scholarly journals Genotypes and Phenotypes of MEF2C Haploinsufficiency Syndrome: New Cases and Novel Point Mutations

2021 ◽  
Vol 9 ◽  
Author(s):  
Lin Wan ◽  
Xinting Liu ◽  
Linyan Hu ◽  
Huimin Chen ◽  
Yulin Sun ◽  
...  
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Point Mutations ◽  
Clinical Manifestations ◽  
Poor Performance ◽  
Genetic Alterations ◽  
Mendelian Inheritance ◽  
Whole Exome ◽  
Patients With Epilepsy ◽  
Free Status

Aim: MEF2C haploinsufficiency syndrome (MCHS) is a severe neurodevelopmental disorder. We describe the clinical phenotypes and genotypes of seven patients with MCHS to enhance the understanding of clinical manifestations and genetic alterations associated with MCHS.Method: Seven patients (6 females and 1 male, aged between 2 years 5 months and 6 years) who had MEF2C mutations, and their parents underwent trio-based whole-exome sequencing; subsequently, their clinical features were assessed. A literature review of patients with MCHS was performed by searching the PubMed and Online Mendelian Inheritance in Man databases.Results: Seven mutations were identified, of which six were unreported in the past; of the reported cases, five patients had de novo mutations but two had an undefined inheritance pattern. All patients presented delays in developmental milestones, severe intellectual disabilities and lack of speech. Six patients exhibited infantile hypotonia, five patients experienced stereotypic movements and were unable to walk, four patients exhibited poor eye contact indicative of autism and two showed poor performance. While six patients experienced seizure, five among them became seizure free after receiving anti-seizure medicine. Three patients showed a regression in their development, whereas the mothers of two patients exhibited mosaicism but were healthy without any abovementioned symptoms.Interpretation: Regression was not a common phenomenon but occurred in MCHS. The prognosis of MCHS patients with epilepsy was good, but most patients can achieve a seizure-free status. Healthy people may have low-level mosaicism and carry a pathogenic MEF2C mutation.

scholarly journals Mouse Models Characterize GNAO1 Encephalopathy as a Neurodevelopmental Disorder Leading to Motor Anomalies: from a Severe G203R to a Milder C215Y Mutation

2021 ◽  
Author(s):  
Denis Silachev ◽  
Alexey Koval ◽  
Mikhail Savitsky ◽  
Guru Padmasola ◽  
Charles Quairiaux ◽  
...  
Keyword(s):  
Mouse Models ◽  
De Novo ◽  
Late Onset ◽  
Wide Spectrum ◽  
Neurodevelopmental Disorder ◽  
Point Mutations ◽  
Clinical Manifestations ◽  
Epileptic Seizures ◽  
Motor Dysfunction ◽  
Neuronal Precursor Cells

Abstract GNAO1 encephalopathy characterized by a wide spectrum of neurological deficiencies in pediatric patients originates from de novo heterozygous mutations in the gene encoding Gαo, the major neuronal G protein. Efficient treatments and even the proper understanding of the underlying etiology are currently lacking for this dominant disease. Adequate animal models of GNAO1 encephalopathy are urgently needed. Here we describe establishment and characterization of mouse models of the disease based on two point mutations in GNAO1 with different clinical manifestations. One of them is G203R leading to the early-onset epileptic seizures, motor dysfunction, developmental delay and intellectual disability. The other is C215Y producing much milder clinical outcomes, mostly – late-onset motor hyperactivity. The resultant mouse models show distinct phenotypes: severe neonatal lethality in GNAO1[G203R]/+ mice vs. normal vitality in GNAO1[C215Y]/+. The latter model further revealed strong hyperactivity and hyperlocomotion in a panel of behavioral assays, without signs of epilepsy, recapitulating the patients’ manifestations. Importantly, despite these differences the two models similarly revealed prenatal brain developmental anomalies, such as enlarged lateral ventricles and decreased numbers of neuronal precursor cells in the cortex. Thus, our work unveils GNAO1 encephalopathy as to a large extent neurodevelopmental malady. We expect that this understanding and the tools we established will be instrumental for future therapeutic developments.

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 Case Report: A Novel De Novo Missense Mutation of the GRIA2 Gene in a Chinese Case of Neurodevelopmental Disorder With Language Impairment

2021 ◽  
Vol 12 ◽  
Author(s):  
Bingbo Zhou ◽  
Chuan Zhang ◽  
Lei Zheng ◽  
Zhiqiang Wang ◽  
Xue Chen ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
Language Impairment ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Behavioral Abnormalities ◽  
Whole Exome ◽  
Chinese Case

Introduction: Neurodevelopmental disorders with language impairment and behavioral abnormalities (NEDLIB) are a disease caused by heterozygous variants in the glutamate ionotropic receptor AMPA type subunit 2 (GRIA2) gene, which manifest as impaired mental development or developmental delay, behavioral abnormalities including autistic characteristics, and language disorders. Currently, only a few mutations in the GRIA2 gene have been discovered.Methods: A GRIA2 variation was detected in a patient by whole-exome sequencing, and the site was validated by Sanger sequencing from the family.Results: We report a Chinese case of NEDLIB in a girl with language impairment and developmental delay through whole-exome sequencing (WES). Genetic analysis showed that there was a de novo missense mutation, c.1934T > G (p.Leu645Arg), in the GRIA2 gene (NM_001083619.1), which has never been reported before.Conclusion: Our case shows the potential diagnostic role of WES in NEDLIB, expands the GRIA2 gene mutation spectrum, and further deepens the understanding of NEDLIB. Deepening the study of the genetic and clinical heterogeneity, treatment, and prognosis of the disease is still our future challenge and focus.

scholarly journals Cancer Genetics and Epigenetics in Cancer Risk Assesment

2021 ◽  
Vol 5 (2) ◽  
pp. 41
Author(s):  
Anna Meiliana ◽  
Nurrani Mustika Dewi ◽  
Andi Wijaya
Keyword(s):  
Cancer Cells ◽  
Cancer Genetics ◽  
Point Mutations ◽  
Genetic Alterations ◽  
Genetic Mutations ◽  
Control Mechanisms ◽  
Normal Tissues ◽  
Knowing That ◽  
Whole Exome ◽  
Methylation Patterns

Compared to the normal tissues, cancer cells tend to have higher proliferation rate and often lost their ability to undergo apoptosis. In addition, cancer cells can separate themselves from their original tissue thus causing metastasis in other part of body. While undergoing program cell death, disordered cellular programming can happen. The main causes of this cellular programming anomaly are epigenetic and genetic alterations, which have been known as two separate mechanisms in carcinogenetic. A recent outcome of whole exome sequencing of thousands of human cancers has been the unexpected discovery of many inactivating mutations in genes that control the epigenome. These mutations have the potential to disturb the DNA methylation patterns, histone modifications, and nucleosome positioning, hence, the causing gene expression alternation. Genetic alteration of the epigenome therefore contributes to cancer just as epigenetic process can cause point mutations and disable DNA repair functions. Epigenetic mechanisms changes could cause genetic mutations, and genetic mutations in epigenetic regulators could cause epigenome changes. Knowing that epigenome play a major role in the hierarchy of gene control mechanisms suggests that mutations might have impact on multiple pathways related to cancer phenotype. This pinpoint the fact that recently, the way the genes are organized and controlled are suggested to be a relevant factor for human carcinogenesis.Keywords: cancer genetic, cancer epigenetic, oncogens, tumor suppressor genes, driver mutation, passenger mutation

scholarly journals A Novel WT1 Mutation Identified in a 46,XX Testicular/Ovotesticular DSD Patient Results in the Retention of Intron 9

Biology ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1248
Author(s):  
Dmytro Sirokha ◽  
Olexandra Gorodna ◽  
Yakov Vitrenko ◽  
Nataliya Zelinska ◽  
Rafal Ploski ◽  
...  
Keyword(s):  
Splice Site ◽  
Rna Binding ◽  
De Novo ◽  
Zinc Fingers ◽  
Point Mutations ◽  
Whole Exome ◽  
Alternative Donor ◽  
Wt1 Mutation ◽  
Wt1 Protein ◽  
Genetic Rearrangements

The 46,XX testicular DSD (disorder/difference of sexual development) and 46,XX ovotesticular DSD (46,XX TDSD and 46,XX OTDSD) phenotypes are caused by genetic rearrangements or point mutations resulting in imbalance between components of the two antagonistic, pro-testicular and pro-ovarian pathways; however, the genetic causes of 46,XX TDSD/OTDSD are not fully understood, and molecular diagnosis for many patients with the conditions is unavailable. Only recently few mutations in the WT1 (WT1 transcription factor; 11p13) gene were described in a group of 46,XX TDSD and 46,XX OTDSD individuals. The WT1 protein contains a DNA/RNA binding domain consisting of four zinc fingers (ZnF) and a three-amino acid (KTS) motif that is present or absent, as a result of alternative splicing, between ZnF3 and ZnF4 (±KTS isoforms). Here, we present a patient with 46,XX TDSD/OTDSD in whom whole exome sequencing revealed a heterozygous de novo WT1 c.1437A>G mutation within an alternative donor splice site which is used for −KTS WT1 isoform formation. So far, no mutation in this splice site has been identified in any patient group. We demonstrated that the mutation results in the retention of intron 9 in the mature mRNA of the 46,XX TDSD/OTDSD patient. In cases when the erroneous mRNA is translated, exclusively the expression of a truncated WT1 +KTS protein lacking ZnF4 and no −KTS protein occurs from the mutated allele of the patient. We discuss potential mechanisms and pathways which can be disturbed upon two conditions: Absence of Zn4F and altered +KTS/−KTS ratio.

scholarly journals Mice with GNAO1 R209H Movement Disorder Variant Display Hyperlocomotion Alleviated by Risperidone

2019 ◽  
Author(s):  
Casandra L. Larrivee ◽  
Huijie Feng ◽  
Josiah A. Quinn ◽  
Vincent S. Shaw ◽  
Jeffrey R. Leipprandt ◽  
...  
Keyword(s):  
Mouse Model ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Clinical Manifestations ◽  
Brain Regions ◽  
Psychomotor Development ◽  
Nucleotide Exchange ◽  
Involuntary Movements ◽  
Gait Abnormality ◽  
The Brain

AbstractNeurodevelopmental disorder with involuntary movements (NEDIM, OMIM: 617493) is a severe, early onset neurological condition characterized by a delay in psychomotor development, hypotonia, and hyperkinetic involuntary movements. Heterozygous de novo mutations in the GNAO1 gene cause NEDIM. Gαo, the gene product of GNAO1, is the alpha subunit of Go, a member of the heterotrimeric Gi/o family of G-proteins. Go is found abundantly throughout the brain but the pathophysiological mechanisms linking Gαo functions to clinical manifestations of GNAO1-related disorders are still poorly understood. One of the most common mutant alleles among the GNAO1 encephalopathies is the c.626G>A or p.Arg209His (R209H) mutation. We developed heterozygous knock-in Gnao1+/R209H mutant mice using CRISPR/Cas9 methodology to assess whether a mouse model could replicate aspects of the NEDIM clinical pattern. Mice carrying the R209H mutation exhibited increased locomotor activity and a modest gait abnormality at 8-12 weeks. In contrast to mice carrying other mutations in Gnao1, the Gnao1+/R209H mice did not show enhanced seizure susceptibility. Levels of protein expression in multiple brain regions were unchanged from WT mice but the nucleotide exchange rate of mutant R209H Gαo was 9 times faster than WT. The atypical neuroleptic risperidone has shown efficacy in a patient with the R209H mutation. It also alleviated the hyperlocomotion phenotype observed in our mouse model but suppressed locomotion in WT mice as well. In this study, we show that Gnao1+/R209H mice mirror elements of the patient phenotype and respond to an approved pharmacological agent.

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.

Cyclin-Dependent Kinase-Like 5 (CDKL5) Mutation Screening in Rett Syndrome and Related Disorders

2010 ◽  
Vol 13 (2) ◽  
pp. 168-178 ◽  
Author(s):  
Rose White ◽  
Gladys Ho ◽  
Swetlana Schmidt ◽  
Ingrid E. Scheffer ◽  
Alexandra Fischer ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Early Onset ◽  
De Novo ◽  
Wide Spectrum ◽  
Neurodevelopmental Disorder ◽  
Mutation Screening ◽  
Clinical Manifestations ◽  
Epileptic Encephalopathy ◽  
Cyclin Dependent Kinase ◽  
Aicardi Syndrome

AbstractRett syndrome (RTT) is a severe neurodevelopmental disorder affecting females almost exclusively and is characterized by a wide spectrum of clinical manifestations. Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene have been found in up to 95% of classical RTT cases and a lesser proportion of atypical cases. Recently, mutations in another X-linked gene, CDKL5 (cyclin-dependent kinase-like 5) have been found to cause atypical RTT, in particular the early onset seizure (Hanefeld variant) and one female with autism. In this study we screened several cohorts of children for CDKL5 mutations, totaling 316 patients, including individuals with a clinical diagnosis of RTT but who were negative for MECP2 mutations (n = 102), males with X-linked mental retardation (n = 9), patients with West syndrome (n = 52), patients with autism (n = 59), patients with epileptic encephalopathy (n = 33), patients with Aicardi syndrome (n = 7) and other patients with intellectual disability with or without seizures (n = 54). In all, seven polymorphic variations and four de novo mutations (c.586C>T [p.S196L]; c.58G>C [p.G20R]; c.2504delC [p.P835fs]; deletion of exons 1 - 3) were identified, and in all instances of the latter the clinical phenotype was that of an epileptic encephalopathy. These results suggest that pathogenic CDKL5 mutations are unlikely to be identified in the absence of severe early-onset seizures and highlight the importance of screening for large intragenic and whole gene deletions.

scholarly journals A Novel De Novo Frameshift Mutation in KAT6A Identified by Whole Exome Sequencing

2018 ◽  
Vol 08 (01) ◽  
pp. 010-014 ◽  
Author(s):  
Wafa Alazaizeh ◽  
Asem Alkhateeb
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Frameshift Mutation ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Brain Magnetic Resonance Imaging ◽  
Comparative Genomic ◽  
Feeding Difficulties ◽  
Whole Exome

AbstractIntellectual disability is a common condition with multiple etiologies. The number of monogenic causes has increased steadily in recent years due to the implementation of next generation sequencing. Here, we describe a 2-year-old boy with global developmental delay and intellectual disability. The child had feeding difficulties since birth. He had delayed motor skills and muscular hypotonia. Brain magnetic resonance imaging revealed diffuse white matter loss and thinning of the corpus callosum. Banded karyotype and comparative genomic hybridization (CGH) array were normal. Whole exome sequencing revealed a novel de novo frameshift mutation c.3390delA (p.Lys1130Asnfs*4) in KAT6A gene (NM_006766.4). The heterozygous mutation was confirmed by Sanger sequencing in the patient and its absence in his parents. KAT6A that encodes a histone acetyltransferase has been recently found to be associated with a neurodevelopmental disorder autosomal dominant mental retardation 32 (OMIM: no. 616268). Features of this disorder are nonspecific, which makes it difficult to characterize the condition based on the clinical symptoms alone. Therefore, our findings confirm the utility of whole exome sequencing to quickly and reliably identify the etiology of such conditions.

Cleft Palate as Distinguishing Feature in a Patient with GABRB3 Epileptic Encephalopathy

2019 ◽  
Vol 50 (06) ◽  
pp. 378-381
Author(s):  
Daniel Bamborschke ◽  
Matthias Pergande ◽  
Hülya Sevcan Daimagüler ◽  
Elisabeth Mangold ◽  
Jörg Dötsch ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Gabaa Receptor ◽  
Knockout Mice ◽  
De Novo ◽  
Index Patient ◽  
Epileptic Encephalopathy ◽  
De Novo Mutation ◽  
Neonatal Onset ◽  
Whole Exome ◽  
Patients With Epilepsy

Mutations in GABAA-receptor subunit genes are associated with a heterogeneous spectrum of epilepsies. Patients with epilepsy caused by mutations in a specific GABAA-receptor (GABRA3) occasionally present with orofacial dysmorphism (e.g., cleft palates). While cleft palates have been described in Gabrb3 knockout mice and in humans with GABRB3 variants without epilepsy, the specific combination of epilepsy and cleft palate in humans with GABRB3 mutations has not yet been reported.We describe a patient with epileptic encephalopathy (EE) who presented with therapy-refractory neonatal-onset myoclonic seizures and severe developmental delay. Electroencephalogram showed burst suppression pattern at neonatal age and hypsarrhythmia at infantile age. Initial magnetic resonance imaging was unremarkable. As he additionally presented with a cleft palate, we were curious whether cleft palate and EE had the same genetic origin. Whole exome sequencing of the index patient revealed a novel pathogenic heterozygous de novo mutation in GABRB3 (c.899T > C; p.I300T). In consistency with Gabrb3 knockout mice data, this is the first report of cleft palate in a patient with GABRB3 associated EE.We suggest to add cleft palate to the phenotypic GABRB3 spectrum and to screen for mutations in GABAA-receptors in patients with EE and orofacial dysmorphism.

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