scholarly journals Identification of a Novel De Novo Variant in the PAX3 Gene in Waardenburg Syndrome by Diagnostic Exome Sequencing: The First Molecular Diagnosis in Korea

2015 ◽  
Vol 35 (3) ◽  
pp. 362-365 ◽  
Author(s):  
Mi-Ae Jang ◽  
Taeheon Lee ◽  
Junnam Lee ◽  
Eun-Hae Cho ◽  
Chang-Seok Ki
Keyword(s):  
Exome Sequencing ◽  
Molecular Diagnosis ◽  
De Novo ◽  
Waardenburg Syndrome ◽  
Pax3 Gene ◽  
De Novo Variant

scholarly journals DeNovoCNN: A deep learning approach to de novo variant calling in next generation sequencing data

2021 ◽  
Author(s):  
Gelana Khazeeva ◽  
Karolis Sablauskas ◽  
Bart van der Sanden ◽  
Wouter Steyaert ◽  
Michael Kwint ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
De Novo ◽  
Genetic Disorders ◽  
Variant Calling ◽  
Next Generation Sequencing Data ◽  
Sequencing Data ◽  
Accurate Identification ◽  
Whole Exome ◽  
De Novo Variant ◽  
Generation Sequencing

De novo mutations (DNMs) are an important cause of genetic disorders. The accurate identification of DNMs from sequencing data is therefore fundamental to rare disease research and diagnostics. Unfortunately, identifying reliable DNMs remains a major challenge due to sequence errors, uneven coverage, and mapping artifacts. Here, we developed a deep convolutional neural network (CNN) DNM caller (DeNovoCNN), that encodes alignment of sequence reads for a trio as 160×164 resolution images. DeNovoCNN was trained on DNMs of whole exome sequencing (WES) of 2003 trios achieving on average 99.2% recall and 93.8% precision. We find that DeNovoCNN has increased recall/sensitivity and precision compared to existing de novo calling approaches (GATK, DeNovoGear, Samtools) based on the Genome in a Bottle reference dataset. Sanger validations of DNMs called in both exome and genome datasets confirm that DeNovoCNN outperforms existing methods. Most importantly, we show that DeNovoCNN is robust against different exome sequencing and analyses approaches, thereby allowing it to be applied on other datasets. DeNovoCNN is freely available and can be run on existing alignment (BAM/CRAM) and variant calling (VCF) files from WES and WGS without a need for variant recalling.

scholarly journals Genetic background of ataxia in children younger than 5 years in Finland

2020 ◽  
Vol 6 (4) ◽  
pp. e444
Author(s):  
Erika Ignatius ◽  
Pirjo Isohanni ◽  
Max Pohjanpelto ◽  
Päivi Lahermo ◽  
Simo Ojanen ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Molecular Diagnosis ◽  
Genetic Background ◽  
De Novo ◽  
Substantial Contribution ◽  
Considerable Proportion ◽  
Genotyping Array ◽  
Genome Wide ◽  
A Genome ◽  
Tertiary Center

ObjectiveTo characterize the genetic background of molecularly undefined childhood-onset ataxias in Finland.MethodsThis study examined a cohort of patients from 50 families with onset of an ataxia syndrome before the age of 5 years collected from a single tertiary center, drawing on the advantages offered by next generation sequencing. A genome-wide genotyping array (Illumina Infinium Global Screening Array MD-24 v.2.0) was used to search for copy number variation undetectable by exome sequencing.ResultsExome sequencing led to a molecular diagnosis for 20 probands (40%). In the 23 patients examined with a genome-wide genotyping array, 2 additional diagnoses were made. A considerable proportion of probands with a molecular diagnosis had de novo pathogenic variants (45%). In addition, the study identified a de novo variant in a gene not previously linked to ataxia: MED23. Patients in the cohort had medically actionable findings.ConclusionsThere is a high heterogeneity of causative mutations in this cohort despite the defined age at onset, phenotypical overlap between patients, the founder effect, and genetic isolation in the Finnish population. The findings reflect the heterogeneous genetic background of ataxia seen worldwide and the substantial contribution of de novo variants underlying childhood ataxia.

An Activating Variant in CTNNB1 is Associated with a Sclerosing Bone Dysplasia and Adrenocortical Neoplasia

2020 ◽  
Vol 105 (3) ◽  
pp. 688-695 ◽  
Author(s):  
Hui Peng ◽  
Zandra A Jenkins ◽  
Ruby White ◽  
Sam Connors ◽  
Matthew F Hunter ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Bone Development ◽  
Bone Dysplasia ◽  
Adrenocortical Adenoma ◽  
Gain Of Function ◽  
Sclerosing Bone Dysplasia ◽  
Whole Exome ◽  
De Novo Variant

Abstract Context The WNT/β-catenin pathway is central to the pathogenesis of various human diseases including those affecting bone development and tumor progression. Objective To evaluate the role of a gain-of-function variant in CTNNB1 in a child with a sclerosing bone dysplasia and an adrenocortical adenoma. Design Whole exome sequencing with corroborative biochemical analyses. Patients We recruited a child with a sclerosing bone dysplasia and an adrenocortical adenoma together with her unaffected parents. Intervention Whole exome sequencing and performance of immunoblotting and luciferase-based assays to assess the cellular consequences of a de novo variant in CTNNB1. Main Outcome Measure(s)/Result A de novo variant in CTNNB1 (c.131C>T; p.[Pro44Leu]) was identified in a patient with a sclerosing bone dysplasia and an adrenocortical adenoma. A luciferase-based transcriptional assay of WNT signaling activity verified that the activity of β-catenin was increased in the cells transfected with a CTNNB1p.Pro44Leu construct (P = 4.00 × 10–5). The β-catenin p.Pro44Leu variant was also associated with a decrease in phosphorylation at Ser45 and Ser33/Ser37/Thr41 in comparison to a wild-type (WT) CTNNB1 construct (P = 2.16 × 10–3, P = 9.34 × 10–8 respectively). Conclusion Increased β-catenin activity associated with a de novo gain-of-function CTNNB1 variant is associated with osteosclerotic phenotype and adrenocortical neoplasia.

scholarly journals P.131 De novo PIK3CB mutation associated with macrocephaly and diffuse polymicrogyria

2018 ◽  
Vol 45 (s2) ◽  
pp. S51-S51
Author(s):  
KD Kernohan ◽  
HJ McMillan ◽  
A McBride ◽  
T Hartley ◽  
DA Dyment ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Developmental Delay ◽  
De Novo ◽  
Periventricular White Matter ◽  
Pik3ca Mutations ◽  
Functional Studies ◽  
Signal Abnormality ◽  
Complex Functions ◽  
Severe Hypotonia ◽  
De Novo Variant

Background: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB) is a member of the PI3K complex. This complex has two p110 members; PIK3CA (p110a) and PIK3CB (p110b) which are both ubiquitously expressed. PI3K complex functions to phosphorylate PIP2 to PIP3 which activates AKT and subsequently mTOR. PIK3CA mutations have been previously linked with macrocephaly and developmental delay. Methods: An 18 month old girl was investigated for severe hypotonia, developmental delay and macrocephaly. Head circumference was >97%ile at birth and 53.0 cm (>99%ile, +5.4 SD) at 13 months old. She had no hydrocephalus or epilepsy. MRI brain (18 months old) re-identified megalencephaly and diffuse polymicrogyria. Symmetric signal abnormality was noted in the periventricular white matter, unchanged between 8 and 18 month images. MR spectroscopy was unrevealing. At 18 months she remains unable to sit independently. Exome sequencing was performed and functional studies to further support variant pathogenicity. Results: Exome sequencing identified de novo variant in PIK3CB: c.1735G>T; p.Asp579Tyr. No mutations were noted in other genes known to cause developmental delay, macrocephaly or overgrowth syndromes. Functional studies in patient cells showed dysregulation of PIK3CB and downstream signalling, providing support for causality of this novel disease gene. Conclusions: We believe that our patient’s macrocephaly (+5.4 SD) and diffuse polymicrogyria results from altered PIK3CB function.

scholarly journals Whole-Exome Sequencing Identifies One De Novo Variant in the FGD6 Gene in a Thai Family with Autism Spectrum Disorder

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Chuphong Thongnak ◽  
Areerat Hnoonual ◽  
Duangkamol Tangviriyapaiboon ◽  
Suchaya Silvilairat ◽  
Apichaya Puangpetch ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Bioinformatics Pipeline ◽  
Whole Exome ◽  
De Novo Variant ◽  
Genetic Analyzer

Autism spectrum disorder (ASD) has a strong genetic basis, although the genetics of autism is complex and it is unclear. Genetic testing such as microarray or sequencing was widely used to identify autism markers, but they are unsuccessful in several cases. The objective of this study is to identify causative variants of autism in two Thai families by using whole-exome sequencing technique. Whole-exome sequencing was performed with autism-affected children from two unrelated families. Each sample was sequenced on SOLiD 5500xl Genetic Analyzer system followed by combined bioinformatics pipeline including annotation and filtering process to identify candidate variants. Candidate variants were validated, and the segregation study with other family members was performed using Sanger sequencing. This study identified a possible causative variant for ASD, c.2951G>A, in the FGD6 gene. We demonstrated the potential for ASD genetic variants associated with ASD using whole-exome sequencing and a bioinformatics filtering procedure. These techniques could be useful in identifying possible causative ASD variants, especially in cases in which variants cannot be identified by other techniques.

Early Infantile Epileptic Encephalopathy with a de novo variant in ZEB2 identified by exome sequencing

2016 ◽  
Vol 59 (2) ◽  
pp. 70-74 ◽  
Author(s):  
Natalia Babkina ◽  
Joshua L. Deignan ◽  
Hane Lee ◽  
Eric Vilain ◽  
Raman Sankar ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
De Novo ◽  
Epileptic Encephalopathy ◽  
De Novo Variant

scholarly journals New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing

2021 ◽  
Vol 22 (24) ◽  
pp. 13439
Author(s):  
Lucia Pia Bruno ◽  
Gabriella Doddato ◽  
Floriana Valentino ◽  
Margherita Baldassarri ◽  
Rossella Tita ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Molecular Diagnosis ◽  
De Novo ◽  
Genetic Locus ◽  
Autism Spectrum ◽  
Bioinformatic Tools ◽  
Pathogenic Variants ◽  
Whole Exome

Intellectual disability (ID) is characterized by impairments in the cognitive processes and in the tasks of daily life. It encompasses a clinically and genetically heterogeneous group of neurodevelopmental disorders often associated with autism spectrum disorder (ASD). Social and communication abilities are strongly compromised in ASD. The prevalence of ID/ASD is 1–3%, and approximately 30% of the patients remain without a molecular diagnosis. Considering the extreme genetic locus heterogeneity, next-generation sequencing approaches have provided powerful tools for candidate gene identification. Molecular diagnosis is crucial to improve outcome, prevent complications, and hopefully start a therapeutic approach. Here, we performed parent–offspring trio whole-exome sequencing (WES) in a cohort of 60 mostly syndromic ID/ASD patients and we detected 8 pathogenic variants in genes already known to be associated with ID/ASD (SYNGAP1, SMAD6, PACS1, SHANK3, KMT2A, KCNQ2, ACTB, and POGZ). We found four de novo disruptive variants of four novel candidate ASD/ID genes: MBP, PCDHA1, PCDH15, PDPR. We additionally selected via bioinformatic tools many variants in unknown genes that alone or in combination can contribute to the phenotype. In conclusion, our data confirm the efficacy of WES in detecting pathogenic variants of known and novel ID/ASD genes.

De Novo variant in GNB2 associated with neurodevelopmental disease

2021 ◽  
Vol 132 ◽  
pp. S282
Author(s):  
Florencia del Viso ◽  
Lisa Lansdon ◽  
Emily Fleming ◽  
Bonnie Sullivan ◽  
Carol Saunders
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disease ◽  
De Novo Variant

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.

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