scholarly journals Expansion of the Genotypic and Phenotypic Spectrum of WASF1-Related Neurodevelopmental Disorder

2021 ◽  
Vol 11 (7) ◽  
pp. 931
Author(s):  
Siddharth Srivastava ◽  
Erica L. Macke ◽  
Lindsay C. Swanson ◽  
David Coulter ◽  
Eric W. Klee ◽  
...  
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Case Series ◽  
Monozygotic Twins ◽  
Copy Number Variant ◽  
Limited Information ◽  
Phenotypic Spectrum ◽  
New Variant ◽  
Genetic Landscape ◽  
Syndrome Protein

In humans, de novo truncating variants in WASF1 (Wiskott–Aldrich syndrome protein family member 1) have been linked to presentations of moderate-to-profound intellectual disability (ID), autistic features, and epilepsy. Apart from one case series, there is limited information on the phenotypic spectrum and genetic landscape of WASF1-related neurodevelopmental disorder (NDD). In this report, we describe detailed clinical characteristics of six individuals with WASF1-related NDD. We demonstrate a broader spectrum of neurodevelopmental impairment including more mildly affected individuals. Further, we report new variant types, including a copy number variant (CNV), resulting in the partial deletion of WASF1 in monozygotic twins, and three missense variants, two of which alter the same residue, p.W161. This report adds further evidence that de novo variants in WASF1 cause an autosomal dominant NDD.

scholarly journals The prenatal diagnosis and clinical outcomes of fetuses with 15q11.2 copy number variants: a case series of 36 patients

2021 ◽  
Author(s):  
Jessica Kang ◽  
Chien Nan Lee ◽  
Yi-Ning Su ◽  
Ming-Wei Lin ◽  
Yi-Yun Tai ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Developmental Delay ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Case Series ◽  
Copy Number Variant ◽  
University Hospital ◽  
Limited Information ◽  
Ultrasound Findings

Objective: The prenatal genetic counseling of fetus diagnosed with the 15q11.2 copy number variant (CNV) involving the BP1-BP2 region has been difficult due to limited information and controversial opinion on prognosis. Design: Case series. Setting: This study uses data from National Taiwan University Hospital. Sample: Data of 36 pregnant women who underwent prenatal microarray analysis from 2012 to 2017 and were assessed at National Taiwan University Hospital. Methods: Data were collected by reviewing patients’ medical record. Comparison of patient characteristics, prenatal ultrasound findings and postnatal outcomes between different cases involving the 15q11.2 BP1-BP2 region were presented. Main outcome measured: Postnatal prognosis. Results: Out of the 36 patients diagnosed with CNVs involving the BP1-BP2 region, 5 were diagnosed with microduplication and 31 with microdeletion. Abnormal ultrasound findings were recorded in 12 cases prenatally. De novo microduplications were observed in 25% of the cases and microdeletions were found in 14%. Amongst the cases, 10 pregnant women received termination of pregnancy and 26 gave birth to healthy individuals (27 babies in total). Conclusion: The prognoses of 15q11.2 CNVs were controversial and recent studies have revealed its connection with developmental delay and autism. In our study, no obvious developmental delay or neurological disorders were detected postnatally in the 1 case of 15q11.2 microduplication and 25 cases of microdeletion.

scholarly journals Novel KCNH1 Mutations Associated with Epilepsy: Broadening the Phenotypic Spectrum of KCNH1-Associated Diseases

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 132
Author(s):  
Randi von Wrede ◽  
Monika Jeub ◽  
Idil Ariöz ◽  
Christian E. Elger ◽  
Hubertus von Voss ◽  
...  
Keyword(s):  
De Novo ◽  
Focal Cortical Dysplasia ◽  
Case Series ◽  
Epileptic Encephalopathy ◽  
Associated Diseases ◽  
Phenotypic Spectrum ◽  
Reduced Penetrance ◽  
Generalized Epilepsy ◽  
Potential Pathogenicity ◽  
Pore Domain

Here, we describe four patients suffering from a rather broad spectrum of epilepsy-related disorders, ranging from developmental and epileptic encephalopathy with intellectual disability (DEE) to genetic generalized epilepsy (GGE), which all harbor novel KCNH1 mutations. In one family, we found a weak association of a novel nonsense mutation with epilepsy, suggesting reduced penetrance, and which shows, in agreement with previous findings, that gain-of-function effects rather than haploinsufficiency are important for the pathogenicity of mutations. De novo missense variants in the pore region of the channel result in severe phenotypes presenting usually with DEE with various malformations. The potential pathogenicity of a novel KCNH1 germline mutation located outside of the critical pore domain observed in a GGE patient with a milder phenotype is supported by the fact that the very same amino acid exchange was detected as a somatic mutation in the resected brain tissue of a patient suffering from a focal cortical dysplasia type IIb. Thus, our case series broadens the phenotypic spectrum of KCNH1-associated diseases.

scholarly journals De novo ARHGEF9 missense variants associated with neurodevelopmental disorder in females: expanding the genotypic and phenotypic spectrum of ARHGEF9 disease in females

Neurogenetics ◽  
2020 ◽  
Author(s):  
Marcello Scala ◽  
Evelien Zonneveld-Huijssoon ◽  
Marianna Brienza ◽  
Oriano Mecarelli ◽  
Annemarie H. van der Hout ◽  
...  
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Missense Variants ◽  
Phenotypic Spectrum

Copy Number Variation Distribution in Six Monozygotic Twin Pairs Discordant for Schizophrenia

2014 ◽  
Vol 17 (2) ◽  
pp. 108-120 ◽  
Author(s):  
Christina A. Castellani ◽  
Zain Awamleh ◽  
Melkaye G. Melka ◽  
Richard L. O'Reilly ◽  
Shiva M. Singh
Keyword(s):  
Copy Number ◽  
De Novo ◽  
Twin Pair ◽  
Neurodevelopmental Disorder ◽  
Copy Number Variants ◽  
Monozygotic Twins ◽  
Monozygotic Twin ◽  
Chain Reaction ◽  
Number Variation ◽  
Polymerase Chain

We have evaluated copy number variants (CNVs) in six monozygotic twin pairs discordant for schizophrenia. The data from Affymetrix® Human SNP 6.0 arrays™ were analyzed using Affymetrix® Genotyping Console™, Partek® Genomics Suite™, PennCNV, and Golden Helix SVS™. This yielded both program-specific and overlapping results. Only CNVs called by Affymetrix Genotyping Console, Partek Genomics Suite, and PennCNV were used in further analysis. This analysis included an assessment of calls in each of the six twin pairs towards identification of unique CNVs in affected and unaffected co-twins. Real time polymerase chain reaction (PCR) experiments confirmed one CNV loss at 7q11.21 that was found in the affected patient but not in the unaffected twin. The results identified CNVs and genes that were previously implicated in mental abnormalities in four of the six twin pairs. It included PYY (twin pairs 1 and 5), EPHA3 (twin pair 3), KIAA1211L (twin pair 4), and GPR139 (twin pair 5). They represent likely candidate genes and CNVs for the discordance of four of the six monozygotic twin pairs for this heterogeneous neurodevelopmental disorder. An explanation for these differences is ontogenetic de novo events that differentiate in the monozygotic twins during development.

O’Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum

2021 ◽  
pp. jmedgenet-2020-107470
Author(s):  
Clara Velmans ◽  
Anne H O'Donnell-Luria ◽  
Emanuela Argilli ◽  
Frederic Tran Mau-them ◽  
Antonio Vitobello ◽  
...  
Keyword(s):  
Sleep Disturbances ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Case Series ◽  
Autism Spectrum ◽  
Mild Intellectual Disability ◽  
Neurodevelopmental Delay ◽  
Phenotypic Spectrum ◽  
High Prevalence ◽  
High Relative Frequency

BackgroundO’Donnell-Luria-Rodan syndrome (ODLURO) is an autosomal-dominant neurodevelopmental disorder caused by pathogenic, mostly truncating variants in KMT2E. It was first described by O’Donnell-Luria et al in 2019 in a cohort of 38 patients. Clinical features encompass macrocephaly, mild intellectual disability (ID), autism spectrum disorder (ASD) susceptibility and seizure susceptibility.MethodsAffected individuals were ascertained at paediatric and genetic centres in various countries by diagnostic chromosome microarray or exome/genome sequencing. Patients were collected into a case cohort and were systematically phenotyped where possible.ResultsWe report 18 additional patients from 17 families with genetically confirmed ODLURO. We identified 15 different heterozygous likely pathogenic or pathogenic sequence variants (14 novel) and two partial microdeletions of KMT2E. We confirm and refine the phenotypic spectrum of the KMT2E-related neurodevelopmental disorder, especially concerning cognitive development, with rather mild ID and macrocephaly with subtle facial features in most patients. We observe a high prevalence of ASD in our cohort (41%), while seizures are present in only two patients. We extend the phenotypic spectrum by sleep disturbances.ConclusionOur study, bringing the total of known patients with ODLURO to more than 60 within 2 years of the first publication, suggests an unexpectedly high relative frequency of this syndrome worldwide. It seems likely that ODLURO, although just recently described, is among the more common single-gene aetiologies of neurodevelopmental delay and ASD. We present the second systematic case series of patients with ODLURO, further refining the mutational and phenotypic spectrum of this not-so-rare syndrome.

Delineating the genotypic and phenotypic spectrum of HECW2-related neurodevelopmental disorders

2021 ◽  
pp. jmedgenet-2021-107871
Author(s):  
Anushree Acharya ◽  
Haluk Kavus ◽  
Patrick Dunn ◽  
Abdul Nasir ◽  
Leandra Folk ◽  
...  
Keyword(s):  
Motor Coordination ◽  
De Novo ◽  
Language Disorder ◽  
Neurodevelopmental Disorder ◽  
Hect Domain ◽  
Complete Penetrance ◽  
Pathogenic Variants ◽  
Phenotypic Spectrum ◽  
Phenotype Analysis ◽  
Cortical Visual Impairment

BackgroundVariants in HECW2 have recently been reported to cause a neurodevelopmental disorder with hypotonia, seizures and impaired language; however, only six variants have been reported and the clinical characteristics have only broadly been defined.MethodsMolecular and clinical data were collected from clinical and research cohorts. Massive parallel sequencing was performed and identified individuals with a HECW2-related neurodevelopmental disorder.ResultsWe identified 13 novel missense variants in HECW2 in 22 unpublished cases, of which 18 were confirmed to have a de novo variant. In addition, we reviewed the genotypes and phenotypes of previously reported and new cases with HECW2 variants (n=35 cases). All variants identified are missense, and the majority of likely pathogenic and pathogenic variants are located in or near the C-terminal HECT domain (88.2%). We identified several clustered variants and four recurrent variants (p.(Arg1191Gln);p.(Asn1199Lys);p.(Phe1327Ser);p.(Arg1330Trp)). Two variants, (p.(Arg1191Gln);p.(Arg1330Trp)), accounted for 22.9% and 20% of cases, respectively. Clinical characterisation suggests complete penetrance for hypotonia with or without spasticity (100%), developmental delay/intellectual disability (100%) and developmental language disorder (100%). Other common features are behavioural problems (88.9%), vision problems (83.9%), motor coordination/movement (75%) and gastrointestinal issues (70%). Seizures were present in 61.3% of individuals. Genotype-phenotype analysis shows that HECT domain variants are more frequently associated with cortical visual impairment and gastrointestinal issues. Seizures were only observed in individuals with variants in or near the HECT domain.ConclusionWe provide a comprehensive review and expansion of the genotypic and phenotypic spectrum of HECW2 disorders, aiding future molecular and clinical diagnosis and management.

scholarly journals SYT1-associated neurodevelopmental disorder: a case series

Brain ◽  
2018 ◽  
Vol 141 (9) ◽  
pp. 2576-2591 ◽  
Author(s):  
Kate Baker ◽  
Sarah L Gordon ◽  
Holly Melland ◽  
Fabian Bumbak ◽  
Daniel J Scott ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Case Series ◽  
Missense Mutations ◽  
Severe Intellectual Disability ◽  
Specific Manner ◽  
Synaptotagmin 1 ◽  
Presynaptic Vesicle ◽  
Key Features

Baker, Gordon et al. present the first international case series describing the neurodevelopmental disorder associated with Synaptotagmin 1 (SYT1) de novo missense mutations. Key features include movement abnormalities, severe intellectual disability, and hallmark EEG alterations. Expression of patients’ SYT1 mutations in mouse neurons disturbs presynaptic vesicle dynamics in a mutation-specific manner.

scholarly journals A familial case of CAMK2B mutation with variable expressivity

2021 ◽  
Vol 9 ◽  
pp. 2050313X2199098
Author(s):  
Paige Heiman ◽  
Sarah Drewes ◽  
Lina Ghaloul-Gonzalez
Keyword(s):  
Intellectual Disability ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Clinical Manifestations ◽  
Cerebellar Atrophy ◽  
Global Developmental Delay ◽  
De Novo Mutations ◽  
Phenotypic Spectrum ◽  
Behavioral Abnormalities ◽  
Intrafamilial Variability

Variants in CAMK2-associated genes have recently been implicated in neurodevelopmental disorders and intellectual disability. The clinical manifestations reported in patients with mutations in these genes include intellectual disability (ranging from mild to severe), global developmental delay, seizures, delayed speech, behavioral abnormalities, hypotonia, episodic ataxia, progressive cerebellar atrophy, visual impairments, and gastrointestinal issues. Phenotypic heterogeneity has been postulated. We present a child with neurodevelopmental disorder caused by a pathogenic CAMK2B variant inherited from a healthy mother. A more mildly affected sib was determined to have the same variant. Monoallelic mutations in CAMK2B in patients have previously only been reported as de novo mutations. This report adds to the clinical phenotypic spectrum of the disease and demonstrates intrafamilial variability of expression of a CAMK2B mutation.

scholarly journals Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kohei Kitagawa ◽  
Kensuke Matsumura ◽  
Masayuki Baba ◽  
Momoka Kondo ◽  
Tomoya Takemoto ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Behavior ◽  
Mouse Model ◽  
Mouse Models ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutation ◽  
Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

scholarly journals Dravet syndrome associated mutations in GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABAA receptors

2021 ◽  
Author(s):  
Ciria C Hernandez ◽  
XiaoJuan Tian ◽  
Ningning Hu ◽  
Wangzhen Shen ◽  
Mackenzie A Catron ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
De Novo ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
First Year ◽  
Genes Encoding ◽  
Genetic Landscape ◽  
Clonic Seizures ◽  
Trafficking Defects ◽  
First Year Of Life

Abstract Dravet syndrome is a rare, catastrophic epileptic encephalopathy that begins in the first year of life, usually with febrile or afebrile hemiclonic or generalized tonic-clonic seizures followed by status epilepticus. De novo variants in genes that mediate synaptic transmission such as SCN1A and PCDH19 are often associated with Dravet syndrome. Recently, GABAA receptor subunit genes (GABRs) encoding α1 (GABRA1), β3 (GABRB3) and γ2 (GABRG2), but not β2 (GABRB2) or β1 (GABRB1), subunits are frequently associated with Dravet syndrome or Dravet syndrome-like phenotype. We performed next generation sequencing on 870 patients with Dravet syndrome and identified nine variants in three different GABRs. Interestingly, the variants were all in genes encoding the most common GABAA receptor, the α1β2γ2 receptor. Mutations in GABRA1 (c.644T>C, p.L215P; c.640C>T, p.R214C; c.859G>A; V287I; c.641G>A, p.R214H) and GABRG2 (c.269C>G, p.T90R; c.1025C>T, p.P342L) presented as de novo cases, while in GABRB2 two variants were de novo (c.992T>C, p.F331S; c.542A>T, p.Y181F) and one was autosomal dominant and inherited from the maternal side (c.990_992del, p.330_331del). We characterized the effects of these GABR variants on GABAA receptor biogenesis and channel function. We found that defects in receptor gating were the common deficiency of GABRA1 and GABRB2 Dravet syndrome variants, while mainly trafficking defects were found with the GABRG2 (c.269C>G, p.T90R) variant. It seems that variants in α1 and β2 subunits are less tolerated than in γ2 subunits, since variant α1 and β2 subunits express well but were functionally deficient. This suggests that all of these GABR variants are all targeting GABR genes that encode the assembled α1β2γ2 receptor, and regardless of which of the three subunits are mutated, variants in genes coding for α1, β2 and γ2 receptor subunits make them candidate causative genes in the pathogenesis of Dravet syndrome.

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