Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing

2019 ◽  
Vol 56 (6) ◽  
pp. 396-407 ◽  
Author(s):  
Kazuhiro Iwama ◽  
Takeshi Mizuguchi ◽  
Eri Takeshita ◽  
Eiji Nakagawa ◽  
Tetsuya Okazaki ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rett Syndrome ◽  
De Novo ◽  
Diagnostic Yield ◽  
Single Nucleotide Variants ◽  
Serine Threonine Kinase ◽  
Whole Exome ◽  
Genetic Landscape ◽  
Strong Candidate

BackgroundRett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 (MECP2). Our objective to investigate the genetic landscape of MECP2-negative typical/atypical RTT and RTT-like phenotypes using whole exome sequencing (WES).MethodsWe performed WES on 77 MECP2-negative patients either with typical RTT (n=11), atypical RTT (n=22) or RTT-like phenotypes (n=44) incompatible with the RTT criteria.ResultsPathogenic or likely pathogenic single-nucleotide variants in 28 known genes were found in 39 of 77 (50.6%) patients. WES-based CNV analysis revealed pathogenic deletions involving six known genes (including MECP2) in 8 of 77 (10.4%) patients. Overall, diagnostic yield was 47 of 77 (61.0 %). Furthermore, strong candidate variants were found in four novel genes: a de novo variant in each of ATPase H+ transporting V0 subunit A1 (ATP6V0A1), ubiquitin-specific peptidase 8 (USP8) and microtubule-associated serine/threonine kinase 3 (MAST3), as well as biallelic variants in nuclear receptor corepressor 2 (NCOR2).ConclusionsOur study provides a new landscape including additional genetic variants contributing to RTT-like phenotypes, highlighting the importance of comprehensive genetic analysis.

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

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 Identification of de novo mutations for ARID1B haploinsufficiency associated with Coffin–Siris syndrome 1 in three Chinese families via array-CGH and whole exome sequencing

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Guanting Lu ◽  
Qiongling Peng ◽  
Lianying Wu ◽  
Jian Zhang ◽  
Liya Ma
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Array Cgh ◽  
De Novo ◽  
Current Knowledge ◽  
Comparative Genomic ◽  
De Novo Mutations ◽  
Single Nucleotide Variants ◽  
Whole Exome

Abstract Background Coffin–Siris syndrome (CSS) is a multiple malformation syndrome characterized by intellectual disability associated with coarse facial features, hirsutism, sparse scalp hair, and hypoplastic or absent fifth fingernails or toenails. CSS represents a small group of intellectual disability, and could be caused by at least twelve genes. The genetic background is quite heterogenous, making it difficult for clinicians and genetic consultors to pinpoint the exact disease types. Methods Array-Comparative Genomic Hybridization (array-CGH) and whole exome sequencing (WES) were applied for three trios affected with intellectual disability and clinical features similar with those of Coffin–Siris syndrome. Sanger sequencing was used to verify the detected single-nucleotide variants (SNVs). Results All of the three cases were female with normal karyotypes of 46, XX, born of healthy, non-consanguineous parents. A 6q25 microdeletion (arr[hg19]6q25.3(155,966,487–158,803,979) × 1) (2.84 Mb) (case 1) and two loss-of-function (LoF) mutations of ARID1B [c.2332 + 1G > A in case 2 and c.4741C > T (p.Q1581X) in case 3] were identified. All of the three pathogenic abnormalities were de novo, not inherited from their parents. After comparison of publicly available microdeletions containing ARID1B, four types of microdeletions leading to insufficient production of ARID1B were identified, namely deletions covering the whole region of ARID1B, deletions covering the promoter region, deletions covering the termination region or deletions covering enhancer regions. Conclusion Here we identified de novo ARID1B mutations in three Chinese trios. Four types of microdeletions covering ARID1B were identified. This study broadens current knowledge of ARID1B mutations for clinicians and genetic consultors.

scholarly journals Whole exome sequencing identifies genomic alterations in proximal and distal colorectal cancer

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Ryia-Illani Mohd Yunos ◽  
Nurul-Syakima Ab Mutalib ◽  
Sheau Sean Khor ◽  
Sazuita Saidin ◽  
Mohd Ridhwan Abd Razak ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Anatomical Location ◽  
Single Nucleotide Variants ◽  
Functional Studies ◽  
Whole Exome ◽  
Genetic Landscape ◽  
Ion Proton ◽  
Pi3k Signalling

Majority of colorectal cancer (CRC) patients are presented with advanced disease at diagnosis, particularly in cases of proximal CRCs. Little is known about the relationship between the genetic landscape and the anatomical location of the tumour; as well as the prognostication in CRC patients. The objectives of this study were to determine the somatic single nucleotide variants (SNV) and the cellular pathways between the proximal and distal CRCs. Whole exome sequencing was performed on the Ion Proton platform on 10 pairs of normal and CRC samples. The sequencing results were analysed using the Torrent Suite Software and the variants were annotated using ANNOVAR; followed by validation with Sanger sequencing. APC is the most frequently altered gene in both proximal and distal CRCs. KRAS and ATM genes were particularly altered in the proximal CRCs with a frequency of 60% and 40%, respectively. On the other hand, TP53 mutations did not show any CRC anatomical predominance. There were five recurrent novel variants in proximal CRCs and no recurrent variants identified in distal CRC. Wnt signalling pathway was the most frequently altered pathway in both proximal and distal CRCs whereas TGF-? and PI3K signalling pathways were predominantly altered in the proximal CRCs. We found that proximal CRCs presented with more variants and different altered pathways as compared to distal CRCs. However, further study in a larger series of samples coupled with functional studies will be required to confirm the identified variants and determine their roles in the pathogenesis of proximal and distal CRCs.

scholarly journals Application of Trio-Whole Exome Sequencing in Genetic Diagnosis and Therapy in Chinese Children With Epilepsy

2021 ◽  
Vol 14 ◽  
Author(s):  
Tiejia Jiang ◽  
Jia Gao ◽  
Lihua Jiang ◽  
Lu Xu ◽  
Congying Zhao ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Copy Number ◽  
Pediatric Patients ◽  
De Novo ◽  
Treatment Options ◽  
Copy Number Variants ◽  
Genetic Diagnosis ◽  
Single Nucleotide Variants ◽  
Whole Exome

Epilepsy is one of the most common neurological disorders in pediatric patients with other underlying neurological defects. Identifying the underlying etiology is crucial for better management of the disorder. We performed trio-whole exome sequencing in 221 pediatric patients with epilepsy. Probands were divided into seizures with developmental delay/intellectual disability (DD/ID) and seizures without DD/ID groups. Pathogenic (P) or likely pathogenic (LP) variants were identified in 71/110 (64.5%) patients in the seizures with DD/ID group and 21/111 (18.9%) patients in the seizures without DD/ID group (P < 0.001). Eighty-seven distinct P/LP single nucleotide variants (SNVs)/insertion deletions (Indels) were detected, with 55.2% (48/87) of them being novel. All aneuploidy and P/LP copy number variants (CNVs) larger than 100 Kb were identifiable by both whole-exome sequencing and copy number variation sequencing (CNVseq) in 123 of individuals (41 pedigrees). Ten of P/LP CNVs in nine patients and one aneuploidy variant in one patient (Patient #56, #47, XXY) were identified by CNVseq. Herein, we identified seven genes (NCL, SEPHS2, PA2G4, SLC35G2, MYO1C, GPR158, and POU3F1) with de novo variants but unknown pathogenicity that were not previously associated with epilepsy. Potential effective treatment options were available for 32 patients with a P/LP variant, based on the molecular diagnosis. Genetic testing may help identify the molecular etiology of early onset epilepsy and DD/ID and further aid to choose the appropriate treatment strategy for patients.

scholarly journals Clinical efficiency of simultaneous CNV-seq and whole-exome sequencing for testing fetal structural anomalies

2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Xinlin Chen ◽  
Yulin Jiang ◽  
Ruiguo Chen ◽  
Qingwei Qi ◽  
Xiujuan Zhang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Diagnostic Yield ◽  
Turnaround Time ◽  
Hubei Province ◽  
World Health ◽  
Fetal Anomaly ◽  
Whole Exome ◽  
Structural Anomalies

Abstract Background Birth defects are responsible for approximately 7% of neonatal deaths worldwide by World Health Organization in 2004. Many methods have been utilized for examining the congenital anomalies in fetuses. This study aims to investigate the efficiency of simultaneous CNV-seq and whole-exome sequencing (WES) in the diagnosis of fetal anomaly based on a large Chinese cohort. Methods In this cohort study, 1800 pregnant women with singleton fetus in Hubei Province were recruited from 2018 to 2020 for prenatal ultrasonic screening. Those with fetal structural anomalies were transferred to the Maternal and Child Health Hospital of Hubei Province through a referral network in Hubei, China. After multidisciplinary consultation and decision on fetal outcome, products of conception (POC) samples were obtained. Simultaneous CNV-seq and WES was conducted to identify the fetal anomalies that can compress initial DNA and turnaround time of reports. Results In total, 959 couples were finally eligible for the enrollment. A total of 227 trios were identified with a causative alteration (CNV or variant), among which 191 (84.14%) were de novo. Double diagnosis of pathogenic CNVs and variants have been identified in 10 fetuses. The diagnostic yield of multisystem anomalies was significantly higher than single system anomalies (32.28% vs. 22.36%, P  = 0.0183). The diagnostic rate of fetuses with consistent intra- and extra-uterine phenotypes (172/684) was significantly higher than the rate of these with inconsistent phenotypes (17/116, P  = 0.0130). Conclusions Simultaneous CNV-seq and WES analysis contributed to fetal anomaly diagnosis and played a vital role in elucidating complex anomalies with compound causes.

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 One test for all: whole exome sequencing significantly improves the diagnostic yield in growth retarded patients referred for molecular testing for Silver–Russell syndrome

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Robert Meyer ◽  
Matthias Begemann ◽  
Christian Thomas Hübner ◽  
Daniela Dey ◽  
Alma Kuechler ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Uniparental Disomy ◽  
Molecular Testing ◽  
Main Body ◽  
Comprehensive Overview ◽  
Maternal Uniparental Disomy ◽  
Whole Exome ◽  
Silver Russell Syndrome

Abstract Background Silver-Russell syndrome (SRS) is an imprinting disorder which is characterised by severe primordial growth retardation, relative macrocephaly and a typical facial gestalt. The clinical heterogeneity of SRS is reflected by a broad spectrum of molecular changes with hypomethylation in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat) as the most frequent findings. Monogenetic causes are rare, but a clinical overlap with numerous other disorders has been reported. However, a comprehensive overview on the contribution of mutations in differential diagnostic genes to phenotypes reminiscent to SRS is missing due to the lack of appropriate tests. With the implementation of next generation sequencing (NGS) tools this limitation can now be circumvented. Main body We analysed 75 patients referred for molecular testing for SRS by a NGS-based multigene panel, whole exome sequencing (WES), and trio-based WES. In 21/75 patients a disease-causing variant could be identified among them variants in known SRS genes (IGF2, PLAG1, HMGA2). Several patients carried variants in genes which have not yet been considered as differential diagnoses of SRS. Conclusions WES approaches significantly increase the diagnostic yield in patients referred for SRS testing. Several of the identified monogenetic disorders have a major impact on clinical management and genetic counseling.

scholarly journals Exome sequencing in paediatric patients with movement disorders

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Anna Ka-Yee Kwong ◽  
Mandy Ho-Yin Tsang ◽  
Jasmine Lee-Fong Fung ◽  
Christopher Chun-Yu Mak ◽  
Kate Lok-San Chan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Movement Disorders ◽  
Rare Variants ◽  
Diagnostic Yield ◽  
Neurological Diseases ◽  
Genetic Diagnosis ◽  
Potential Treatment ◽  
Paediatric Patients ◽  
Whole Exome

Abstract Background Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. Results We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. Conclusions A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management. The study highlights the potential of implementing precision medicine in the patients.

scholarly journals A domestic cat whole exome sequencing resource for trait discovery

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alana R. Rodney ◽  
Reuben M. Buckley ◽  
Robert S. Fulton ◽  
Catrina Fronick ◽  
Todd Richmond ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Diseases ◽  
Domestic Cat ◽  
Whole Genome Sequence ◽  
Exome Capture ◽  
Single Nucleotide Variants ◽  
Whole Exome ◽  
Olfactory Receptor Genes ◽  
Feline Model

AbstractOver 94 million domestic cats are susceptible to cancers and other common and rare diseases. Whole exome sequencing (WES) is a proven strategy to study these disease-causing variants. Presented is a 35.7 Mb exome capture design based on the annotated Felis_catus_9.0 genome assembly, covering 201,683 regions of the cat genome. Whole exome sequencing was conducted on 41 cats with known and unknown genetic diseases and traits, of which ten cats had matching whole genome sequence (WGS) data available, used to validate WES performance. At 80 × mean exome depth of coverage, 96.4% of on-target base coverage had a sequencing depth > 20-fold, while over 98% of single nucleotide variants (SNVs) identified by WGS were also identified by WES. Platform-specific SNVs were restricted to sex chromosomes and a small number of olfactory receptor genes. Within the 41 cats, we identified 31 previously known causal variants and discovered new gene candidate variants, including novel missense variance for polycystic kidney disease and atrichia in the Peterbald cat. These results show the utility of WES to identify novel gene candidate alleles for diseases and traits for the first time in a feline model.

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