scholarly journals Simultaneous Detection of CNVs and SNVs Improves the Diagnostic Yield of Fetuses with Ultrasound Anomalies and Normal Karyotypes

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1397
Author(s):  
Qingwei Qi ◽  
Yulin Jiang ◽  
Xiya Zhou ◽  
Hua Meng ◽  
Na Hao ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Diagnostic Yield ◽  
Simultaneous Detection ◽  
Genetic Diagnosis ◽  
Copy Number Variations ◽  
Molecular Diagnostic ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Single Nucleotide Variants ◽  
Sequential Approach

The routine assessment to determine the genetic etiology for fetal ultrasound anomalies follows a sequential approach, which usually takes about 6–8 weeks turnaround time (TAT). We evaluated the clinical utility of simultaneous detection of copy number variations (CNVs) and single nucleotide variants (SNVs)/small insertion-deletions (indels) in fetuses with a normal karyotype with ultrasound anomalies. We performed CNV detection by chromosomal microarray analysis (CMA) or low pass CNV-sequencing (CNV-seq), and in parallel SNVs/indels detection by trio-based clinical exome sequencing (CES) or whole exome sequencing (WES). Eight-three singleton pregnancies with a normal fetal karyotype were enrolled in this prospective observational study. Pathogenic or likely pathogenic variations were identified in 30 cases (CNVs in 3 cases, SNVs/indels in 27 cases), indicating an overall molecular diagnostic rate of 36.1% (30/83). Two cases had both a CNV of uncertain significance (VOUS) and likely pathogenic SNV, and one case carried both a VOUS CNV and an SNV. We demonstrated that simultaneous analysis of CNVs and SNVs/indels can improve the diagnostic yield of prenatal diagnosis with shortened reporting time, namely, 2–3 weeks. Due to the relatively long TAT for sequential procedure for prenatal genetic diagnosis, as well as recent sequencing technology advancements, it is clinically necessary to consider the simultaneous evaluation of CNVs and SNVs/indels to enhance the diagnostic yield and timely TAT, especially for cases in the late second trimester or third trimester.

scholarly journals Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder

JAMA ◽  
2015 ◽  
Vol 314 (9) ◽  
pp. 895 ◽  
Author(s):  
Kristiina Tammimies ◽  
Christian R. Marshall ◽  
Susan Walker ◽  
Gaganjot Kaur ◽  
Bhooma Thiruvahindrapuram ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Molecular Diagnostic ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Whole Exome

scholarly journals Exome Sequencing Identifies a c.148-1G>C Mutation of TBX5 in a Holt-Oram Family with Unusual Genotype-Phenotype Correlations

2015 ◽  
Vol 37 (3) ◽  
pp. 1066-1074 ◽  
Author(s):  
Qianqian Guo ◽  
Jia Shen ◽  
Yang Liu ◽  
Tian Pu ◽  
Kun Sun ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Heart Defects ◽  
Direct Sequencing ◽  
Splice Acceptor Site ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Acceptor Site ◽  
Single Nucleotide Variants ◽  
Site Mutation ◽  
Nonsense Mediated Decay

Background/Aims: Congenital heart defects (CHD) can occur with upper limbs deformities. Holt-Oram syndrome is the main type of heart-hand syndromes, characterized by upper limb radial ray malformations, CHD and/or conduction abnormalities. Mutations of the TBX5 gene, most of which are found within the T-box domain, are one cause of the disease. We aimed to find the cause of the disease in a family with two children exhibiting symptoms of Holt-Oram syndrome while the parents tend to be normal. Methods: Chromosomal microarray analysis and exome sequencing were applied in the proband segments bearing the specific mutation and single nucleotide variants (SNVs) suspected of being involved in the disease were analyzed by polymerase chain reaction and direct sequencing. Results: A splice acceptor site mutation c.148-1G>C of TBX5 was detected in both the father and the proband. The mutation may result in an aberrant transcript which will most probably undergo nonsense-mediated decay (NMD) system resulting in haploinsufficiency of TBX5 protein. In the meantime, 3 candidated SNVs were detected. Conclusions: c.148-1G>C of TBX5 should be the pathogenic cause of the disease in this family. Works have been done to find a possible explanation of the unusual genotype-phenotype correlations in this family and further studies are still needed.

scholarly journals The genetic landscape of intellectual disability and epilepsy in adults and the elderly: a systematic genetic work-up of 150 individuals

2021 ◽  
Author(s):  
Pia Zacher ◽  
Thomas Mayer ◽  
Frank Brandhoff ◽  
Tobias Bartolomaeus ◽  
Diana Le Duc ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Diagnostic Yield ◽  
Fragile X ◽  
Genetic Diagnostics ◽  
High Yield ◽  
Chromosomal Microarray ◽  
Limited Information ◽  
Single Nucleotide Variants ◽  
Elderly Individuals

Abstract Purpose Genetic diagnostics of neurodevelopmental disorders with epilepsy (NDDE) are predominantly applied in children, thus limited information is available regarding adults or elderly. Methods We investigated 150 adult/elderly individuals with NDDE by conventional karyotyping, FMR1 testing, chromosomal microarray, panel sequencing, and for unresolved cases, also by exome sequencing (nsingle = 71, ntrios = 24). Results We identified (likely) pathogenic variants in 71 cases (47.3%) comprising fragile X syndrome (n = 1), disease-causing copy number (n = 23), and single-nucleotide variants (n = 49). Seven individuals displayed multiple independent genetic diagnoses. The diagnostic yield correlated with the severity of intellectual disability. Individuals with anecdotal evidence of exogenic early-life events (e.g., nuchal cord, complications at delivery) with alleged/unproven association to the disorder had a particularly high yield of 58.3%. Screening for disease-specific comorbidities was indicated in 45.1% and direct treatment consequences arose in 11.8% of diagnosed individuals. Conclusion Panel/exome sequencing displayed the highest yield and should be considered as first-tier diagnostics in NDDE. This high yield and the numerous indications for additional screening or treatment modifications arising from genetic diagnoses indicate a current medical undersupply of genetically undiagnosed adult/elderly individuals with NDDE. Moreover, knowledge of the course of elderly individuals will ultimately help in counseling newly diagnosed individuals with NDDE.

scholarly journals High Detection Rate of Copy Number Variations Using Capture Sequencing Data: A Retrospective Study

2020 ◽  
Vol 66 (3) ◽  
pp. 455-462 ◽  
Author(s):  
Yu Sun ◽  
Xiantao Ye ◽  
Yanjie Fan ◽  
Lili Wang ◽  
Xiaomei Luo ◽  
...  
Keyword(s):  
Copy Number ◽  
Diagnostic Yield ◽  
Copy Number Variations ◽  
Systematic Evaluation ◽  
High Yield ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Large Sample Size ◽  
Analytical Sensitivity ◽  
Capture Sequencing

Abstract Background Capture sequencing (CS) is widely applied to detect small genetic variations such as single nucleotide variants or indels. Algorithms based on depth comparison are becoming available for detecting copy number variation (CNV) from CS data. However, a systematic evaluation with a large sample size has not been conducted to evaluate the efficacy of CS-based CNV detection in clinical diagnosis. Methods We retrospectively studied 3010 samples referred to our diagnostic laboratory for CS testing. We used 68 chromosomal microarray analysis–positive samples (true set [TS]) and 1520 reference samples to build a robust CS-CNV pipeline. The pipeline was used to detect candidate clinically relevant CNVs in 1422 undiagnosed samples (undiagnosed set [UDS]). The candidate CNVs were confirmed by an alternative method. Results The CS-CNV pipeline detected 78 of 79 clinically relevant CNVs in TS samples, with analytical sensitivity of 98.7% and positive predictive value of 49.4%. Candidate clinically relevant CNVs were identified in 106 UDS samples. CNVs were confirmed in 96 patients (90.6%). The diagnostic yield was 6.8%. The molecular etiology includes aneuploid (n = 7), microdeletion/microduplication syndrome (n = 40), and Mendelian disorders (n = 49). Conclusions These findings demonstrate the high yield of CS-based CNV. With further improvement of our CS-CNV pipeline, the method may have clinical utility for simultaneous evaluation of CNVs and small variations in samples referred for pre- or postnatal analysis.

scholarly journals Exome sequencing as a first-tier test for copy number variant detection : retrospective evaluation and prospective screening in 2418 cases.

2021 ◽  
Author(s):  
Quentin TESTARD ◽  
Xavier VANHOYE ◽  
Laure RAYMOND ◽  
Jean-Francois TALY ◽  
Marie-Emmanuelle NAUD-BARREYRE ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Copy Number ◽  
Diagnostic Yield ◽  
Incidental Finding ◽  
Copy Number Variant ◽  
Chronic Kidney Failure ◽  
Copy Number Variations ◽  
Chromosomal Microarray ◽  
Diagnostic Work ◽  
Work Up

Purpose: Despite exome (ES) or genome sequencing (GS) availability, chromosomal microarray (CMA) remains the first-line diagnostic tests in most rare disorders diagnostic work-up, looking for Copy-number variations (CNV), with a diagnostic yield of 10-20%. The question of the equivalence of CMA and ES in CNV calling is an organisational and economic question, especially when ordering a GS after a negative CMA and/or ES. Methods: This work measures the equivalence between CMA and GATK4 exome sequencing depth of coverage method in detecting coding CNV on a retrospective cohort of 615 unrelated individuals. A prospective detection of ES CNV on a cohort of 1803 unrelated individuals was performed. Results: On the retrospective validation cohort every CNV was accurately detected (64/64 events). In the prospective cohort, 32 diagnostics were performed among the 1803 individuals with CNVs ranging from 704bp to aneuploidy. An incidental finding was reported. The overall increase in diagnostic yield was of 1.7%, varying from 1.2% in individuals with multiple congenital anomalies to 1.9% in individuals with chronic kidney failure. Conclusions: Combining SNV and CNV detection increases the suitability of exome sequencing as a first-tier diagnostic test for suspected rare mendelian disorders. Before considering the prescription of a GS after a negatif ES, a careful reanalysis with updated CNV calling and SNV annotation should be considered.

Abstract 11800: Whole Exome Sequencing in a Large Pedigree With DCM Identifies a Novel Mutation in RBM20

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Tomas Robyns ◽  
Johan Van Cleemput ◽  
Rik Willems ◽  
Shalini Jhangiani ◽  
Donna Muzny ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Scoring System ◽  
Diagnostic Yield ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Single Nucleotide Variants ◽  
Large Pedigree ◽  
Whole Exome

Background and hypothesis: Familial dilated cardiomyopathy (DCM) is genetically heterogeneous and is associated with mutations in at least 30 different genes. None of these genes have an expected diagnostic yield of more than 10% complicating genetic diagnosis. Whole exome sequencing (WES) is a powerful alternative for the identification of the causal gene, however variant interpretation remains challenging. We performed WES in a large family with autosomal dominant DCM complicated by end stage heart failure and ventricular arrhythmias. The index of this family was evaluated previously by means of targeted gene panel analysis including 28 genes, but no causal mutation was found. Methods and results: WES was applied on 2 affected cousins. First, shared heterozygous variants (single nucleotide variants, small insertions and deletions) located inside the exon or at the exon/intron boundary were selected. Synonymous variants were excluded, except if they were located at the exon/intron boundaries. Variants with a minor allele frequency of >0.1% in publically available exome databases (1000 Genomes and ESP) were excluded. Furthermore, variants that were present in an in-house exome cohort performed for other disease entities were also excluded since these probably represent local SNV’s. The remaining 19 variants were evaluated using a comprehensive scoring system that includes different in-silico analysis tools, orthologous and paralogous conservation and population frequencies. Subsequently Sanger sequencing was performed for 10 variants that were classified as likely pathogenic (N=1) or variants of unknown significance (N=9) according to the scoring system in order to confirm the presence of the variant and to evaluate co-segregation. Only one variant in exon 9 of the RBM20 gene (c.2714T>A, p.Met950Lys, NM_001334363) showed full co-segregation in the 7 affected family members resulting in a maximum 2-point LOD score of 2.1 and suggesting this as the pathogenic mutation responsible for the phenotype. Recently mutations in RBM20 have been linked to dilated cardiomyopathy caused by defective splicing of the giant sarcomeric protein titin. Conclusions: We report the identification of a novel mutation in RBM20 by WES in a large pedigree with DCM.

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 Targeted Exome Sequencing Provided Comprehensive Genetic Diagnosis of Congenital Anomalies of the Kidney and Urinary Tract

2020 ◽  
Vol 9 (3) ◽  
pp. 751 ◽  
Author(s):  
Yo Han Ahn ◽  
Chung Lee ◽  
Nayoung K. D. Kim ◽  
Eujin Park ◽  
Hee Gyung Kang ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Exome Sequencing ◽  
Congenital Anomalies ◽  
Genetic Diagnosis ◽  
Copy Number Variations ◽  
Single Nucleotide Variants ◽  
Korean Children ◽  
Targeted Exome Sequencing ◽  
Genetic Causes ◽  
Pathogenic Variants

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. The search for genetic causes of CAKUT has led to genetic diagnosis in approximately 5–20 % of CAKUT patients from Western countries. In this study, genetic causes of CAKUT in Korean children were sought using targeted exome sequencing (TES) of 60 genes reported to cause CAKUT in human or murine models. We identified genetic causes in 13.8% of the 94 recruited patients. Pathogenic single nucleotide variants of five known disease-causing genes, HNF1B, PAX2, EYA1, UPK3A, and FRAS1 were found in 7 cases. Pathogenic copy number variations of 6 patients were found in HNF1B, EYA1, and CHD1L. Genetic abnormality types did not significantly differ according to CAKUT phenotypes. Patients with pathogenic variants of targeted genes had syndromic features more frequently than those without (p < 0.001). This is the first genetic analysis study of Korean patients with CAKUT. Only one-seventh of patients were found to have pathogenic mutations in known CAKUT-related genes, indicating that there are more CAKUT-causing genes or environmental factors to discover.

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