scholarly journals De novo missense variants in SLC32A1 cause a neurodevelopmental disorder with epilepsy due to impaired GABAergic neurotransmission

2021 ◽  
Author(s):  
Konrad Platzer ◽  
Heinrich Sticht ◽  
Caleb Bupp ◽  
Mythily Ganapathi ◽  
Elaine M. Pereira ◽  
...  
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disorder ◽  
High Frequency Stimulation ◽  
Transport Pathway ◽  
Gabaergic Neurotransmission ◽  
Missense Variants ◽  
Quantal Size ◽  
Severe Intellectual Disability ◽  
Dyskinetic Movement ◽  
Frequency Stimulation

We describe four patients with a neurodevelopmental disorder and de novo missense variants in SLC32A1, the gene that encodes the vesicular GABA transporter (VGAT). The main phenotype comprises moderate to severe intellectual disability, early onset epilepsy within the first 18 months of life and a choreatic, dystonic or dyskinetic movement disorder. In silico modeling and functional analyses in cultured neurons reveal that three of these variants, which are located in helices that line the putative GABA transport pathway, result in reduced quantal size, consistent with impaired filling of synaptic vesicles with GABA. The fourth variant, located in the VGAT N-terminus, does not affect quantal size, but increases presynaptic release probability, leading to more severe synaptic depression during high frequency stimulation. Thus, variants in VGAT can impair GABAergic neurotransmission via at least two mechanisms, by affecting synaptic vesicle filling and by altering synaptic short-term plasticity. This work establishes de novo missense variants in SLC32A1 as a novel cause for a neurodevelopmental disorder with epilepsy.

scholarly journals Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Ilaria Mannucci ◽  
Nghi D. P. Dang ◽  
Hannes Huber ◽  
Jaclyn B. Murry ◽  
Jeff Abramson ◽  
...  
Keyword(s):  
De Novo ◽  
Clinical Course ◽  
Neurodevelopmental Disorder ◽  
Global Developmental Delay ◽  
Helicase Activity ◽  
Speech Impairment ◽  
Human Phenotype ◽  
Missense Variants ◽  
The Impact ◽  
Global Translation

Abstract Background We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder. Methods Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays. Results We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype. Conclusions Our study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories.

Recurrent de novo missense variants in GNB2 can cause syndromic intellectual disability

2021 ◽  
pp. jmedgenet-2020-107462
Author(s):  
Natalie B Tan ◽  
Alistair T Pagnamenta ◽  
Matteo P Ferla ◽  
Jonathan Gadian ◽  
Brian HY Chung ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
G Proteins ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Missense Variant ◽  
Cellular Functions ◽  
Missense Variants ◽  
Neurodevelopmental Disease ◽  
Genes Encoding ◽  
International Data

PurposeBinding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Gα and Gβγ units. Human diseases have been reported for all five Gβ proteins. A de novo missense variant in GNB2 was recently reported in one individual with developmental delay/intellectual disability (DD/ID) and dysmorphism. We aim to confirm GNB2 as a neurodevelopmental disease gene, and elucidate the GNB2-associated neurodevelopmental phenotype in a patient cohort.MethodsWe discovered a GNB2 variant in the index case via exome sequencing and sought individuals with GNB2 variants via international data-sharing initiatives. In silico modelling of the variants was assessed, along with multiple lines of evidence in keeping with American College of Medical Genetics and Genomics guidelines for interpretation of sequence variants.ResultsWe identified 12 unrelated individuals with five de novo missense variants in GNB2, four of which are recurrent: p.(Ala73Thr), p.(Gly77Arg), p.(Lys89Glu) and p.(Lys89Thr). All individuals have DD/ID with variable dysmorphism and extraneurologic features. The variants are located at the universally conserved shared interface with the Gα subunit, which modelling suggests weaken this interaction.ConclusionMissense variants in GNB2 cause a congenital neurodevelopmental disorder with variable syndromic features, broadening the spectrum of multisystem phenotypes associated with variants in genes encoding G-proteins.

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.

scholarly journals Missense variants causing Wiedemann-Steiner syndrome preferentially occur in the KMT2A-CXXC domain and are accurately classified using AlphaFold2

2022 ◽  
Author(s):  
Tinna Reynisdottir ◽  
Kimberley Anderson ◽  
Leandros Boukas ◽  
Hans Bjornsson
Keyword(s):  
In Silico ◽  
Hippocampal Neurons ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Classification Performance ◽  
Saturation Mutagenesis ◽  
Biological Knowledge ◽  
Missense Variants ◽  
Mechanistic Basis ◽  
Insight Into

Wiedemann-Steiner syndrome (WSS) is a neurodevelopmental disorder caused by de novo variants in KMT2A, which encodes a multi–domain histone methyltransferase. To gain insight into the currently unknown pathogenesis of WSS, we examined the spatial distribution of likely WSS–causing variants across the 15 different domains of KMT2A. Compared to variants in healthy controls, WSS variants exhibit a 64.1–fold overrepresentation within the CXXC domain – which mediates binding to unmethylated CpGs – suggesting a major role for this domain in mediating the phenotype. In contrast, we find no significant overrepresentation within the catalytic SET domain. Corroborating these results, we find that hippocampal neurons from Kmt2a–deficient mice demonstrate disrupted H3K4me1 preferentially at CpG-rich regions, but this has no systematic impact on gene expression. Motivated by these results, we combine accurate prediction of the CXXC domain structure by AlphaFold2 with prior biological knowledge to develop a classification scheme for missense variants in the CXXC domain. Our classifier achieved 96.0% positive and 92.3% negative predictive value on a hold–out test set. This classification performance enabled us to subsequently perform an in silico saturation mutagenesis and classify a total of 445 variants according to their functional effects. Our results yield a novel insight into the mechanistic basis of WSS and provide an example of how AlphaFold2 can contribute to the in silico characterization of variant effects with very high accuracy, establishing a paradigm potentially applicable to many other Mendelian disorders.

Abstract 19466: Preliminary Experience Using Multiplexed Imaging of the Sympathetic Autonomic Nervous System - Impact on Outcome of Catheter Ablation of Atrial Fibrillation

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Sabine Ernst ◽  
Francesca Menichetti ◽  
Rafael Baavour ◽  
Nathaniel Roth ◽  
Jamshed Bomanji ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Catheter Ablation ◽  
High Frequency ◽  
De Novo ◽  
Imaging Study ◽  
High Frequency Stimulation ◽  
High Uptake ◽  
Af Ablation ◽  
Uptake Sites ◽  
Frequency Stimulation

Introduction: Catheter ablation of ganglionated plexi (GP) as an add on to pulmonary vein (PV) isolation has been reported to significantly improve outcome of atrial fibrillation (AF) ablation. In order to facilitate localization of these GPs, a novel imaging study is proposed, assessing the uptake of iodine-123 metaiodobenzylguanidine (mIBG, an analog of norepinephrine)in combination with 3D surface reconstruction from contrast computed tomography (cCT) or cardiac magnetic resonance (CMR). Methods: A total of 8 patients (5 male, median age 58 yrs) underwent mIBG SPECT using a dedicated cardiac camera (D-SPECT, SUMO, Spectrum Dynamics). This data was merged with 3D CMR or cCT and finally imported into CARTO (Biosense Webster). Using the individual mediastinum uptake as a normalizing factor, high uptake sites in the epicardial fat pads around the left atrium (LA) were identified. Five patients had paroxysmal AF whilst 3 present in persistent (n=2) or longstanding persistent (n=1) AF. Only 3 patients were treated de-novo, with the remaining failing in median 2 previous ablation procedures. Invasively, high uptake sites were mapped using high frequency stimulation (HFS) to confirm GP locations, which were subsequently ablated. PV (re) isolation and CFAE ablation was performed as needed. Results: Both the mIBG and CT or CMR scans were performed without complications. Focal mIBG uptake sites corresponded to anatomical GP sites, but individual variations of additional GPs were observed. Using HFS stimulation, GP sites were confirmed, but exact localization was highly depending on accurate image registration. Median follow-up of 9.2 months with all PAF and persistent AF patients in SR (1 AT redo), while the long-standing AF relapsed. Conclusion: The combination of mIBG SPECT and 3D anatomical imaging (SUMO protocol) provides a novel type of “road map” for localizing GPs during AF ablation. GPs were variable in number and location and were invasively confirmed using high frequency stimulation. Addition of GP ablation to standard AF ablation strategies seems beneficial in patients with paroxysmal or persistent AF. Further studies in larger patient cohorts are needed to confirm these initial observations.

scholarly journals Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

2021 ◽  
Author(s):  
Felix Marbach ◽  
◽  
Georgi Stoyanov ◽  
Florian Erger ◽  
Constantine A. Stratakis ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Global Developmental Delay ◽  
Missense Variants ◽  
Large Patient ◽  
Significant Enrichment

Abstract Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.

scholarly journals Predicting functional effect of missense variants using graph attention neural networks

2021 ◽  
Author(s):  
Haicang Zhang ◽  
Michelle S. Xu ◽  
Wendy K. Chung ◽  
Yufeng Shen
Keyword(s):  
Neural Networks ◽  
Large Scale ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Missense Variants ◽  
Scale Population ◽  
Scan Data ◽  
Main Component

AbstractAccurate prediction of damaging missense variants is critically important for interpretating genome sequence. While many methods have been developed, their performance has been limited. Recent progress in machine learning and availability of large-scale population genomic sequencing data provide new opportunities to significantly improve computational predictions. Here we describe gMVP, a new method based on graph attention neural networks. Its main component is a graph with nodes capturing predictive features of amino acids and edges weighted by coevolution strength, which enables effective pooling of information from local protein sequence context and functionally correlated distal positions. Evaluated by deep mutational scan data, gMVP outperforms published methods in identifying damaging variants in TP53, PTEN, BRCA1, and MSH2. Additionally, it achieves the best separation of de novo missense variants in neurodevelopmental disorder cases from the ones in controls. Finally, the model supports transfer learning to optimize gain- and loss-of-function predictions in sodium and calcium channels. In summary, we demonstrate that gMVP can improve interpretation of missense variants in clinical testing and genetic studies.

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

scholarly journals Heterozygous variants that disturb the transcriptional repressor activity of FOXP4 cause a developmental disorder with speech/language delays and multiple congenital abnormalities

2020 ◽  
Author(s):  
Lot Snijders Blok ◽  
Arianna Vino ◽  
Joery den Hoed ◽  
Hunter R. Underhill ◽  
Danielle Monteil ◽  
...  
Keyword(s):  
Clinical Data ◽  
Developmental Disorders ◽  
Congenital Abnormalities ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Transcriptional Repressor ◽  
Missense Variant ◽  
Language Delays ◽  
Loss Of Function ◽  
Missense Variants

Abstract Purpose Heterozygous pathogenic variants in various FOXP genes cause specific developmental disorders. The phenotype associated with heterozygous variants in FOXP4 has not been previously described. Methods We assembled a cohort of eight individuals with heterozygous and mostly de novo variants in FOXP4: seven individuals with six different missense variants and one individual with a frameshift variant. We collected clinical data to delineate the phenotypic spectrum, and used in silico analyses and functional cell-based assays to assess pathogenicity of the variants. Results We collected clinical data for six individuals: five individuals with a missense variant in the forkhead box DNA-binding domain of FOXP4, and one individual with a truncating variant. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia, cervical spine abnormalities, and ptosis. Luciferase assays showed loss-of-function effects for all these variants, and aberrant subcellular localization patterns were seen in a subset. The remaining two missense variants were located outside the functional domains of FOXP4, and showed transcriptional repressor capacities and localization patterns similar to the wild-type protein. Conclusion Collectively, our findings show that heterozygous loss-of-function variants in FOXP4 are associated with an autosomal dominant neurodevelopmental disorder with speech/language delays, growth defects, and variable congenital abnormalities.

scholarly journals Genotype-phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

2020 ◽  
Author(s):  
Ilaria Mannucci ◽  
Nan Cher Yeo ◽  
Hannes Huber ◽  
Jaclyn Murry ◽  
Jeff Abramson ◽  
...  
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Missense Variant ◽  
Stress Granule ◽  
Helicase Activity ◽  
Speech Impairment ◽  
Granule Formation ◽  
Missense Variants ◽  
Functional Analyses ◽  
Global Translation

Background We aimed to define the clinical and mutational spectrum, and to provide novel molecular insights into DHX30-associated neurodevelopmental disorder. Methods Clinical and genetic data from affected individuals were collected through family support group, GeneMatcher and our network of collaborators. Novel missense variants were investigated by in-vitro and in-vivo assays. These analyses included investigation of stress granule formation, global translation, ATPase and helicase activity, as well as the effect of selected variants on embryonal development in Zebrafish. Results We identified altogether 25 previously unreported individuals. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30 and global translation, trigger stress granule formation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented a milder clinical course, similar to an individual bearing a de novo mosaic missense variant within HCM. Late-onset severe ataxia was observed in an individual with a de novo missense variant within the ratchet-like domain, and early-onset lethal epileptic encephalopathy in an individual with a homozygous missense variant within the helicase core region but not within a HCM. We report ten novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. Functional analyses confirmed pathogenicity of all missense variants, and suggest the existence of clinically distinct subtypes that correlate with their location and nature. Moreover, we established here DHX30 as an ATP-dependent RNA helicase. Conclusions Our study highlights the usefulness of social media in order to define novel Mendelian disorders, and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected, clinicians, molecular genetics diagnostic laboratories and research laboratories.

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