scholarly journals Case Report: Prenatal Whole-Exome Sequencing to Identify a Novel Heterozygous Synonymous Variant in NIPBL in a Fetus With Cornelia de Lange Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Fengchang Qiao ◽  
Cuiping Zhang ◽  
Yan Wang ◽  
Gang Liu ◽  
Binbin Shao ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Cornelia De Lange Syndrome ◽  
Splice Donor Site ◽  
Synonymous Mutations ◽  
Craniofacial Dysmorphism ◽  
Whole Exome ◽  
Synonymous Variant ◽  
Cornelia De Lange

Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder characterized by a wide spectrum of abnormalities, including craniofacial dysmorphism, upper limb anomalies, pre- and post-natal growth restrictions, hirsutism and intellectual disability. Approximately 60% of cases are caused by NIPBL variants. Herein we report on a prenatal case presented with bilateral upper-extremity malformations and cardiac defects. Whole-exome sequencing (WES) was performed on the fetus–parental trio and a de novo heterozygous synonymous variant in NIPBL [chr5:37020979; NM_133433.4: c.5328G>A, p. (Gln1776=)] was identified. Reverse transcriptase–polymerase chain reaction (RT–PCR) was conducted to evaluate the potential splicing effect of this variant, which confirmed that the variant caused a deletion of exon 27 (103 bp) by disrupting the splice-donor site and changed the reading frame with the insertion of at least three stop codons. Our finding not only expands the mutation spectrum of NIPBL gene but also establishes the crucial role of WES in searching for underlying genetic variants. In addition, our research raises the important issue that synonymous mutations may be potential pathogenic variants and should not be neglected in clinical diagnoses.

scholarly journals De novo NIPBL Mutations in Vietnamese Patients with Cornelia de Lange Syndrome

Medicina ◽  
2020 ◽  
Vol 56 (2) ◽  
pp. 76
Author(s):  
Duong Chi Thanh ◽  
Can Thi Bich Ngoc ◽  
Ngoc-Lan Nguyen ◽  
Chi Dung Vu ◽  
Nguyen Van Tung ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Cornelia De Lange Syndrome ◽  
Heterozygous Mutation ◽  
Body Parts ◽  
Efficient Tool ◽  
Whole Exome ◽  
Cornelia De Lange ◽  
In Silico Analyses

Cornelia de Lange Syndrome (CdLS) is a rare congenital genetic disease causing abnormal unique facial phenotypes, several defects in organs and body parts, and mental disorder or intellectual disorder traits. Main causes of CdLS have been reported as variants in cohesin complex genes, in which mutations in the NIPBL gene have been estimated to account for up to 80%. Our study included three Vietnamese patients with typical CdLS phenotypes. Whole exome sequencing revealed two known heterozygous mutations c.6697G>A (p.Val2233Met) and c.2602C>T (p.Arg868X), and a novel heterozygous mutation c.4504delG (p.Val1502fsX87) in the NIPBL gene of the three patients. In silico analyses of the identified mutations predicted possible damaging and truncating effects on the NIPBL protein. Inherited analyses in the patients’ families showed that all of the mutations are de novo. Our results lead a definitive diagnosis of patients with CdLS and expand the spectrum of mutations in the NIPBL gene. These findings also confirm whole exome sequencing is an efficient tool for genetic screening of CdLS.

scholarly journals Patients Carrying 9q31.1-q32 Deletion Share Common Features with Cornelia de Lange Syndrome

2015 ◽  
Vol 35 (1) ◽  
pp. 270-280 ◽  
Author(s):  
Ruixue Cao ◽  
Tian Pu ◽  
Shaohai Fang ◽  
Fei Long ◽  
Jing Xie ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Limb Development ◽  
Cornelia De Lange Syndrome ◽  
Pcr Analysis ◽  
Cgh Array ◽  
Whole Exome ◽  
Cornelia De Lange ◽  
Development Objectives ◽  
Structural Maintenance Of Chromosomes

Background: Cornelia de Lange Syndrome (CdLS) is a rare but severe clinically heterogeneous developmental disorder characterized by facial dysmorphia, growth and cognitive retardation, and abnormalities of limb development. Objectives: To determine the pathogenesis of a patient with CdLS. Methods: We studied a patient with CdLS by whole exome sequencing, karyotyping and Agilent CGH Array. The results were confirmed by quantitative real-time PCR analysis of the patient and her parents. Further comparison of our patient and cases with partially overlapping deletions retrieved from the literature and databases was undertaken. Results: Whole exome sequencing had excluded the mutation of cohesion genes such as NIPBL,SMC1A and SMC3. The result of karyotyping showed a deletion of chromosome 9q31.1-q32 and the result of Agilent CGH Array further displayed a 12.01-Mb region of deletion at chromosome bands 9q31.1-q32. Reported cases with the deletion of 9q31.1-q32 share similar features with our CdLS patient. One of the genes in the deleted region, SMC2, belongs to the Structural Maintenance of Chromosomes (SMC) family and regulates gene expression and DNA repair. Conclusions: Patients carrying the deletion of 9q31.1-q32 showed similar phenotypes with CdLS.

scholarly journals A New Mutation Identified by Whole Exome Sequencing in a Cornelia de Lange Syndrome Newborn

2018 ◽  
Vol 131 (19) ◽  
pp. 2384-2385
Author(s):  
Hua Zhang ◽  
Li-Ming Yang ◽  
Lu Yuan ◽  
Xin Tan ◽  
Fu-Qing Zhang
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Cornelia De Lange Syndrome ◽  
New Mutation ◽  
Whole Exome ◽  
Cornelia De Lange

scholarly journals Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

2021 ◽  
Author(s):  
Adam L. Numis ◽  
Gilberto da Gente ◽  
Elliott H. Sherr ◽  
Hannah C. Glass
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
List Type ◽  
Sequencing Analysis ◽  
Neonatal Seizures ◽  
Pathogenic Variants ◽  
Targeted Analysis ◽  
Whole Exome ◽  
Epilepsy Gene

Abstract Background The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known. Methods Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches. Results Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy. Conclusions In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy. Impact We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

scholarly journals Analysis workflow to assess de novo genetic variants from human whole-exome sequencing

2021 ◽  
Vol 2 (1) ◽  
pp. 100383
Author(s):  
Nicholas S. Diab ◽  
Spencer King ◽  
Weilai Dong ◽  
Garrett Allington ◽  
Amar Sheth ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Variants ◽  
De Novo ◽  
Whole Exome ◽  
Analysis Workflow

scholarly journals Whole Exome Sequencing in Coloboma/Microphthalmia: Identification of Novel and Recurrent Variants in Seven Genes

Genes ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 65
Author(s):  
Patricia Haug ◽  
Samuel Koller ◽  
Jordi Maggi ◽  
Elena Lang ◽  
Silke Feil ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Screening ◽  
De Novo ◽  
Efficient Tool ◽  
Sequencing Technologies ◽  
Whole Exome ◽  
Screening And Identification ◽  
High Throughput Dna Sequencing ◽  
New Mutations

Coloboma and microphthalmia (C/M) are related congenital eye malformations, which can cause significant visual impairment. Molecular diagnosis is challenging as the genes associated to date with C/M account for only a small percentage of cases. Overall, the genetic cause remains unknown in up to 80% of patients. High throughput DNA sequencing technologies, including whole-exome sequencing (WES), are therefore a useful and efficient tool for genetic screening and identification of new mutations and novel genes in C/M. In this study, we analyzed the DNA of 19 patients with C/M from 15 unrelated families using singleton WES and data analysis for 307 genes of interest. We identified seven novel and one recurrent potentially disease-causing variants in CRIM1, CHD7, FAT1, PTCH1, PUF60, BRPF1, and TGFB2 in 47% of our families, three of which occurred de novo. The detection rate in patients with ocular and extraocular manifestations (67%) was higher than in patients with an isolated ocular phenotype (46%). Our study highlights the significant genetic heterogeneity in C/M cohorts and emphasizes the diagnostic power of WES for the screening of patients and families with C/M.

Whole exome sequencing identifies FOXL2, FOXA2 and FOXA3 as candidate genes for monogenic congenital anomalies of the kidneys and urinary tract

2021 ◽  
Author(s):  
Bixia Zheng ◽  
Steve Seltzsam ◽  
Chunyan Wang ◽  
Luca Schierbaum ◽  
Sophia Schneider ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Exome Sequencing ◽  
Candidate Genes ◽  
Whole Exome Sequencing ◽  
Congenital Anomalies ◽  
De Novo ◽  
Horseshoe Kidney ◽  
Missense Variant ◽  
Whole Exome ◽  
Fox Genes

Abstract Background Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the most common cause of chronic kidney disease in the first three decades of life. Variants in four Forkhead box (FOX) transcription factors have been associated with CAKUT. We hypothesized that other FOX genes, if highly expressed in developing kidney, may also represent monogenic causes of CAKUT. Methods We here performed whole exome sequencing (WES) in 541 families with CAKUT and generated 4 lists of CAKUT candidate genes: A) 36 FOX genes showing high expression during renal development, B) 4 FOX genes known to cause CAKUT to validate list A; C) 80 genes that we identified as unique potential novel CAKUT candidate genes when performing WES in 541 CAKUT families, and D) 175 genes identified from WES as multiple potential novel CAKUT candidate genes. Results To prioritize potential novel CAKUT candidates in FOX gene family, we overlapped 36 FOX genes (list A) with list C and D of WES-derived CAKUT candidates. Intersection with list C, identified a de novo FOXL2 in-frame deletion in a patient with eyelid abnormalities and ureteropelvic junction obstruction, and a homozygous FOXA2 missense variant in a patient with horseshoe kidney. Intersection with list D, identified a heterozygous FOXA3 missense variant in a CAKUT family with multiple affected individuals. Conclusion We hereby identified FOXL2, FOXA2 and FOXA3 as novel monogenic candidate genes of CAKUT, supporting the utility of a paralog-based approach to discover mutated genes associated with human disease.

scholarly journals Whole exome sequencing reveals a de novo missense variant in EEF1A2 in a Rett syndrome‐like patient

2019 ◽  
Vol 7 (12) ◽  
pp. 2476-2482 ◽  
Author(s):  
Simranpreet Kaur ◽  
Nicole J. Van Bergen ◽  
Wendy Anne Gold ◽  
Stefanie Eggers ◽  
Sebastian Lunke ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rett Syndrome ◽  
De Novo ◽  
Missense Variant ◽  
Whole Exome

scholarly journals Identification of a β-Arrestin 2 Mutation Related to Autism by Whole-Exome Sequencing

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Yunfei Tang ◽  
Yamei Liu ◽  
Lei Tong ◽  
Shini Feng ◽  
Dongshu Du ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Developmental Stages ◽  
De Novo ◽  
Repetitive Behavior ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Potential Contribution ◽  
De Novo Mutations ◽  
Whole Exome

Autism spectrum disorder (ASD) is a complex neurological disease characterized by impaired social communication and interaction skills, rigid behavior, decreased interest, and repetitive activities. The disease has a high degree of genetic heterogeneity, and the genetic cause of ASD in many autistic individuals is currently unclear. In this study, we report a patient with ASD whose clinical features included social interaction disorder, communication disorder, and repetitive behavior. We examined the patient’s genetic variation using whole-exome sequencing technology and found new de novo mutations. After analysis and evaluation, ARRB2 was identified as a candidate gene. To study the potential contribution of the ARRB2 gene to the human brain development and function, we first evaluated the expression profile of this gene in different brain regions and developmental stages. Then, we used weighted gene coexpression network analysis to analyze the associations between ARRB2 and ASD risk genes. Additionally, the spatial conformation and stability of the ARRB2 wild type and mutant proteins were examined by simulations. Then, we further established a mouse model of ASD. The results showed abnormal ARRB2 expression in the mouse ASD model. Our study showed that ARRB2 may be a risk gene for ASD, but the contribution of de novo ARRB2 mutations to ASD is unclear. This information will provide references for the etiology of ASD and aid in the mechanism-based drug development and treatment.

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