scholarly journals Biallelic truncation variants in ATP9A are associated with a novel autosomal recessive neurodevelopmental disorder

2021 ◽  
Author(s):  
Francesca Mattioli ◽  
Hossein Darvish ◽  
Sohail Aziz Paracha ◽  
Abbas Tafakhori ◽  
Saghar Ghasemi Firouzabadi ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mouse Model ◽  
Autosomal Recessive ◽  
High Throughput Sequencing ◽  
Neurodevelopmental Disorder ◽  
Behavioral Changes ◽  
Causative Role ◽  
Speech Impairment ◽  
Lipid Flippase

Intellectual disability (ID) is a highly heterogeneous disorder with hundreds of associated genes. Despite progress in the identification of the genetic causes of ID following the introduction of high-throughput sequencing, about half of affected individuals still remain without a molecular diagnosis. Consanguineous families with affected individuals provide a unique opportunity to identify novel recessive causative genes. In this report we describe a novel autosomal recessive neurodevelopmental disorder. We identified two consanguineous families with homozygous variants predicted to alter the splicing of ATP9A which encodes a transmembrane lipid flippase of the class II P4-ATPases. The three individuals homozygous for these putatively truncating variants presented with severe ID, motor and speech impairment, and behavioral anomalies. Consistent with a causative role of ATP9A in these patients, a previously described Atp9a-/- mouse model showed behavioral changes.

scholarly journals Biallelic truncation variants in ATP9A are associated with a novel autosomal recessive neurodevelopmental disorder

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Francesca Mattioli ◽  
Hossein Darvish ◽  
Sohail Aziz Paracha ◽  
Abbas Tafakhori ◽  
Saghar Ghasemi Firouzabadi ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mouse Model ◽  
Autosomal Recessive ◽  
High Throughput Sequencing ◽  
Neurodevelopmental Disorder ◽  
Behavioral Changes ◽  
Causative Role ◽  
Speech Impairment ◽  
Lipid Flippase

AbstractIntellectual disability (ID) is a highly heterogeneous disorder with hundreds of associated genes. Despite progress in the identification of the genetic causes of ID following the introduction of high-throughput sequencing, about half of affected individuals still remain without a molecular diagnosis. Consanguineous families with affected individuals provide a unique opportunity to identify novel recessive causative genes. In this report, we describe a novel autosomal recessive neurodevelopmental disorder. We identified two consanguineous families with homozygous variants predicted to alter the splicing of ATP9A which encodes a transmembrane lipid flippase of the class II P4-ATPases. The three individuals homozygous for these putatively truncating variants presented with severe ID, motor and speech impairment, and behavioral anomalies. Consistent with a causative role of ATP9A in these patients, a previously described Atp9a−/− mouse model showed behavioral changes.

scholarly journals Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Kerstin Ure ◽  
Hui Lu ◽  
Wei Wang ◽  
Aya Ito-Ishida ◽  
Zhenyu Wu ◽  
...  
Keyword(s):  
Social Skills ◽  
Mouse Model ◽  
Rett Syndrome ◽  
Therapeutic Option ◽  
Neurodevelopmental Disorder ◽  
Gabaergic Neurons ◽  
Inhibitory Neurons ◽  
Extended Lifespan ◽  
Inhibitory Signaling

The postnatal neurodevelopmental disorder Rett syndrome, caused by mutations in MECP2, produces a diverse array of symptoms, including loss of language, motor, and social skills and the development of hand stereotypies, anxiety, tremor, ataxia, respiratory dysrhythmias, and seizures. Surprisingly, despite the diversity of these features, we have found that deleting Mecp2 only from GABAergic inhibitory neurons in mice replicates most of this phenotype. Here we show that genetically restoring Mecp2 expression only in GABAergic neurons of male Mecp2 null mice enhanced inhibitory signaling, extended lifespan, and rescued ataxia, apraxia, and social abnormalities but did not rescue tremor or anxiety. Female Mecp2+/- mice showed a less dramatic but still substantial rescue. These findings highlight the critical regulatory role of GABAergic neurons in certain behaviors and suggest that modulating the excitatory/inhibitory balance through GABAergic neurons could prove a viable therapeutic option in Rett syndrome.

scholarly journals Recessive variants in ZNF142 cause a complex neurodevelopmental disorder with intellectual disability, speech impairment, seizures, and dystonia

2019 ◽  
Vol 21 (11) ◽  
pp. 2532-2542 ◽  
Author(s):  
Kamal Khan ◽  
Michael Zech ◽  
Angela T. Morgan ◽  
David J. Amor ◽  
Matej Skorvanek ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Neurodevelopmental Disorder ◽  
Speech Impairment

scholarly journals Homozygous SLC6A17 Mutations Cause Autosomal-Recessive Intellectual Disability with Progressive Tremor, Speech Impairment, and Behavioral Problems

2015 ◽  
Vol 96 (3) ◽  
pp. 386-396 ◽  
Author(s):  
Zafar Iqbal ◽  
Marjolein H. Willemsen ◽  
Marie-Amélie Papon ◽  
Luciana Musante ◽  
Marco Benevento ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Behavioral Problems ◽  
Autosomal Recessive ◽  
Speech Impairment

scholarly journals Pathogenic variants in PIDD1 lead to an autosomal recessive neurodevelopmental disorder with pachygyria and psychiatric features

2021 ◽  
Author(s):  
Maha S. Zaki ◽  
Andrea Accogli ◽  
Ghayda Mirzaa ◽  
Fatima Rahman ◽  
Hiba Mohammed ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Autosomal Recessive ◽  
Neurodevelopmental Disorder ◽  
Death Domain ◽  
Multiprotein Complex ◽  
Related Disorder ◽  
Pathogenic Variants ◽  
Domain Protein ◽  
Caspase 2 ◽  
And Behavior

AbstractThe PIDDosome is a multiprotein complex, composed by the p53-induced death domain protein 1 (PIDD1), the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 that induces apoptosis in response to DNA damage. In the recent years, biallelic pathogenic variants in CRADD have been associated with a neurodevelopmental disorder (MRT34; MIM 614499) characterized by pachygyria with a predominant anterior gradient, megalencephaly, epilepsy and intellectual disability. More recently, biallelic pathogenic variants in PIDD1 have been described in a few families with apparently nonsydnromic intellectual disability. Here, we aim to delineate the genetic and radio-clinical features of PIDD1-related disorder. Exome sequencing was carried out in six consanguineous families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals as well as reviewing all the data from previously reported cases. We identified five distinct novel homozygous variants (c.2584C>T p.(Arg862Trp), c.1340G>A p.(Trp447*), c.2116_2120del p.(Val706Hisfs*30), c.1564_1565delCA p.(Gln522fs*44), and c.1804_1805del p.(Gly602fs*26) in eleven subjects displaying intellectual disability, behaviorial and psychiatric features, and a typical anterior-predominant pachygyria, remarkably resembling the CRADD-related neuroimaging pattern. In summary, we outline the phenotypic and molecular spectrum of PIDD1 biallelic variants supporting the evidence that the PIDD1/CRADD/caspase-2 signaling is crucial for normal gyration of the developing human neocortex as well as cognition and behavior.

Autosomal Recessive Primary Microcephaly (MCPH): An Update

2017 ◽  
Vol 48 (03) ◽  
pp. 135-142 ◽  
Author(s):  
Deborah Morris-Rosendahl ◽  
Angela Kaindl ◽  
Sami Zaqout
Keyword(s):  
Intellectual Disability ◽  
Head Circumference ◽  
Autosomal Recessive ◽  
Neurodevelopmental Disorder ◽  
Speech Disorder ◽  
Rare Disorder ◽  
Primary Microcephaly ◽  
Expressive Speech ◽  
Autosomal Recessive Primary Microcephaly

AbstractAutosomal recessive primary microcephaly (MCPH; MicroCephaly Primary Hereditary) is a genetically heterogeneous neurodevelopmental disorder characterized by a significantly reduced head circumference present already at birth and intellectual disability. Inconsistent features include hyperactivity, an expressive speech disorder, and epilepsy. Here, we provide a brief overview on this rare disorder pertinent for clinicians.

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.

Autism with Seizures and Intellectual Disability: Possible Causative Role of Gain-of-function of the Inwardly-Rectifying K+ Channel Kir4.1

2011 ◽  
Vol 43 (1) ◽  
pp. 239-247 ◽  
Author(s):  
Federico Sicca ◽  
Paola Imbrici ◽  
Maria Cristina D'Adamo ◽  
Francesca Moro ◽  
Fabrizia Bonatti ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
K Channel ◽  
Causative Role ◽  
Gain Of Function ◽  
Inwardly Rectifying

scholarly journals Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Dorothy P Schafer ◽  
Christopher T Heller ◽  
Georgia Gunner ◽  
Molly Heller ◽  
Christopher Gordon ◽  
...  
Keyword(s):  
Mouse Model ◽  
Rett Syndrome ◽  
Neural Circuits ◽  
Neurodevelopmental Disorder ◽  
Cell Types ◽  
Null Mouse ◽  
Causative Role ◽  
Specific Loss ◽  
Synapse Loss ◽  
Circuit Defects

Microglia, the resident CNS macrophages, have been implicated in the pathogenesis of Rett Syndrome (RTT), an X-linked neurodevelopmental disorder<xref ref-type="bibr" rid="bib19"/><xref ref-type="bibr" rid="bib15"/><xref ref-type="bibr" rid="bib37"/><xref ref-type="bibr" rid="bib47"/>. However, the mechanism by which microglia contribute to the disorder is unclear and recent data suggest that microglia do not play a causative role<xref ref-type="bibr" rid="bib67"/>. Here, we use the retinogeniculate system to determine if and how microglia contribute to pathogenesis in a RTT mouse model, the Mecp2 null mouse (Mecp2tm1.1Bird/y). We demonstrate that microglia contribute to pathogenesis by excessively engulfing, thereby eliminating, presynaptic inputs at end stages of disease (≥P56 Mecp2 null mice) concomitant with synapse loss. Furthermore, loss or gain of Mecp2 expression specifically in microglia (Cx3cr1CreER;Mecp2fl/yor Cx3cr1CreER; Mecp2LSL/y) had little effect on excessive engulfment, synapse loss, or phenotypic abnormalities. Taken together, our data suggest that microglia contribute to end stages of disease by dismantling neural circuits rendered vulnerable by loss of Mecp2 in other CNS cell types.

scholarly journals A novel heterozygous ZBTB18 missense mutation in a family with non-syndromic intellectual disability and structural brain abnormalities

2021 ◽  
Author(s):  
Nana Li ◽  
Meixian Wang ◽  
Yanna Zou ◽  
Zhen Liu ◽  
Ying Deng ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
High Throughput Sequencing ◽  
Autosomal Dominant ◽  
Rare Variants ◽  
Neurodevelopmental Disorder ◽  
Zinc Ion ◽  
Cognitive Capacity ◽  
Chinese Family ◽  
Prediction Tools ◽  
Heterozygous Variant

Abstract Background Intellectual Disability (ID) is a characterized by significantly impaired adaptive behavior and cognitive capacity. Currently, high throughput sequencing approaches have led to the identification of genetic causes for ID in 25-50% of cases, while the causes of inherited ID are less well known. Here, we have investigated the genetic cause for non-syndromic ID in a Han Chinese family. Methods Whole genome sequencing was performed on identical twin sisters diagnosed with ID, their respective children as well as their asymptomatic parents. Data was filtered for rare variants and in silico prediction tools used to establish pathogenic alleles. Candidate mutations were validated by Sanger sequencing. Molecular modelling was conducted to establish the effects of the mutation on the protein encoded by a candidate coding gene. Results A novel heterozygous variant in the ZBTB18 gene c.1323C>G (p.His441Gln) was identified. This variant co-segregated with affected individuals in an autosomal dominant pattern and was not detected in asymptomatic family members. Molecular studies reveal that a p.His441Gln substitution disrupts the coordination of a zinc ion within the second zinc finger and disrupts the capacity for ZBTB18 to bind DNA. Conclusions c.1323C>G mutation in ZBTB18 gene on 1 chromosome may be related with the phenotype of intellectual disability in this family. WGS is an efficient method to perform molecular diagnosis for hereditary ID. This is the first report of an inherited ZBTB18 mutation for ID and suggests that mutations that disrupt C2H2 motifs underlie human neurodevelopmental disorder.

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