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 An Unusual Case of Infantile Spasms Due to a Pathogenic Variant in the MECP2 Gene

2019 ◽  
Vol 18 (01) ◽  
pp. 039-044
Author(s):  
Behshad Charkhand ◽  
Natarie Liu ◽  
Karlene T. Barrett ◽  
Walla Al-Hertani ◽  
Morris H. Scantlebury
Keyword(s):  
Unusual Case ◽  
De Novo ◽  
Epileptic Encephalopathy ◽  
Infantile Spasms ◽  
Mecp2 Gene ◽  
Disease Etiology ◽  
Epileptic Spasms ◽  
Uncertain Significance ◽  
Atypical Presentations ◽  
De Novo Variant

AbstractThe infantile spasms (IS) syndrome is a developmental epileptic encephalopathy disorder characterized by epileptic spasms occurring in infancy, hypsarrhythmia on the electroencephalography (EEG) and developmental arrest or regression. The etiologies include structural, metabolic, and genetic causes. We report an unusual case of IS due to a de novo variant in the MECP2 gene. The patient also had variants of uncertain significance in the SCN9A and SCN5A genes inherited from the father and mother, respectively. This report highlights the need for broad genetic testing in MECP2-related disorders with atypical presentations to better understand the disease etiology.

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.

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.

Exome Sequencing Identifying Dual Mutations in Calcium Signaling Genes GNAO1 and ATP2B3 in a Patient with Early Infantile Epileptic Encephalopathy

2016 ◽  
Vol 15 (04) ◽  
pp. 183-186
Author(s):  
Fatema Serajee ◽  
Ahm Huq ◽  
Keisuke Ueda
Keyword(s):  
Calcium Signaling ◽  
Exome Sequencing ◽  
Missense Mutation ◽  
Calcium Homeostasis ◽  
De Novo ◽  
Intractable Epilepsy ◽  
Epileptic Encephalopathy ◽  
Protein Signaling ◽  
Whole Exome ◽  
Spinocerebellar Ataxia 1

Early infantile epileptic encephalopathy (EIEE) is an age-dependent epileptic encephalopathy. It occurs early in life with various types of seizures, especially tonic spasms and its overall prognosis is poor. We report a 5-year-old boy with EIEE, severe developmental delay, intractable epilepsy, and congenital cerebellar ataxia. His infantile spasms were treated successfully with ACTH, but he later developed intractable focal seizures. Whole exome sequencing revealed a maternally inherited missense mutation in the ATP2B3 gene (c.3338C > T/p.T1113M) and a de novo missense mutation in the GNAO1 gene (c.133G > C/p.G45R). Both genes are associated with calcium signaling pathways. The ATP2B3 gene is associated with intracellular calcium clearance, resulting in abnormal calcium homeostasis and X-linked spinocerebellar ataxia-1. The GNAO1 gene is associated with G protein signaling, affecting calcium signaling, and EIEE. Both mutations are related to maintain cellular calcium homeostasis, but the phenotype was not significantly more severe than those which have been reported.

scholarly journals Spectrum of Movement Disorders in GNAO1 Encephalopathy: in-depth Phenotyping and Literature Review

2020 ◽  
Author(s):  
Soo Yeon Kim ◽  
YoungKyu Shim ◽  
Young Joon Ko ◽  
Soojin Park ◽  
Se Song Jang ◽  
...  
Keyword(s):  
Literature Review ◽  
Exome Sequencing ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
Pathogenic Variants ◽  
Whole Exome

Abstract Background GNAO1 encephalopathy is a rare neurodevelopmental disorder characterized by distinct movement presentations and early onset epileptic encephalopathy. Here, we report the in-depth phenotyping of genetically confirmed patients with GNAO1 encephalopathy, focusing on movement presentations. Results Six patients who participated in Korean Undiagnosed Disease Program were diagnosed to have pathogenic or likely pathogenic variants in GNAO1 using whole exome sequencing. All medical records and personal video clips were analyzed with a literature review. Three of the 6 patients were male. Mean follow-up duration was 39 months (range, 7–78 months) and age at last examination was 8.0 years (range, 3.3–16.9 years). Initial complaints were hypotonia or developmental delay in 5 and right-hand clumsiness in 1 patient, which were noticed at 20 months of age on average (range, 0–75 months). All patients showed global developmental delay and 4 had severely retarded development. Five patients (5/6, 83.3%) had many different movement symptoms with various onset and progression. The symptoms included stereotyped hands movement, non-epileptic myoclonus, dyskinesia, dystonia and choreoathetosis. Whole exome sequencing identified 6 different variants in GNAO1. Three were novel de novo variants and atypical presentation was noted in a patient. One variant turned out to be inherited from patient’s mother who had mosaic variant. Distinct phenotypes in patients with variant p.Glu246Lys and p.Arg209His were elucidated by in-depth phenotyping and literature review. Conclusions We reported 6 patients with GNAO1 encephalopathy showing an extremely diverse clinical spectrum on video. Some characteristic movement features identified by careful inspection may also provide important diagnostic insight and practice guidelines.

scholarly journals Spectrum of Movement Disorders in GNAO1 Encephalopathy: In-Depth Phenotyping and Case-by-Case Analysis

2020 ◽  
Author(s):  
Soo Yeon Kim ◽  
YoungKyu Shim ◽  
Young Joon Ko ◽  
Soojin Park ◽  
Se Song Jang ◽  
...  
Keyword(s):  
Literature Review ◽  
Exome Sequencing ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
Pathogenic Variants ◽  
Whole Exome

Abstract Background: GNAO1 encephalopathy is a rare neurodevelopmental disorder characterized by distinct movement presentations and early onset epileptic encephalopathy. Here, we report the in-depth phenotyping of genetically confirmed patients with GNAO1 encephalopathy, focusing on movement presentations.Results: Six patients who participated in Korean Undiagnosed Disease Program were diagnosed to have pathogenic or likely pathogenic variants in GNAO1 using whole exome sequencing. All medical records and personal video clips were analyzed with a literature review. Three of the 6 patients were male. Median follow-up duration was 41 months (range, 7–78 months) and age at last examination was 7.4 years (range, 3.3–16.9 years). Initial complaints were hypotonia or developmental delay in 5 and right-hand clumsiness in 1 patient, which were noticed at median age of 3 months (range, 0–75 months). All patients showed global developmental delay and 4 had severely retarded development. Five patients (5/6, 83.3%) had many different movement symptoms with various onset and progression. The symptoms included stereotyped hands movement, non-epileptic myoclonus, dyskinesia, dystonia and choreoathetosis. Whole exome sequencing identified 6 different variants in GNAO1. Three were novel de novo variants and atypical presentation was noted in a patient. One variant turned out to be inherited from patient’s mother who had mosaic variant. Distinct and characteristics movement phenotypes in patients with variant p.Glu246Lys and p.Arg209His were elucidated by in-depth phenotyping and literature review. Conclusions: We reported 6 patients with GNAO1 encephalopathy showing an extremely diverse clinical spectrum on video. Some characteristic movement features identified by careful inspection may also provide important diagnostic insight and practice guidelines.

scholarly journals Spectrum of movement disorders in GNAO1 encephalopathy: in-depth phenotyping and case-by-case analysis

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Soo Yeon Kim ◽  
YoungKyu Shim ◽  
Young Joon Ko ◽  
Soojin Park ◽  
Se Song Jang ◽  
...  
Keyword(s):  
Literature Review ◽  
Exome Sequencing ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
Pathogenic Variants ◽  
Whole Exome

Abstract Background GNAO1 encephalopathy is a rare neurodevelopmental disorder characterized by distinct movement presentations and early onset epileptic encephalopathy. Here, we report the in-depth phenotyping of genetically confirmed patients with GNAO1 encephalopathy, focusing on movement presentations. Results Six patients who participated in Korean Undiagnosed Disease Program were diagnosed to have pathogenic or likely pathogenic variants in GNAO1 using whole exome sequencing. All medical records and personal video clips were analyzed with a literature review. Three of the 6 patients were male. Median follow-up duration was 41 months (range 7–78 months) and age at last examination was 7.4 years (range 3.3–16.9 years). Initial complaints were hypotonia or developmental delay in 5 and right-hand clumsiness in 1 patient, which were noticed at median age of 3 months (range 0–75 months). All patients showed global developmental delay and 4 had severely retarded development. Five patients (5/6, 83.3%) had many different movement symptoms with various onset and progression. The symptoms included stereotyped hands movement, non-epileptic myoclonus, dyskinesia, dystonia and choreoathetosis. Whole exome sequencing identified 6 different variants in GNAO1. Three were novel de novo variants and atypical presentation was noted in a patient. One variant turned out to be inherited from patient’s mother who had mosaic variant. Distinct and characteristics movement phenotypes in patients with variant p.Glu246Lys and p.Arg209His were elucidated by in-depth phenotyping and literature review. Conclusions We reported 6 patients with GNAO1 encephalopathy showing an extremely diverse clinical spectrum on video. Some characteristic movement features identified by careful inspection may also provide important diagnostic insight and practice guidelines.

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.

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