scholarly journals Variants in the SK2 channel gene (KCNN2) lead to dominant neurodevelopmental movement disorders

Brain ◽  
2020 ◽  
Author(s):  
Fanny Mochel ◽  
Agnès Rastetter ◽  
Berten Ceulemans ◽  
Konrad Platzer ◽  
Sandra Yang ◽  
...  
Keyword(s):  
Cerebellar Ataxia ◽  
Movement Disorders ◽  
De Novo ◽  
Brain Mri ◽  
Missense Variant ◽  
Loss Of Function ◽  
Patch Clamp Technique ◽  
Abnormal Gait ◽  
Frameshift Deletion ◽  
Uncertain Significance

Abstract KCNN2 encodes the small conductance calcium-activated potassium channel 2 (SK2). Rodent models with spontaneous Kcnn2 mutations show abnormal gait and locomotor activity, tremor and memory deficits, but human disorders related to KCNN2 variants are largely unknown. Using exome sequencing, we identified a de novo KCNN2 frameshift deletion in a patient with learning disabilities, cerebellar ataxia and white matter abnormalities on brain MRI. This discovery prompted us to collect data from nine additional patients with de novo KCNN2 variants (one nonsense, one splice site, six missense variants and one in-frame deletion) and one family with a missense variant inherited from the affected mother. We investigated the functional impact of six selected variants on SK2 channel function using the patch-clamp technique. All variants tested but one, which was reclassified to uncertain significance, led to a loss-of-function of SK2 channels. Patients with KCNN2 variants had motor and language developmental delay, intellectual disability often associated with early-onset movement disorders comprising cerebellar ataxia and/or extrapyramidal symptoms. Altogether, our findings provide evidence that heterozygous variants, likely causing a haploinsufficiency of the KCNN2 gene, lead to novel autosomal dominant neurodevelopmental movement disorders mirroring phenotypes previously described in rodents.

scholarly journals Primary aldosteronism associated with a germline variant in CACNA1H

2019 ◽  
Vol 12 (5) ◽  
pp. e229031 ◽  
Author(s):  
Kendra Wulczyn ◽  
Edward Perez-Reyes ◽  
Robert L Nussbaum ◽  
Meyeon Park
Keyword(s):  
Primary Aldosteronism ◽  
De Novo ◽  
Missense Variant ◽  
Laboratory Evaluation ◽  
Loss Of Function ◽  
Aldosterone Secretion ◽  
Whole Exome ◽  
Voltage Dependent ◽  
Cell Current ◽  
Voltage Sensing Domain

The CACNA1H gene encodes the pore-forming α1 subunit of the T-type voltage-dependent calcium channel CaV3.2, expressed abundantly in the adrenal cortex. Mutations in CACNA1H are associated with various forms of primary aldosteronism (PA), including familial hyperaldosteronism type 4 (FH4). We describe a patient with refractory hypokalaemia and elevated aldosterone secretion independent of renin activity. Despite the absence of overt hypertension in this patient, the laboratory evaluation was consistent with a diagnosis of PA. Whole-exome sequencing revealed a de novo missense variant, R890H, in the voltage sensing domain of CACNA1H. Expression of the variant channel in cells resulted in decreased whole-cell current, consistent with a loss-of-function. We hypothesise this variant is the genetic cause of pathological aldosterone secretion in this patient, and thereby expand the current understanding of the genetic basis of FH4.

scholarly journals De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies including Myoclonic Atonic Epilepsy

2021 ◽  
Author(s):  
Sathiya N. Manivannan ◽  
Jolien Roovers ◽  
Noor Smal ◽  
Candace T. Myers ◽  
Dilsad Turkdogan ◽  
...  
Keyword(s):  
De Novo ◽  
Statistical Tests ◽  
Essential Feature ◽  
Missense Variant ◽  
Anaphase Promoting Complex ◽  
Loss Of Function ◽  
Childhood Onset ◽  
Epileptic Encephalopathies ◽  
Missense Variants ◽  
Generalized Epilepsy

FZR1, which encodes the Cdh1 subunit of the Anaphase Promoting Complex, plays an important role in neurodevelopment, both through the control of the cell cycle and through its multiple functions in post-mitotic neurons. In this study, the evaluation of 250 unrelated patients with developmental epileptic encephalopathies (DEE) and a connection on GeneMatcher led to the identification of three de novo missense variants in FZR1. Two variants led to the same amino acid change. All individuals had a DEE with childhood-onset generalized epilepsy, intellectual disability, mild ataxia, and normal head circumference. Two individuals were diagnosed with the DEE subtype Myoclonic Atonic Epilepsy (MAE). We provide gene burden testing using two independent statistical tests to support FZR1 association with DEE. Further, we provide functional evidence that the missense variants are loss-of-function (LOF) alleles using Drosophila neurodevelopment assays. Using three fly mutant alleles of the Drosophila homolog fzr and overexpression studies, we show that patient variants do not support proper neurodevelopment. Along with a recent report of a patient with neonatal-onset DEE with microcephaly who also carries a de novo FZR1 missense variant, our study consolidates the relationship between FZR1 and DEE, and expands the associated phenotype. We conclude that heterozygous LOF of FZR1 leads to DEE associated with a spectrum of neonatal to childhood-onset seizure types, developmental delay, and mild ataxia. Microcephaly can be present but is not an essential feature of FZR1-encephalopathy. In summary, our approach of targeted sequencing using novel gene candidates and functional testing in Drosophila will help solve undiagnosed MAE/DEE cases.

scholarly journals A genome-wide DNA methylation signature for SETD1B-related syndrome

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
I. M. Krzyzewska ◽  
S. M. Maas ◽  
P. Henneman ◽  
K. v. d. Lip ◽  
A. Venema ◽  
...  
Keyword(s):  
Clinical Utility ◽  
De Novo ◽  
Histone H3 ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Variant Of Uncertain Significance ◽  
Epigenetic Marker ◽  
Genome Wide ◽  
A Genome ◽  
Uncertain Significance

Abstract SETD1B is a component of a histone methyltransferase complex that specifically methylates Lys-4 of histone H3 (H3K4) and is responsible for the epigenetic control of chromatin structure and gene expression. De novo microdeletions encompassing this gene as well as de novo missense mutations were previously linked to syndromic intellectual disability (ID). Here, we identify a specific hypermethylation signature associated with loss of function mutations in the SETD1B gene which may be used as an epigenetic marker supporting the diagnosis of syndromic SETD1B-related diseases. We demonstrate the clinical utility of this unique epi-signature by reclassifying previously identified SETD1B VUS (variant of uncertain significance) in two patients.

scholarly journals Missense variant contribution to USP9X-female syndrome

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Lachlan A. Jolly ◽  
Euan Parnell ◽  
Alison E. Gardner ◽  
Mark A. Corbett ◽  
Luis A. Pérez-Jurado ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
De Novo ◽  
Missense Variant ◽  
Loss Of Function ◽  
Partial Loss ◽  
The Core ◽  
Combined Application ◽  
Phenotypic Information ◽  
Pathogenic Variation ◽  
Males And Females

AbstractUSP9X is an X-chromosome gene that escapes X-inactivation. Loss or compromised function of USP9X leads to neurodevelopmental disorders in males and females. While males are impacted primarily by hemizygous partial loss-of-function missense variants, in females de novo heterozygous complete loss-of-function mutations predominate, and give rise to the clinically recognisable USP9X-female syndrome. Here we provide evidence of the contribution of USP9X missense and small in-frame deletion variants in USP9X-female syndrome also. We scrutinise the pathogenicity of eleven such variants, ten of which were novel. Combined application of variant prediction algorithms, protein structure modelling, and assessment under clinically relevant guidelines universally support their pathogenicity. The core phenotype of this cohort overlapped with previous descriptions of USP9X-female syndrome, but exposed heightened variability. Aggregate phenotypic information of 35 currently known females with predicted pathogenic variation in USP9X reaffirms the clinically recognisable USP9X-female syndrome, and highlights major differences when compared to USP9X-male associated neurodevelopmental disorders.

scholarly journals Novel clinical and genetic insight into CXorf56-associated intellectual disability

2019 ◽  
Vol 28 (3) ◽  
pp. 367-372 ◽  
Author(s):  
Maria Eugenia Rocha ◽  
Tainá Regina Damaceno Silveira ◽  
Erina Sasaki ◽  
Daíse Moreno Sás ◽  
Charles Marques Lourenço ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
De Novo ◽  
Causative Role ◽  
Loss Of Function ◽  
Abnormal Gait ◽  
Genomic Approach ◽  
Neurological Features ◽  
Male Patients ◽  
Molecular Anatomy

AbstractIntellectual disability (ID) is one of most frequent reasons for genetic consultation. The complex molecular anatomy of ID ranges from complete chromosomal imbalances to single nucleotide variant changes occurring de novo, with thousands of genes identified. This extreme genetic heterogeneity challenges the molecular diagnosis, which mostly requires a genomic approach. CXorf56 is largely uncharacterized and was recently proposed as a candidate ID gene based on findings in a single Dutch family. Here, we describe nine cases (six males and three females) from three unrelated families. Exome sequencing and combined database analyses, identified family-specific CXorf56 variants (NM_022101.3:c.498_503del, p.(Glu167_Glu168del) and c.303_304delCTinsACCC, p.(Phe101Leufs*20)) that segregated with the ID phenotype. These variants are presumably leading to loss-of-function, which is the proposed disease mechanism. Clinically, CXorf56-related disease is a slowly progressive neurological disorder. The phenotype is more severe in hemizygote males, but might also manifests in heterozygote females, which showed skewed X-inactivation patterns in blood. Male patients might present previously unreported neurological features such as epilepsy, abnormal gait, tremor, and clonus, which extends the clinical spectrum of the disorder. In conclusion, we confirm the causative role of variants in CXorf56 for an X-linked form of intellectual disability with additional neurological features. The gene should be considered for molecular diagnostics of patients with ID, specifically when family history is suggestive of X-linked inheritance. Further work is needed to understand the role of this gene in neurodevelopment and intellectual disability.

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 The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation

2019 ◽  
Author(s):  
Robert G. Mealer ◽  
Bruce G. Jenkins ◽  
Chia-Yen Chen ◽  
Mark J. Daly ◽  
Tian Ge ◽  
...  
Keyword(s):  
Brain Mri ◽  
Trace Element Analysis ◽  
Missense Variant ◽  
Common Variant ◽  
Loss Of Function ◽  
Element Analysis ◽  
Glycome Profiling ◽  
Depth Analysis ◽  
Mri Scans ◽  
The Common

AbstractA common missense variant in SLC39A8 is convincingly associated with schizophrenia and several additional phenotypes. Homozygous loss-of-function mutations in SLC39A8 result in undetectable serum manganese (Mn) and a Congenital Disorder of Glycosylation (CDG) due to the exquisite sensitivity of glycosyltransferases to Mn concentration. Here, we identified several Mn-related changes in human carriers of the common SLC39A8 missense allele. Analysis of structural brain MRI scans showed a dose-dependent change in the ratio of T2w to T1w signal in several regions. Comprehensive trace element analysis confirmed a specific reduction of only serum Mn, and plasma protein N-glycome profiling revealed reduced complexity and branching. N-glycome profiling from two individuals with SLC39A8-CDG showed similar but more severe alterations in branching that improved with Mn supplementation, suggesting that the common variant exists on a spectrum of hypofunction with potential for reversibility. Characterizing the functional impact of this variant will enhance our understanding of schizophrenia pathogenesis and identify novel therapeutic targets and biomarkers of disease.SummaryA common variant in the manganese transporter SLC39A8 is associated with numerous phenotypes including schizophrenia. Mealer et. al. presents an in-depth analysis of brain MRI and plasma glycomics in human carriers of the common variant, identifying several manganese-related changes with potential for diagnostic and therapeutic biomarker development.

scholarly journals Pathogenic DNM1 Gene Variant Presenting With Unusually Nonsevere Neurodevelopmental Phenotype: A Case Report

2021 ◽  
Vol 7 (5) ◽  
pp. e618
Author(s):  
Elaine Choi ◽  
Breanne Dale ◽  
Rajesh RamachandranNair ◽  
Resham Ejaz
Keyword(s):  
Developmental Delays ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Brain Mri ◽  
Intractable Epilepsy ◽  
Missense Variant ◽  
Chromosomal Microarray ◽  
Gtpase Domain ◽  
Pathogenic Variants ◽  
Neurodevelopmental Phenotype

Background and ObjectivesTo date, all reports of pathogenic variants affecting the GTPase domain of the DNM1 gene have a clinically severe neurodevelopmental phenotype, including severe delays or intractable epilepsy. We describe a case with moderate developmental delays and self-resolved epilepsy.MethodsThe patient was followed by our neurology and genetics teams. After clinical examination and EEG to characterize the patient's presentation, we conducted etiologic workup including brain MRI, chromosomal microarray, genetic and metabolic investigations, and nerve conduction studies. Subsequently, we arranged an Intellectual Disability Plus Trio Panel.ResultsOur patient presented with seizures at 2 days old, requiring phenobarbital. She also had hypotonia, mild dysmorphic features, and mild ataxia. Although initial workup returned unremarkable, the trio gene panel identified a de novo heterozygous pathogenic missense variant in the DNM1 GTPase domain. Now 4 years old, she has been seizure-free for 3 years without ongoing treatment and has nonsevere developmental delays (e.g., ambulates independently and speaks 2-word phrases).DiscussionOur case confirms that not all individuals with DNM1 pathogenic variants, even affecting the GTPase domain, will present with intractable epilepsy or severe delays. Expanding the known clinical spectrum of dynamin-related neurodevelopmental disorder is crucial for patient prognostication and counseling.

scholarly journals Highly clustered de novo frameshift variants in the neuronal splicing factor NOVA2 result in a specific abnormal C terminal part and cause a severe form of intellectual disability with autistic features

2019 ◽  
Author(s):  
Francesca Mattioli ◽  
Gaelle Hayot ◽  
Nathalie Drouot ◽  
Bertrand Isidor ◽  
Jérémie Courraud ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Rna Binding ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Brain Mri ◽  
Severe Form ◽  
Neural Cells ◽  
Loss Of Function ◽  
Ataxic Gait ◽  
Feeding Difficulties

ABSTRACTThe Neuro-Oncological Ventral Antigen 2 NOVA2 protein is a major factor regulating neuron specific alternative splicing, previously associated with an acquired neurologic condition, the paraneoplastic opsoclonus-myoclonus ataxia (POMA). We report here six individuals with de novo frameshift variants in the NOVA2 gene affected with a severe neurodevelopmental disorder characterized by intellectual disability (ID), motor and speech delay, autistic features, hypotonia, feeding difficulties, spasticity or ataxic gait and abnormal brain MRI. The six variants lead to the same reading frame, adding a common 133 aa long proline rich C-terminus part instead of the last KH RNA binding domain. We detected forty-one genes differentially spliced after NOVA2 inactivation in human neural cells. The mutant NOVA2 protein shows decreased ability to bind a target RNA, to regulate specific splicing events and to rescue the phenotype of altered retinotectal axonal pathfinding induced by loss of NOVA2 ortholog in zebrafish. Our results suggest a partial loss-of-function mechanism rather than a full heterozygous loss of function, although a specific contribution of the novel C terminal extension cannot be excluded on the basis of the genetic findings.

scholarly journals Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness

2020 ◽  
Vol 29 (13) ◽  
pp. 2218-2239 ◽  
Author(s):  
Anne Slavotinek ◽  
Doriana Misceo ◽  
Stephanie Htun ◽  
Linda Mathisen ◽  
Eirik Frengen ◽  
...  
Keyword(s):  
Short Stature ◽  
Mammalian Cells ◽  
Developmental Delays ◽  
Brain Mri ◽  
Missense Variant ◽  
Cerebellar Hypoplasia ◽  
Loss Of Function ◽  
Feeding Difficulties ◽  
In Trans ◽  
Rna Exosome

Abstract The RNA exosome is an essential ribonuclease complex required for processing and/or degradation of both coding and non-coding RNAs. We identified five patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome. The clinical features of these patients include failure to thrive, short stature, feeding difficulties, developmental delays that affect motor skills, hypotonia and esotropia. Brain MRI revealed cerebellar hypoplasia and ventriculomegaly. While we ascertained five patients, three patients with distinct variants of EXOSC5 were studied in detail. The first patient had a deletion involving exons 5–6 of EXOSC5 and a missense variant, p.Thr114Ile, that were inherited in trans, the second patient was homozygous for p.Leu206His and the third patient had paternal isodisomy for chromosome 19 and was homozygous for p.Met148Thr. The additional two patients ascertained are siblings who had an early frameshift mutation in EXOSC5 and the p.Thr114Ile missense variant that were inherited in trans. We employed three complementary approaches to explore the requirement for EXOSC5 in brain development and assess consequences of pathogenic EXOSC5 variants. Loss of function for exosc5 in zebrafish results in shortened and curved tails/bodies, reduced eye/head size and edema. We modeled pathogenic EXOSC5 variants in both budding yeast and mammalian cells. Some of these variants cause defects in RNA exosome function as well as altered interactions with other RNA exosome subunits. These findings expand the number of genes encoding RNA exosome subunits linked to human disease while also suggesting that disease mechanism varies depending on the specific pathogenic variant.

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