De novo SETD5
 loss-of-function variant as a cause for intellectual disability in a 10-year old boy with an aberrant blind ending bronchus

Abstract Background：The pathogenic variation of CASK gene can cause CASK related mental disorders. The main clinical manifestations are microcephaly with pontine and cerebellar hypoplasia, X-linked mental disorders with or without nystagmus and FG syndrome. The main pathogenic mechanism is the loss of function of related protein caused by mutation. We reported a Chinese male newborn with a de novo variant in CASK gene. Case presentation：We present an 18-day-old baby with intellectual disability and brain hypoplasia. Whole-exome sequencing was performed, which detected a hemizygous missense mutation c.764G>A of CASK gene. The mutation changed the 255th amino acid from Arg to His. Software based bioinformatics analyses were conducted to infer its functional effect.Conclusions：In this paper, a de novo mutation of CASK gene was reported. Moreover, a detailed description of all the cases described in the literature is reported.CASK mutations cause a variety of clinical phenotypes. Its diagnosis is difficult due to the lack of typical clinical symptoms. Genetic testing should be performed as early as possible if this disease is suspected. This case provides an important reference for the diagnosis and treatment of future cases.

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Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families

10.1101/092346 ◽

2016 ◽

Author(s):

Ricardo Harripaul ◽

Nasim Vasli ◽

Anna Mikhailov ◽

Muhammad Arshad Rafiq ◽

Kirti Mittal ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Autosomal Recessive ◽

De Novo ◽

Clinical Diagnostics ◽

High Yield ◽

Disease Genes ◽

Missense Mutations ◽

Loss Of Function ◽

Whole Exome

Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations(ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7,andUSP44),and missense mutations include the first reports of variants inBDNForTET1associated with ID. The genes identified also showed overlap withde novogene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.

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De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

European Journal of Human Genetics ◽

10.1038/ejhg.2015.282 ◽

2016 ◽

Vol 24 (8) ◽

pp. 1145-1153 ◽

Cited By ~ 16

Author(s):

Dorien Lugtenberg ◽

Margot R F Reijnders ◽

Michaela Fenckova ◽

Emilia K Bijlsma ◽

Raphael Bernier ◽

...

Keyword(s):

Intellectual Disability ◽

De Novo ◽

Loss Of Function ◽

Learning Deficits

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A novel de novo hemizygous ARHGEF9 mutation associated with severe intellectual disability and epilepsy: a case report

Journal of International Medical Research ◽

10.1177/03000605211058372 ◽

2021 ◽

Vol 49 (11) ◽

pp. 030006052110583

Author(s):

Tong Qiu ◽

Qian Dai ◽

Qiu Wang

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Developmental Delay ◽

De Novo ◽

Clinical Symptoms ◽

Genetic Diagnosis ◽

Epileptic Seizures ◽

Autism Spectrum ◽

Loss Of Function ◽

Severe Intellectual Disability

ARHGEF9 encodes collybistin, a brain-specific guanosine diphosphate-guanosine-5′-triphosphate exchange factor that plays an important role in clustering of gephyrin and γ-aminobutyric acid type A receptors in the postsynaptic membrane. Overwhelming evidence suggests that defects in this protein can cause X-linked intellectual disability, which comprises a series of clinical phenotypes, including autism spectrum disorder, behavior disorder, intellectual disability, and febrile seizures. Here, we report a boy with clinical symptoms of severe intellectual disability, epilepsy, and developmental delay and regression. Trio exome sequencing ( trio-clinical exome sequencing) identified a novel hemizygous deletion, c.656_c.669delACTTCTTTGAGGCC (p. His219Leu fs*9), in exon 5 of ARHGEF9. This variant was not reported in either the Genome Aggregation Database or our database of 309 patients with neurodevelopmental disorders. Oxcarbazepine and levetiracetam reduced the frequency of the patient’s epileptic seizures to a certain extent, but psychomotor developmental delay and developmental regression became more obvious with age. This case study seeks to report a de novo loss-of-function mutation of ARHGEF9, aiming to emphasize the genetic diagnosis of X-linked intellectual disability and further improve knowledge of the ethnic distribution of ARHGEF9 mutations.

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Novel clinical and genetic insight into CXorf56-associated intellectual disability

European Journal of Human Genetics ◽

10.1038/s41431-019-0558-3 ◽

2019 ◽

Vol 28 (3) ◽

pp. 367-372 ◽

Cited By ~ 1

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.

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Neuroimaging Findings in Patients with EBF3 Mutations: Report of Two Cases

Molecular Syndromology ◽

10.1159/000513583 ◽

2021 ◽

pp. 1-8

Author(s):

Mar Jiménez de la Peña ◽

Ana Jiménez de Domingo ◽

Pilar Tirado ◽

Beatriz Calleja-Pérez ◽

Luis A. Alcaraz ◽

...

Keyword(s):

Transcription Factor ◽

Intellectual Disability ◽

Neurodevelopmental Disorders ◽

Autosomal Dominant ◽

De Novo ◽

Diffusion Tensor ◽

Loss Of Function ◽

Normal Range ◽

Early B Cell Factor ◽

And Diffusion

Early B cell factor 3 (EBF3) is a transcription factor involved in brain development. Heterozygous, loss-of-function mutations in EBF3 have been reported in an autosomal dominant neurodevelopmental syndrome characterized by hypotonia, ataxia, and developmental delay (sometimes described as “HADD”s). We report 2 unrelated cases with novel de novo EBF3 mutations: c.455G>T (p.Arg152Leu) and c.962dup (p.Tyr321*) to expand the genotype/phenotype correlations of this disorder; clinical, neuropsychological, and MRI studies were used to define the phenotype. IQ was in the normal range and diffusion tensor imaging revealed asymmetric alterations of the longitudinal fasciculus in both cases. Our results demonstrate that EBF3 mutations can underlie neurodevelopmental disorders without intellectual disability. Long tract abnormalities have not been previously recognized and suggest that they may be an unrecognized and characteristic feature in this syndrome.

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Human RNA Nm-MTase FTSJ1: new tRNA targets and role in the regulation of brain-specific genes

10.1101/2021.02.06.430044 ◽

2021 ◽

Author(s):

Dilyana G. Dimitrova ◽

Mira Brazane ◽

Tao Ye ◽

Virginie Marchand ◽

Elise Schaefer ◽

...

Keyword(s):

Intellectual Disability ◽

Molecular Mechanisms ◽

De Novo ◽

Enrichment Analysis ◽

Clinical Settings ◽

Loss Of Function ◽

Brain Functions ◽

Wobble Position ◽

Go Enrichment ◽

Silencing Pathways

ABSTRACTFTSJ1 is a phyllogenetically conserved human 2’-O-methyltransferase (Nm-MTase) which modifies position 32 as well as the wobble position 34 in the AntiCodon Loop (ACL) of specific tRNAs: tRNAPhe(GAA), tRNATrp(CCA) and tRNALeu(UAA). FTSJ1’s loss of function has been linked to Non-Syndromic X-Linked Intellectual Disability (NSXLID), and more recently in cancers. However, the exact molecular mechanisms underlying FTSJ1-related pathogenesis are unknown and a potential extended variety of FTSJ1’s tRNA targets hasn’t been fully addressed yet. We performed unbiased and comprehensive RiboMethSeq analysis of the Nm profiles for human tRNA population extracted from cells derived from NSXLID patients’ blood bearing various characterized loss of function mutations in FTSJ1. In addition, we reported a novel FTSJ1 pathogenic variant from a NSXLID patient bearing a de novo mutation in the FTSJ1 gene. Some of the newly identified FTSJ1’s tRNA targets are also conserved in Drosophila as shown by our previous study on the fly homologues Trm7_32 and Trm7_34, whose loss affects small RNA silencing pathways. In the current study, we reveal a conserved deregulation in both the miRNA and mRNA populations when FTSJ1 function is compromised. In addition, a cross-analysing between deregulated miRNA and mRNA obtained in FTSJ1 mutants highlighted upregulation of miR10a-5p which has the capacity to silence the SPARC gene mRNA, downregulated in FTSJ1 mutant cells. This suggests that FTSJ1 loss may influence gene expression deregulation by modulation of miRNA silencing. A gene-ontology (GO) enrichment analysis of the deregulated mRNAs primarily matched to brain morphogenesis terms, followed by metabolism and translation related genes. In parallel, the deregulated miRNAs are mostly known for their implication in brain functions and cancers. Based on these results, we suggest that miRNA silencing variations may play a role in the pathological mechanisms of FTSJ1-dependent NSXLID. Finally, our results highlight miR-181a-5p as a potential companion diagnostic test in clinical settings for FTSJ1-related intellectual disability.

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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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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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