A Novel WAC Loss of Function Mutation in an Individual Presenting with Encephalopathy Related to Status Epilepticus during Sleep (ESES)

WAC (WW Domain Containing Adaptor With Coiled-Coil) mutations have been reported in only 20 individuals presenting a neurodevelopmental disorder characterized by intellectual disability, neonatal hypotonia, behavioral problems, and mildly dysmorphic features. Using targeted deep sequencing, we screened a cohort of 630 individuals with variable degrees of intellectual disability and identified five WAC rare variants: two variants were inherited from healthy parents; two previously reported de novo mutations, c.1661_1664del (p.Ser554*) and c.374C>A (p.Ser125*); and a novel c.381+2T>C variant causing the skipping of exon 4 of the gene, inherited from a reportedly asymptomatic father with somatic mosaicism. A phenotypic evaluation of this individual evidenced areas of cognitive and behavioral deficits. The patient carrying the novel splicing mutation had a clinical history of encephalopathy related to status epilepticus during slow sleep (ESES), recently reported in another WAC individual. This first report of a WAC somatic mosaic remarks the contribution of mosaicism in the etiology of neurodevelopmental and neuropsychiatric disorders. We summarized the clinical data of reported individuals with WAC pathogenic mutations, which together with our findings, allowed for the expansion of the phenotypic spectrum of WAC-related disorders.

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Molecular Dissection of Neurodevelopmental Disorder-Causing Mutations in CYFIP2

Cells ◽

10.3390/cells9061355 ◽

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.

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Recapitulation of the EEF1A2 D252H neurodevelopmental disorder-causing missense mutation in mice reveals a toxic gain of function

Human Molecular Genetics ◽

10.1093/hmg/ddaa042 ◽

2020 ◽

Vol 29 (10) ◽

pp. 1592-1606 ◽

Cited By ~ 1

Author(s):

Faith C J Davies ◽

Jilly E Hope ◽

Fiona McLachlan ◽

Grant F Marshall ◽

Laura Kaminioti-Dumont ◽

...

Keyword(s):

Missense Mutation ◽

Molecular Modelling ◽

Neurodevelopmental Disorders ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Elongation Factor ◽

Missense Mutations ◽

Loss Of Function ◽

De Novo Mutations ◽

Gain Of Function

Abstract Heterozygous de novo mutations in EEF1A2, encoding the tissue-specific translation elongation factor eEF1A2, have been shown to cause neurodevelopmental disorders including often severe epilepsy and intellectual disability. The mutational profile is unusual; ~50 different missense mutations have been identified but no obvious loss of function mutations, though large heterozygous deletions are known to be compatible with life. A key question is whether the heterozygous missense mutations operate through haploinsufficiency or a gain of function mechanism, an important prerequisite for design of therapeutic strategies. In order both to address this question and to provide a novel model for neurodevelopmental disorders resulting from mutations in EEF1A2, we created a new mouse model of the D252H mutation. This mutation causes the eEF1A2 protein to be expressed at lower levels in brain but higher in muscle in the mice. We compared both heterozygous and homozygous D252H and null mutant mice using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. Although the proteomic analysis pointed to a loss of function for the D252H mutant protein, the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. Mice that are heterozygous for the missense mutation show no behavioural abnormalities but do have sex-specific deficits in body mass and motor function. The phenotyping of our novel mouse lines, together with analysis of molecular modelling and interacting proteins, suggest that the D252H mutation results in a gain of function.

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Autism spectrum disorder trios from consanguineous populations are enriched for rare biallelic variants, identifying 32 new candidate genes

10.1101/2021.12.24.21268340 ◽

2021 ◽

Author(s):

Ricardo Harripaul ◽

Ansa Rabia ◽

Nasim Vasli ◽

Anna Mikhailov ◽

Ashlyn Rodrigues ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Rare Variants ◽

De Novo ◽

Splice Variants ◽

Neurodevelopmental Disorder ◽

Point Mutations ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Loss Of Function ◽

Candidate Sequence

Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder that affects about 1 in 55 children worldwide and imposes enormous economic and socioemotional burden on families and communities. Genetic studies of ASD have identified de novo copy number variants (CNVs) and point mutations that contribute significantly to the genetic architecture of ASD, but the majority of these studies were conducted in outbred populations, which are not ideal for detecting autosomal recessive (AR) inheritance. However, several studies have investigated ASD genetics in consanguineous populations and point towards AR as an under-appreciated source of ASD variants. Here, we used trio whole exome sequencing (WES) to look for rare variants for ASD in 115 proband-mother-father trios from populations with high rates of consanguinity, namely Pakistan, Iran, and Saudi Arabia. In total, we report 87 candidate sequence variants, with 57% biallelic, 21% autosomal dominant/de novo, and the rest X-linked. 52% of the variants were loss of function (LoF) or putative LoF (splice site, stop loss) and 47% non-synonymous. Our analysis indicates an enrichment of previously identified and candidate AR genes. These include variants in genes previously reported for AR ASD and/or intellectual disability (ID), such as AGA, ASL, ASPA, BTN3A2, CC2D1A, DEAF1, HTRA2, KIF16B, LINS1, MADD, MED25, MTHFR, RSRC1, TECPR2, VPS13B, ZNF335, and 32 previously unreported candidates, including 15 LoF or splice variants, in genes such as DAGLA, EFCAB8, ENPP6, FAXDC2, ILDR2, PKD1L1, SCN10A, and SLC36A1. We also identified candidate biallelic exonic loss CNVs a number of trios, implicating genes including DNAH7, and DHRS4/DHRS4L2.

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Oligogenic rare variant contributions in schizophrenia and their convergence with genes harbouring de novo mutations in schizophrenia, autism and intellectual disability: Evidence from multiplex families

10.1101/829101 ◽

2019 ◽

Cited By ~ 1

Author(s):

Jibin John ◽

Prachi Kukshal ◽

Triptish Bhatia ◽

Ricardo Harripaul ◽

V L Nimgaonkar ◽

...

Keyword(s):

Intellectual Disability ◽

Protein Sequence ◽

De Novo ◽

Threshold Effect ◽

Loss Of Function ◽

De Novo Mutations ◽

Disease Manifestation ◽

Gene Sets ◽

Heterogeneous Nature ◽

Multiplex Families

AbstractClinical and genetic heterogeneity has been documented extensively in schizophrenia, a common behavioural disorder with heritability estimates of about 80%. Common and rare de novo variant based studies have provided notable evidence for the likely involvement of a range of pathways including glutamatergic, synaptic signalling and neurodevelopment. To complement these studies, we sequenced exomes of 11 multimember affected schizophrenia families from India. Variant prioritisation performed based on their rarity (MAF <0.01), shared presence among the affected individuals in the respective families and predicted deleterious nature, yielded a total of 785 inherited rare protein sequence altering variants in 743 genes among the 11 families. These showed an enrichment of genes involved in the extracellular matrix and cytoskeleton components, synaptic and neuron related ontologies and neurodevelopmental pathways, consistent with major etiological hypotheses. We also noted an overrepresentation of genes from previously reported gene sets with de novo protein sequence altering variants in schizophrenia, autism, intellectual disability; FMRP target and loss of function intolerant genes. Furthermore, a minimum of five genes known to manifest behavioural/neurological and nervous system abnormalities in rodent models had deleterious variants in them shared among all affected individuals in each of the families. Majority of such variants segregated within and not across families providing strong suggestive evidence for the genetically heterogeneous nature of disease. More importantly, study findings unequivocally support the classical paradigm of cumulative contribution of multiple genes, notably with an apparent threshold effect for disease manifestation and offer a likely explanation for the unclear mode of inheritance in familial schizophrenia.

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Okur-Chung Neurodevelopmental Syndrome-linked CK2α mutations have reduced kinase activity

10.21203/rs.3.rs-233118/v1 ◽

2021 ◽

Author(s):

Isabel Dominguez ◽

Jose Cruz Gamero ◽

Victor Corasolla ◽

Nicolas Dacher ◽

Sampath Rangasamy ◽

...

Keyword(s):

Intellectual Disability ◽

Social Interaction ◽

Protein Kinase ◽

Behavioral Problems ◽

Mammalian Cells ◽

Kinase Activity ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Biological Studies ◽

Repetitive Movements

Abstract The Okur-Chung Neurodevelopmental Syndrome, or OCNDS, is a newly discovered rare neurodevelopmental disorder. It is characterized by developmental delay, intellectual disability, behavioral problems (hyperactivity, repetitive movements and social interaction deficits), hypotonia, epilepsy and language/verbalization deficits. OCNDS is linked to de novo variants in CSNK2A1, that lead to missense or deletion/truncating mutations in the encoded protein, the protein kinase CK2a. Eighteen different missense CK2a mutants have been identified to date, however no biochemical or cell biological studies have yet been performed to clarify the functional impact of such mutations. Here, we show that 15 different missense CK2a mutations lead to varying degrees of loss of kinase activity as recombinant purified proteins and when mutants are ectopically expressed in mammalian cells. We further detect changes in the phosphoproteome of three patient derived fibroblast lines and show that the subcellular localization of CK2a is altered for some of the OCNDS-linked mutants and in patient derived fibroblasts. Our data argue that reduced kinase activity and abnormal localization of CK2a may underlie the OCNDS phenotype.

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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

10.1101/858696 ◽

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.

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Molecular dissection of neurodevelopmental disorder-causing mutations in CYFIP2

10.1101/2020.02.11.943332 ◽

2020 ◽

Author(s):

Matthias Schaks ◽

Klemens Rottner

Keyword(s):

De Novo ◽

Neurodevelopmental Disorder ◽

Small Gtpases ◽

Normal Brain ◽

Moderate Increase ◽

Loss Of Function ◽

De Novo Mutations ◽

Neuronal Morphogenesis ◽

Activating Mutations ◽

Regulatory Complex

AbstractActin remodelling 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 the context of compromised WRC activation with or without reduced Rac activities, which established that the majority of CYFIP2 mutations (5 out of 8) indeed cause constitutive WRC activation. Strikingly, activating mutations are positioned in a conserved WAVE- binding region mediating WRC transinhibition. As opposed to such gain-of-function mutations, a truncating mutant represented a loss-of-function variant, because it failed to interact with WRC components, and two mutants displayed no or at best a moderate increase of WRC activation. Collectively, our data show that 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.

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Variants in CAPZA2, a member of an F-actin capping complex, cause intellectual disability and developmental delay

Human Molecular Genetics ◽

10.1093/hmg/ddaa078 ◽

2020 ◽

Vol 29 (9) ◽

pp. 1537-1546

Author(s):

Yan Huang ◽

Xiao Mao ◽

Richard H van Jaarsveld ◽

Li Shu ◽

Paulien A Terhal ◽

...

Keyword(s):

Intellectual Disability ◽

Motor Development ◽

Actin Polymerization ◽

De Novo ◽

Neurodevelopmental Disorder ◽

De Novo Mutations ◽

Lower Efficiency ◽

Capping Protein ◽

Actin Capping Protein ◽

Actin Capping

Abstract The actin cytoskeleton is regulated by many proteins including capping proteins that stabilize actin filaments (F-actin) by inhibiting actin polymerization and depolymerization. Here, we report two pediatric probands who carry damaging heterozygous de novo mutations in CAPZA2 (HGNC: 1490) and exhibit neurological symptoms with shared phenotypes including global motor development delay, speech delay, intellectual disability, hypotonia and a history of seizures. CAPZA2 encodes a subunit of an F-actin-capping protein complex (CapZ). CapZ is an obligate heterodimer consisting of α and β heterodimer conserved from yeast to human. Vertebrate genomes contain three α subunits encoded by three different genes and CAPZA2 encodes the α2 subunit. The single orthologue of CAPZA genes in Drosophila is cpa. Loss of cpa leads to lethality in early development and expression of the human reference; CAPZA2 rescues this lethality. However, the two CAPZA2 variants identified in the probands rescue this lethality at lower efficiency than the reference. Moreover, expression of the CAPZA2 variants affects bristle morphogenesis, a process that requires extensive actin polymerization and bundling during development. Taken together, our findings suggest that variants in CAPZA2 lead to a non-syndromic neurodevelopmental disorder in children.

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Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy

Human Genetics ◽

10.1007/s00439-021-02283-2 ◽

2021 ◽

Author(s):

Ilaria Parenti ◽

◽

Daphné Lehalle ◽

Caroline Nava ◽

Erin Torti ◽

...

Keyword(s):

Intellectual Disability ◽

Behavioral Problems ◽

Neuronal Development ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Speech Delay ◽

Nurd Complex ◽

Behavioral Disturbances ◽

Nucleosome Remodeling ◽

Motor Delay

AbstractLocated in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic–clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.

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A familial case of CAMK2B mutation with variable expressivity

SAGE Open Medical Case Reports ◽

10.1177/2050313x21990982 ◽

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.

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