scholarly journals Heterozygous variants in KMT2E cause a spectrum of neurodevelopmental disorders and epilepsy

2019 ◽  
Author(s):  
Anne H O'Donnell-Luria ◽  
Lynn S Pais ◽  
Victor Faundes ◽  
Jordan C Wood ◽  
Abigail Sveden ◽  
...  
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Epileptic Encephalopathy ◽  
Dominant Negative ◽  
Mild Intellectual Disability ◽  
Negative Effects ◽  
Missense Variants ◽  
Neurodevelopmental Abnormalities ◽  
Almost All ◽  
Gastrointestinal Abnormalities

We delineate a KMT2E gene-related neurodevelopmental disorder based on 38 individuals in 36 families. This includes 31 distinct heterozygous variants in the KMT2E gene (28 ascertained from Matchmaker Exchange and 3 previously reported), and 4 individuals with chromosome 7q22.2-22.23 microdeletions encompassing the KMT2E gene (1 previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants, and was responsive to treatment with anti-epileptic medications in almost all. Over 70% of the individuals were male and expressivity was variable by sex, with epilepsy more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant negative effects specific to these missense variants in KMT2E may explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

scholarly journals Loss–of–function variants in the KCNQ5 gene are associated with genetic generalized epilepsies

2021 ◽  
Author(s):  
Johanna Krueger ◽  
Julian Schubert ◽  
Josua Kegele ◽  
Audrey Labalme ◽  
Miaomiao Mao ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
De Novo ◽  
Surface Expression ◽  
Epileptic Encephalopathy ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
K Channel ◽  
Loss Of Function ◽  
Normal Surface ◽  
Missense Variants

Objective: De novo missense variants in KCNQ5, encoding the voltage–gated K+ channel KV7.5, have been described as a cause of developmental and epileptic encephalopathy (DEE) or intellectual disability (ID). We set out to identify disease–related KCNQ5 variants in genetic generalized epilepsy (GGE) and their underlying mechanisms. Methods: 1292 families with GGE were studied by next-generation sequencing. Whole–cell patch–clamp recordings, biotinylation and phospholipid overlay assays were performed in mammalian cells combined with docking and homology modeling. Results: We identified three deleterious heterozygous missense variants, one truncation and one splice site alteration in five independent families with GGE with predominant absence seizures, two variants were also associated with mild to moderate ID. All three missense variants displayed a strongly decreased current density indicating a loss–of–function (LOF). When mutant channels were co–expressed with wild–type (WT) KV7.5 or KV7.5 and KV7.3 channels, three variants also revealed a significant dominant–negative effect on WT channels. Other gating parameters were unchanged. Biotinylation assays indicated a normal surface expression of the variants. The p.Arg359Cys variant altered PI(4,5)P2–interaction, presumably in the non–conducting preopen–closed state. Interpretation: Our study indicates that specific deleterious KCNQ5 variants are associated with GGE, partially combined with mild to moderate ID. The disease mechanism is a LOF partially with dominant–negative effects through functional, rather than trafficking deficits. LOF of KV7.5 channels will reduce the M–current, likely resulting in increased excitability of KV7.5–expressing neurons. Further studies on a network level are necessary to understand which circuits are affected and how the variants induce generalized seizures.

scholarly journals Pathogenic MAST3 variants in the STK domain are associated with epilepsy

2021 ◽  
Author(s):  
Egidio Spinelli ◽  
Kyle R Christensen ◽  
Emily Bryant ◽  
Amy Schneider ◽  
Jennifer Rakotomamonjy ◽  
...  
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Expression Patterns ◽  
Prenatal Development ◽  
Epileptic Encephalopathy ◽  
Patient Specific ◽  
Gain Of Function ◽  
Missense Variants ◽  
Excitatory Neurons

AbstractObjectiveThe MAST family of microtubule-associated serine-threonine kinases (STK) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum.MethodsUsing exome sequencing we identify MAST3 missense variants in individuals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP-16 in HEK293T cells.ResultsWe identify de novo missense variants in the STK domain in 11 individuals, including two recurrent variants p.G510S (n=5) and p.G515S (n=3). All 11 individuals had Developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at < 2 years of age. All patients developed multiple seizures types, while 9/11 had seizures triggered by fever and 9/11 had drug-resistant seizures. In vitro analysis of HEK293T cells transfected with MAST3 cDNA carrying a subset of these patient-specific missense variants demonstrated variable but generally lower expression, with concomitant increased phosphorylation of the MAST3 target, ARPP-16, compared to wildtype. These findings suggest the patient-specific variants may confer MAST3 gain-of-function. Moreover, single-nuclei RNA sequencing and immunohistochemistry shows that MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally.InterpretationIn summary, we describe MAST3 as a novel epilepsy-associated gene with a potential gain-of-function pathogenic mechanism that may be primarily restricted to excitatory neurons in the cortex.

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.

Heterozygous Missense Pathogenic Variants Within the Second Spectrin Repeat of SPTBN2 Lead to Infantile-Onset Cerebellar Ataxia

2019 ◽  
Vol 35 (2) ◽  
pp. 106-110 ◽  
Author(s):  
Andrea Accogli ◽  
Judith St-Onge ◽  
Nassima Addour-Boudrahem ◽  
Joël Lafond-Lapalme ◽  
Alexandre Dionne Laporte ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cerebellar Ataxia ◽  
De Novo ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Adult Onset ◽  
Spinocerebellar Ataxias ◽  
Spectrin Repeat ◽  
Missense Variants ◽  
Pathogenic Variants

The term spinocerebellar ataxia encompasses a heterogeneous group of neurodegenerative disorders due to pathogenic variants in more than 100 genes, underlying 2 major groups of ataxia: autosomal dominant cerebellar ataxias (ADCA, also known as spinocerebellar ataxias [SCAs]) due to heterozygous variants or polyglutamine triplet expansions leading to adult-onset ataxia, and autosomal recessive spinocerebellar ataxias (ARCAs, also known as SCARs) due to biallelic variants, usually resulting in more severe and earlier-onset cerebellar ataxia. Certain ataxia genes, including SPTBN2 which encodes β-III spectrin, are responsible for both SCA and SCAR, depending on whether the pathogenic variant occurs in a monoallelic or biallelic state, respectively. Accordingly, 2 major phenotypes have been linked to SPTBN2: pathogenic heterozygous in-frame deletions and missense variants result in an adult-onset, slowly progressive ADCA (SCA5) through a dominant negative effect, whereas biallelic loss-of-function variants cause SCAR14, an allelic disorder characterized by infantile-onset cerebellar ataxia and cognitive impairment. Of note, 2 heterozygous missense variants (c.1438C>T, p.R480 W; c.1309C>G, p.R437G), both lying in the second spectrin repeat of SPTBN2, have been linked to infantile-onset cerebellar ataxia, similar to SCAR14. Here, we report a novel de novo heterozygous pathogenic missense variant (c.1310G>A) in SPTBN2 in a child with infantile-onset cerebellar ataxia and mild cognitive impairment. This variant affects the same R437 residue of the second spectrin repeat but results in a different amino acid change (p.R437Q). We review previously reported cases and discuss possible pathomechanisms responsible for the early-onset cerebellar phenotype due to disease-causing variants in the second spectrin repeat.

scholarly journals Translational readthrough of GLA nonsense mutations suggests dominant-negative effects exerted by the interaction of wild-type and missense variants

RNA Biology ◽  
2019 ◽  
Vol 17 (2) ◽  
pp. 254-263 ◽  
Author(s):  
Silvia Lombardi ◽  
Mattia Ferrarese ◽  
Saverio Marchi ◽  
Paolo Pinton ◽  
Mirko Pinotti ◽  
...  
Keyword(s):  
Dominant Negative ◽  
Wild Type ◽  
Negative Effects ◽  
Nonsense Mutations ◽  
Missense Variants ◽  
Translational Readthrough

scholarly journals Molecular Dissection of Neurodevelopmental Disorder-Causing Mutations in CYFIP2

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1355
Author(s):  
Matthias Schaks ◽  
Michael Reinke ◽  
Walter Witke ◽  
Klemens Rottner
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Small Gtpases ◽  
Normal Brain ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Neuronal Morphogenesis ◽  
Variable Extent ◽  
Regulatory Complex ◽  
Almost All

Actin remodeling is frequently regulated by antagonistic activities driving protrusion and contraction downstream of Rac and Rho small GTPases, respectively. WAVE regulatory complex (WRC), which primarily operates downstream of Rac, plays pivotal roles in neuronal morphogenesis. Recently, two independent studies described de novo mutations in the CYFIP2 subunit of WRC, which caused intellectual disability (ID) in humans. Although mutations had been proposed to effect WRC activation, no experimental evidence for this was provided. Here, we made use of CRISPR/Cas9-engineered B16-F1 cell lines that were reconstituted with ID-causing CYFIP variants in different experimental contexts. Almost all CYFIP2-derived mutations (7 out of 8) promoted WRC activation, but to variable extent and with at least two independent mechanisms. The majority of mutations occurs in a conserved WAVE-binding region, required for WRC transinhibition. One mutation is positioned closely adjacent to the Rac-binding A site and appears to ease Rac-mediated WRC activation. As opposed to these gain-of-function mutations, a truncating mutant represented a loss-of-function variant and failed to interact with WRC components. Collectively, our data show that explored CYFIP2 mutations frequently, but not always, coincide with WRC activation and suggest that normal brain development requires a delicate and precisely tuned balance of neuronal WRC activity.

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 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.

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.

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