scholarly journals A Novel de novo Mutation in EBF3 Associated With Hypotonia, Ataxia, and Delayed Development Syndrome in a Chinese Boy

2021 ◽  
Vol 12 ◽  
Author(s):  
Yanru Huang ◽  
Libin Mei ◽  
Yangdan Wang ◽  
Huiming Ye ◽  
Xiaomin Ma ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Clinical Diagnosis ◽  
De Novo ◽  
Pathogenic Mutation ◽  
De Novo Mutation ◽  
Luciferase Reporter ◽  
Global Developmental Delay ◽  
Whole Exome ◽  
Development Delay ◽  
Delayed Development

ObjectiveGlobal developmental delay has markedly high phenotypic and genetic heterogeneity, and is a great challenge for clinical diagnosis. Hypotonia, ataxia, and delayed development syndrome (HADDS), first reported in 2017, is one type of global development delay. The aim of the present study was to investigate the genetic etiology of a Chinese boy with global developmental delay.MethodsWe combined clinical and imaging phenotyping with trio whole-exome sequencing and Sanger sequencing to the patient and his clinically unaffected parents. A luciferase reporter and immunofluorescence were performed to detect the effect of mutation on transcriptional activity and subcellular localization.ResultsThe patient presented with several previously unreported symptoms in the patients with HADDS, including hemangiomas, mild hearing abnormalities and tracheomalacia. A novel EBF3 c.589A > G missense mutation (p.Asn197Asp, p.N197D) was identified in the patient but not in his parents. By constructing the plasmid and transfecting HEK293T cells, EBF3-N197D mutant showed impaired activation of luciferase reporter expression of the p21 promoter, and the mutant affected its entry into the nucleus.ConclusionTo the best of our knowledge, this is the first report of EBF3 pathogenic mutation which associated with HADDS in the Chinese population. Our results expand the phenotypes and pathogenic mutation spectrum of HADDS, thus potentially facilitating the clinical diagnosis and genetic counseling of HADDS patients.

scholarly journals Case Report: A Novel de novo Mutation in DNM1L Presenting With Developmental Delay, Ataxia, and Peripheral Neuropathy

2021 ◽  
Vol 9 ◽  
Author(s):  
Yanping Wei ◽  
Min Qian
Keyword(s):  
Peripheral Neuropathy ◽  
Developmental Delay ◽  
De Novo ◽  
Refractory Epilepsy ◽  
De Novo Mutation ◽  
Global Developmental Delay ◽  
Missense Mutations ◽  
Related Protein ◽  
Resonance Imaging ◽  
Genetic Results

DNM1L encodes dynamin-related protein 1 (Drp1), which is a member of the dynamin superfamily of GTPases and mediates mitochondrial and peroxisomal fission. In humans, several de novo heterozygous missense mutations in DNM1L have been reported, which were characterized by devastating courses with refractory epilepsy, myoclonus, and brain atrophy on MRI. We describe a 4.5-year-old male child harboring a novel de novo mutation in DNM1L presenting a phenotype of developmental delay, ataxia, and peripheral neuropathy. The clinical features, magnetic resonance imaging findings, and genetic results were summarized. Meanwhile, all the cases of DNM1L mutations reported were reviewed. DNM1L variants may need to be considered in phenotypes that include global developmental delay, peripheral neuropathy, and ataxia.

scholarly journals Case Report: De novo Variants of KMT2E Cause O'Donnell-Luria-Rodan Syndrome: Additional Cases and Literature Review

2021 ◽  
Vol 9 ◽  
Author(s):  
Yang Li ◽  
Lijuan Fan ◽  
Rong Luo ◽  
Zuozhen Yang ◽  
Meng Yuan ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Clinical Manifestations ◽  
Global Developmental Delay ◽  
Feeding Difficulties ◽  
Gene Testing ◽  
Whole Exome ◽  
Systemic Disorder ◽  
Synonymous Variant ◽  
Genetics And Genomics

Introduction: O'Donnell-Luria-Rodan syndrome was recently identified as an autosomal dominant systemic disorder caused by variants in KMT2E. It is characterized by global developmental delay, some patients also exhibit autism, seizures, hypotonia, and/or feeding difficulties.Methods: Whole-exome sequencing of family trios were performed for two independent children with unexplained recurrent seizures and developmental delay. Both cases were identified as having de novo variants in KMT2E. We also collected and summarized the clinical data and diagnosed them with O'Donnell-Luria-Rodan syndrome. Structural-prediction programs were used to draw the variants' locations.Results: A 186 G>A synonymous variant [NM_182931.3:exon4: c.186G>A (p.Ala62=)] was found in one family, resulting in alternative splicing acid. A 5417 C>T transition variant [NM_182931.3:exon27: c.5417C>T (p.Pro1806Leu)] was found in another family, resulting in 1806 Pro-to-Leu substitution. Both variants were classified as likely pathogenic according to the ACMG (American College of Medical Genetics and Genomics) guidelines and verified by Sanger sequencing.Conclusion: To date, three studies of O'Donnell-Luria-Rodan syndrome have been reported with heterogeneous clinical manifestations. As a newly recognized inherited systemic disorder, O'Donnell-Luria-Rodan syndrome needs to be paid more attention, especially in gene testing.

scholarly journals Identification of a de novo mutation in KRT5 gene underlying epidermolysis bullosa simplex by whole exome sequencing in a Vietnamese patient

2021 ◽  
Vol 19 (2) ◽  
pp. 223-228
Author(s):  
Ma Thi Huyen Thuong ◽  
Dang Tien Truong ◽  
Nguyen Hai Ha ◽  
Nguyen Dang Ton
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Epidermolysis Bullosa ◽  
De Novo ◽  
Recurrence Risk ◽  
Pathogenic Mutation ◽  
De Novo Mutation ◽  
Causative Mutation ◽  
Epidermolysis Bullosa Simplex ◽  
Whole Exome

Epidermolysis bullosa simplex (EBS) is a group of epidermolysis bullosa (EB) and accounts for 75-85% EB cases. Most EBS patients are caused by mutations in KRT5 or KRT14, encoding for keratin 5 and keratin 14, respectively, which impair the structural entirety of paired intermediate filaments expressed in the fracture of basal keratinocytes and subsequent blistering of the epithelium. This study aimed to identify the causative mutation in a Vietnamese EB case. Whole exome sequencing (WES) was performed in the affected individual and revealed a de novo heterozygous pathogenic mutation in exon 7 of KRT5 gene, resulting in an amino acid change at position 477, with glutamic acid to lysine substitution (p.E477K). The KRT5 p.E477K was strong associated with the very severe or lethal of generalized severe EBS (GS-EBS), characterized by the severe symptoms at birth, improving with age and evolution to palmoplantar keratoderma and nail dysplasia. Our finding will aid the molecular diagnosis, prognosis prediction of the patient with GS-EBS due to p.E477K and significant genetic counselling the family concerning the recurrence risk for future pregnancies.

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 Novel HIVEP2 Variant p.Q1248* is Associated with Developmental Delay: A Case Report

2019 ◽  
Vol 08 (03) ◽  
pp. 157-159
Author(s):  
Angita Jain ◽  
Paldeep S. Atwal
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Global Developmental Delay ◽  
Type I ◽  
Gene Variant ◽  
Medical Genetic ◽  
Whole Exome ◽  
Enhancer Binding Protein ◽  
Immunodeficiency Virus ◽  
Novel Variant

AbstractIn this report, we describe a 5-year-old boy with global developmental delay who presented for medical genetic evaluation. We performed whole exome sequencing that revealed the involvement of a heterogenous variant p.Gln1248Ter (CAG > TAG): c.3742 C > T inherited de novo in exon 5 of HIVEP2 (human immunodeficiency virus type I enhancer binding protein 2; NM_006734.3). The gene variant p.Q1248* is interpreted to be associated as a cause of the intellectual disability. We review pathomechanisms of HIVEP2 and discuss the reasoning behind the pathogenicity of this novel variant. To the best of our knowledge, this the first reported case that demonstrates the p.Q1248* variant as pathogenic.

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 De novo variant in the MAPK8IP3 gene in the differential diagnosis of global development delay. Case report.

2021 ◽  
Author(s):  
Joseph Bruno Bidin Brooks
Keyword(s):  
Case Report ◽  
Developmental Delay ◽  
De Novo ◽  
Symptomatic Treatment ◽  
Global Developmental Delay ◽  
World Population ◽  
Global Development ◽  
Pathogenic Variants ◽  
Development Delay ◽  
Muscle Hypotonia

Context: The global development delay has a high prevalence and heterogeneity in the world population. With the advancement of technology and detection of pathogenic variants detected by sequencing the exome, genes related to global developmental delay could be identified and collaborate for further clinical clarification. Among the studied genes, the MAPK8IP3 gene, became an attractive candidate due to its performance in neuronal axonal transport in vertebrates and invertebrates. This case report was approved by the Ethics Committee of Universidade Metropolitana de Santos. Case Report: The present case refers to a 6-year-old male patient presenting with a clinical picture of global developmental delay without bodily dysmorphia. Cerebellar ataxia, muscle hypotonia and intellectual impairment are important clinical impairments. Skull MRI and complementary exams were normal. The genetic study showed a new and heterozygous pathogenic variant in the MAPK8IP3 gene. Conclusions: Symptomatic treatment with multiprofessional rehabilitation was instituted with partial improvement of symptoms.

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