UBTF Mutation Causes Complex Phenotype of Neurodegeneration and Severe Epilepsy in Childhood

2018 ◽  
Vol 50 (01) ◽  
pp. 057-060 ◽  
Author(s):  
Petra Laššuthová ◽  
Katalin Štěrbová ◽  
Jana Haberlová ◽  
Emílie Vyhnálková ◽  
Jana Neupauerová ◽  
...  
Keyword(s):  
Motor Development ◽  
De Novo ◽  
Unknown Etiology ◽  
Complex Phenotype ◽  
Progressive Decline ◽  
Severe Intellectual Disability ◽  
Whole Exome ◽  
Progressive Neurodegeneration ◽  
Drug Resistant Epilepsy ◽  
De Novo Variant

Introduction Neurodegenerative diseases of childhood present with progressive decline in cognitive, social, and motor function and are frequently associated with seizures in different stages of the disease. Here we report a patient with severe progressive neurodegeneration with drug-resistant epilepsy of unknown etiology from the age of 2 years. Methods and Results Using whole exome sequencing, we found heterozygous missense de novo variant c.628G > A (p.Glu210Lys) in the UBTF gene. This variant was recently described as de novo in 11 patients with similar neurodegeneration characterized by developmental decline initially confined to motor development followed by language regression, appearance of an extrapyramidal movement disorder, and leading to severe intellectual disability. In 3 of the 11 patients described so far, seizures were also present. Conclusions Our report expands the complex phenotype of neurodegeneration associated with the c.628G > A variant in the UBTF gene and helps to clarify the relation between this one single recurrent pathogenic variant described in this gene to date and its phenotype. The UBTF gene should be considered a novel candidate gene in neurodegeneration with or without epilepsy.

scholarly journals A de novo SEMA6B variant in a Chinese patient with progressive myoclonic epilepsy-11 and review of the literature

2021 ◽  
Author(s):  
Qian Li ◽  
Min Liu ◽  
Dan-ping Huang ◽  
Tao Li ◽  
Jing Huang ◽  
...  
Keyword(s):  
De Novo ◽  
Chinese Patient ◽  
Myoclonic Epilepsy ◽  
Chinese Family ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Progressive Neurodegeneration ◽  
Progressive Myoclonic Epilepsy ◽  
Limited Spectrum ◽  
De Novo Variant

Abstract Progressive myoclonic epilepsy is a group of neurodegenerative diseases with complex clinical and genetic heterogeneity, which is associated with spontaneous or action-induced myoclonus and progressive neurodegeneration. Since 2020, 4 families with progressive myoclonic epilepsy-11 [OMIM#618876] have been reported with a very limited spectrum of SEMA6B pathogenic variants. In our study, whole-exome sequencing was used in a proband from a nonconsanguineous Chinese family presenting with growth retardation and recurrent atonic seizures. A deletion mutation (c.1960_1978del, p.Leu654Argfs*25) in the last exon of SEMA6B was detected, which is a de Novo variant and pathogenic. The new genetic evidence we reported here strengthened the gene-disease relationship, and the gene curation level between SEMA6B and progressive myoclonic epilepsy-11 became “strong” following the ClinGen SOP. Therefore, the results of this study broaden the mutation spectrum of SEMA6B in different ethnic groups and strengthen the gene-disease relationship between SEMA6B and progressive myoclonic epilepsy-11.

scholarly journals Novel Dominant KCNQ2 Exon 7 Partial In-Frame Duplication in a Complex Epileptic and Neurodevelopmental Delay Syndrome

2020 ◽  
Vol 21 (12) ◽  
pp. 4447
Author(s):  
Pedro A. Lazo ◽  
Juan L. García ◽  
Paulino Gómez-Puertas ◽  
Íñigo Marcos-Alcalde ◽  
Cesar Arjona ◽  
...  
Keyword(s):  
Protein Function ◽  
De Novo ◽  
3D Structure ◽  
Unknown Origin ◽  
Unknown Etiology ◽  
Neurodevelopmental Delay ◽  
Calmodulin Binding ◽  
Whole Exome ◽  
Dynamics Simulations ◽  
Frame Duplication

Complex neurodevelopmental syndromes frequently have an unknown etiology, in which genetic factors play a pathogenic role. This study utilizes whole-exome sequencing (WES) to examine four members of a family with a son presenting, since birth, with epileptic-like crises, combined with cerebral palsy, severe neuromotor and developmental delay, dystonic tetraparexia, axonal motor affectation, and hyper-excitability of unknown origin. The WES study detected within the patient a de novo heterozygous in-frame duplication of thirty-six nucleotides within exon 7 of the human KCNQ2 gene. This insertion duplicates the first twelve amino acids of the calmodulin binding site I. Molecular dynamics simulations of this KCNQ2 peptide duplication, modelled on the 3D structure of the KCNQ2 protein, suggest that the duplication may lead to the dysregulation of calcium inhibition of this protein function.

scholarly journals A de novo variant in CASK gene causing intellectual disability and brain hypoplasia: A Case Report and Literature Review

2021 ◽  
Author(s):  
Ying Zhang ◽  
Yanyan Nie ◽  
Yu Mu ◽  
Jie Zheng ◽  
Xiaowei Xu ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mental Disorders ◽  
De Novo ◽  
Clinical Symptoms ◽  
Clinical Manifestations ◽  
De Novo Mutation ◽  
Loss Of Function ◽  
Bioinformatics Analyses ◽  
Whole Exome ◽  
De Novo Variant

Abstract Background：The pathogenic variation of CASK gene can cause CASK related mental disorders. The main clinical manifestations are microcephaly with pontine and cerebellar hypoplasia, X-linked mental disorders with or without nystagmus and FG syndrome. The main pathogenic mechanism is the loss of function of related protein caused by mutation. We reported a Chinese male newborn with a de novo variant in CASK gene. Case presentation：We present an 18-day-old baby with intellectual disability and brain hypoplasia. Whole-exome sequencing was performed, which detected a hemizygous missense mutation c.764G>A of CASK gene. The mutation changed the 255th amino acid from Arg to His. Software based bioinformatics analyses were conducted to infer its functional effect.Conclusions：In this paper, a de novo mutation of CASK gene was reported. Moreover, a detailed description of all the cases described in the literature is reported.CASK mutations cause a variety of clinical phenotypes. Its diagnosis is difficult due to the lack of typical clinical symptoms. Genetic testing should be performed as early as possible if this disease is suspected. This case provides an important reference for the diagnosis and treatment of future cases.

scholarly journals Nearly Half of TP53 Germline Variants Predicted To Be Pathogenic in Patients With Osteosarcoma Are De Novo: A Report From the Children’s Oncology Group

2020 ◽  
pp. 1187-1195
Author(s):  
Brandon J. Diessner ◽  
Nathan Pankratz ◽  
Anthony J. Hooten ◽  
Lisa Mirabello ◽  
Aaron L. Sarver ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Rare Variants ◽  
De Novo ◽  
Phase 1 ◽  
Control Measures ◽  
Fisher Exact Test ◽  
Exact Test ◽  
Whole Exome ◽  
History Of ◽  
De Novo Variant

PURPOSE To ascertain the prevalence of recurrent de novo variants among 240 pediatric patients with osteosarcoma (OS; age < 20 years) unselected for family history of cancer. METHODS The identification of de novo variants was implemented in 2 phases. In the first, we identified genes with a rare (minor allele frequency < 0.01) de novo variant in > 1 of the 95 case-parent trios examined by whole-exome sequencing (WES) who passed quality control measures. In phase 2, 145 additional patients with OS were evaluated by targeted sequencing to identify rare de novo variants in genes nominated from phase 1. Recurrent rare variants identified from phase 1 and 2 were verified as either de novo or inherited by Sanger sequencing of affected patients and their parents. Categorical and continuous data were analyzed using Fisher exact test and t tests, respectively. RESULTS Among 95 case-parent trios who underwent WES, we observed 61 de novo variants in 60 genes among 47 patients, with TP53 identified as the only gene with a pathogenic or likely pathogenic (P/LP) de novo variant in more than one case-parent trio. Among all 240 patients with OS, 13 (5.4%) harbored a P/LP TP53 germline variant, of which 6 (46.2%) were confirmed to be de novo. CONCLUSION Apart from TP53, we did not observe any other recurrent de novo P/LP variants in the case-parent trios, suggesting that new mutations in other genes are not a frequent cause of pediatric OS. That nearly half of P/LP TP53 variants in our sample were de novo suggests universal screening for germline TP53 P/LP variants among pediatric patients with OS should be considered.

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 Case report : a novel ASXL3 gene variant in a Sudanese boy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ke Wu ◽  
Yan Cong
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Psychomotor Development ◽  
Gene Variant ◽  
Feeding Difficulties ◽  
Severe Intellectual Disability ◽  
Whole Exome

Abstract Background Bainbridge-Ropers syndrome (BRPS) [OMIM#615485] is a neurodevelopmental disorder, characterized by delayed psychomotor development with generalized hypotonia, moderate to severe intellectual disability, poor or absent speech, feeding difficulties, growth failure, dysmorphic craniofacial features and minor skeletal features. The aim of this study was to investigate the genetic etiology of a Sudanese boy with severe developmental delay, intellectual disability, and craniofacial phenotype using trio-based whole-exome sequencing. To our knowledge, no patients with ASXL3 gene variant c.3043C>T have been reported detailedly in literature. Case presentation The patient (male, 3 years 6 months) was the first born of a healthy non-consanguineous couple originating from Sudan, treated for “psychomotor retardation” for more than 8 months in Yiwu. The patient exhibited severely delayed milestones in physiological and intellectual developmental stages, language impairment, poor eye-contact, lack of subtle motions of fingers, fear of claustrophobic space, hypotonia, clinodactyly, autistic features. Peripheral blood samples were collected from the patient and his parents. Trio-based whole-exome sequencing(Trio-WES) identified a de novo heterozygous ASXL3 gene variant c.3043C>T;p.Q1015X. Sanger sequencing verified variants of this family. Conclusion Trio-WES analysis identified a de novo nonsense variant (c.3043C>T) of ASXL3 gene in a Sudanese boy. To our knowledge, the patient with this variant has not been reported previously in literature. This study presents a new case for ASXL3 gene variants, which expanded the mutational and phenotypic spectrum.

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&gt;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 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.

scholarly journals ARHGEF9 disease

2017 ◽  
Vol 3 (3) ◽  
pp. e148 ◽  
Author(s):  
Michael Alber ◽  
Vera M. Kalscheuer ◽  
Elysa Marco ◽  
Elliott Sherr ◽  
Gaetan Lesca ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Motor Development ◽  
De Novo ◽  
Intractable Epilepsy ◽  
Facial Dysmorphism ◽  
Ph Domain ◽  
Loss Of Function ◽  
Protein Loss ◽  
Severe Intellectual Disability ◽  
Detailed Medical History

Objective:We aimed to generate a review and description of the phenotypic and genotypic spectra of ARHGEF9 mutations.Methods:Patients with mutations or chromosomal disruptions affecting ARHGEF9 were identified through our clinics and review of the literature. Detailed medical history and examination findings were obtained via a standardized questionnaire, or if this was not possible by reviewing the published phenotypic features.Results:A total of 18 patients (including 5 females) were identified. Six had de novo, 5 had maternally inherited mutations, and 7 had chromosomal disruptions. All females had strongly skewed X-inactivation in favor of the abnormal X-chromosome. Symptoms presented in early childhood with delayed motor development alone or in combination with seizures. Intellectual disability was severe in most and moderate in patients with milder mutations. Males with severe intellectual disability had severe, often intractable, epilepsy and exhibited a particular facial dysmorphism. Patients with mutations in exon 9 affecting the protein's PH domain did not develop epilepsy.Conclusions:ARHGEF9 encodes a crucial neuronal synaptic protein; loss of function of which results in severe intellectual disability, epilepsy, and a particular facial dysmorphism. Loss of only the protein's PH domain function is associated with the absence of epilepsy.

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