Mutation ◽  
Genetic Disorders ◽  
Severe Combined Immunodeficiency ◽  
Genetic Diagnosis ◽  
Sample Volume ◽  
Combined Immunodeficiency ◽  
Whole Exome ◽  
And Function

Severe combined immunodeficiency (SCID) comprises a heterogeneous group of genetic disorders caused by early defects in the development and function of T cells. Other lymphocyte lineages (B and/or natural killer cells) are variably affected. With a worldwide frequency of approximately 1:50,000 live births, SCID may result from diverse mutations in over 16 genes. Whole-exome sequencing (WES) provides an opportunity for parallel screening of all those genes. This approach is also useful for genetic diagnosis in parents whose infant expired before genetic testing. Here, we describe a heterozygous novel non-frameshift deletion (c.587_598del p.196_199del) in the adenosine deaminase (ADA) gene identified by WES in healthy parents of an expired child with SCID. The mutation was subsequently confirmed to be homozygous in the deceased baby whose left-over blood sample volume was insufficient for direct WES analysis. In conclusion, we here describe a novel mutation in ADA, a well-known SCID gene.  

scholarly journals The Application of Late Amniocentesis: A Retrospective Study in a Tertiary Fetal Medicine Center in China

2020 ◽  
Author(s):  
Yingting Li ◽  
Huanchen Yan ◽  
Jingsi Chen ◽  
Fei Chen ◽  
Wei Jian ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Copy Number ◽  
Genetic Test ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Test Results ◽  
Whole Exome ◽  
Genetic Test Results

Abstract Background: To assess the indications and complications of late amniocentesis, and the advantage of advanced genetic test results in a tertiary university fetal medical medicine unit.Methods: In this retrospective study, women that underwent amniocentesis at 24+0 to 39+4 weeks, between January 2014 and December 2019, were recruited. Indications, complications, genetic test results, and pregnancy outcomes were reported for each pregnancy. Information was retrieved from patient medical records, checked by research staff, and analyzed. Results: Of the 1277 women (1311 fetuses) included, late detected sonographic abnormalities (86.2%) were the most common indication. The overall preterm birth and intrauterine demise rate were 2.6% and 1.2%, respectively, after amniocentesis. Sixty-six fetuses with aneuploidy (5.1%) and sixty-seven fetuses with pathogenic copy number variations (5.1%) were identified by chromosomal microarray analysis. One pathogenic copy number variation was detected by whole-exome sequencing. The maximal diagnostic yield (36.1%) was in the subgroup of fetuses with the abnormal noninvasive prenatal test, following by multiple abnormalities (23.8%). And 35.8% of the pregnancies were finally terminated.Conclusions: Due to the high detection rates of advanced genetic technologies and safety of the invasive procedure, it is reasonable to recommend late amniocentesis as an effective and credible method to detect late-onset fetal abnormalities. However, chromosomal microarray and whole-exome sequencing may result in uncertain results like variants of uncertain significance. Therefore, comprehensive genetic counseling is necessary.

scholarly journals Utility of Whole-Exome Sequencing in Pediatric and Medical Diagnosis

2020 ◽  
Author(s):  
Mohd Fareed ◽  
Varun Sharma ◽  
Hemender Singh
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Symptoms ◽  
Heart Diseases ◽  
Genetic Disorders ◽  
Single Gene ◽  
Genetic Alterations ◽  
Child Growth ◽  
Chromosomal Microarray ◽  
Whole Exome

Genetic disorders are preeminent determinants of infant mortality. The inherited pediatric-onset genetic disorders have consequential stress on child growth and development: several congenital, complex and rare disorders with indistinguishable clinical symptoms where diagnosis always remains a challenging task. Traditional diagnosis methods include biochemical tests followed by chromosomal microarray and sequencing of a single gene or panel of genes. These methods had several limitations, but with the advent of whole-exome sequencing (WES), genetic testing has become cost-effective and transformative. Exome sequencing has been known for its effectiveness, which appropriately elucidates and distinguishes the heterogeneous disorders to avoid misdiagnosis and decode the underlying genetic alterations. WES has led to discovering genes and genomic variants in a broad spectrum of diseases, including autism, epilepsy, congenital heart diseases, neurodevelopmental diseases, cancer, nephrotic disorders, neural tube defects and fetal structural anomalies. WES is significant in producing immense genomic biomarkers that can be made as appropriate pharmacogenomic targets for drug therapy. In this article, we analyze the recent exploration of WES technology to revolutionize not only the process of genetic variation and disease detection but also the convention of preventative and targeted drug discovery.

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