scholarly journals Computational Identification of Novel Missense Variants in Coding Regions of Genes Associated with Intellectual Disability

2021 ◽  
Vol 11 (2) ◽  
pp. 22-33
Author(s):  
Anna Chang Liu ◽  
◽  
Junmeng Yang ◽  
Tina Yuan ◽  
Yongsheng Bai
Keyword(s):  
Intellectual Disability ◽  
Missense Variants ◽  
Coding Regions ◽  
Computational Identification

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.

scholarly journals Damaging coding variants within kainate receptor channel genes are enriched in individuals with schizophrenia, autism and intellectual disabilities

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Maria Koromina ◽  
Miles Flitton ◽  
Alix Blockley ◽  
Ian R. Mellor ◽  
Helen M. Knight
Keyword(s):  
Intellectual Disability ◽  
Ion Channels ◽  
Autism Spectrum ◽  
Decay Rates ◽  
Kainate Receptors ◽  
Sequencing Data ◽  
Missense Variants ◽  
Functional Studies ◽  
Neurodevelopmental Disease ◽  
Functional Variants

AbstractSchizophrenia (Scz), autism spectrum disorder (ASD) and intellectual disability are common complex neurodevelopmental disorders. Kainate receptors (KARs) are ionotropic glutamate ion channels involved in synaptic plasticity which are modulated by auxiliary NETO proteins. Using UK10K exome sequencing data, we interrogated the coding regions of KAR and NETO genes in individuals with Scz, ASD or intellectual disability and population controls; performed follow-up genetic replication studies; and, conducted in silico and in vitro functional studies. We found an excess of Loss-of-Function and missense variants in individuals with Scz compared with control individuals (p = 1.8 × 10−10), and identified a significant burden of functional variants for Scz (p < 1.6 × 10−11) and ASD (p = 6.9 × 10−18). Single allele associations for 6 damaging missense variants were significantly replicated (p < 5.0 × 10−15) and confirmed GRIK3 S310A as a protective genetic factor. Functional studies demonstrated that three missense variants located within GluK2 and GluK4, GluK2 (K525E) and GluK4 (Y555N, L825W), affect agonist sensitivity and current decay rates. These findings establish that genetic variation in KAR receptor ion channels confers risk for schizophrenia, autism and intellectual disability and provide new genetic and pharmacogenetic biomarkers for neurodevelopmental disease.

scholarly journals Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features

Brain ◽  
2017 ◽  
Vol 140 (11) ◽  
pp. 2879-2894 ◽  
Author(s):  
Cristina Elena Niturad ◽  
Dorit Lev ◽  
Vera M Kalscheuer ◽  
Agnieszka Charzewska ◽  
Julian Schubert ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Gabaa Receptor ◽  
Xenopus Laevis Oocytes ◽  
Incomplete Penetrance ◽  
Single Mutation ◽  
Loss Of Function ◽  
Missense Variants ◽  
Dysmorphic Features ◽  
Α3 Subunit

Abstract Genetic epilepsies are caused by mutations in a range of different genes, many of them encoding ion channels, receptors or transporters. While the number of detected variants and genes increased dramatically in the recent years, pleiotropic effects have also been recognized, revealing that clinical syndromes with various degrees of severity arise from a single gene, a single mutation, or from different mutations showing similar functional defects. Accordingly, several genes coding for GABAA receptor subunits have been linked to a spectrum of benign to severe epileptic disorders and it was shown that a loss of function presents the major correlated pathomechanism. Here, we identified six variants in GABRA3 encoding the α3-subunit of the GABAA receptor. This gene is located on chromosome Xq28 and has not been previously associated with human disease. Five missense variants and one microduplication were detected in four families and two sporadic cases presenting with a range of epileptic seizure types, a varying degree of intellectual disability and developmental delay, sometimes with dysmorphic features or nystagmus. The variants co-segregated mostly but not completely with the phenotype in the families, indicating in some cases incomplete penetrance, involvement of other genes, or presence of phenocopies. Overall, males were more severely affected and there were three asymptomatic female mutation carriers compared to only one male without a clinical phenotype. X-chromosome inactivation studies could not explain the phenotypic variability in females. Three detected missense variants are localized in the extracellular GABA-binding NH2-terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the α3-subunit. Functional studies in Xenopus laevis oocytes revealed a variable but significant reduction of GABA-evoked anion currents for all mutants compared to wild-type receptors. The degree of current reduction correlated partially with the phenotype. The microduplication disrupted GABRA3 expression in fibroblasts of the affected patient. In summary, our results reveal that rare loss-of-function variants in GABRA3 increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern. 10.1093/brain/awx236_video1 awx236media1 5636589232001

scholarly journals Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration

2015 ◽  
Vol 24 (3) ◽  
pp. 392-399 ◽  
Author(s):  
Zafar Iqbal ◽  
Lucia Püttmann ◽  
Luciana Musante ◽  
Attia Razzaq ◽  
Muhammad Yasir Zahoor ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Autosomal Recessive ◽  
Missense Variants

scholarly journals Kirrel3-mediated synapse formation is attenuated by disease-associated missense variants

2019 ◽  
Author(s):  
Matthew R. Taylor ◽  
E. Anne Martin ◽  
Brooke Sinnen ◽  
Rajdeep Trilokekar ◽  
Emmanuelle Ranza ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
Synapse Formation ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Cellular Interactions ◽  
Loss Of Function ◽  
Wild Type ◽  
Missense Variants

ABSTRACTMissense variants in Kirrel3 are repeatedly identified as risk factors for autism spectrum disorder and intellectual disability but it has not been reported if or how these variants disrupt Kirrel3 function. Previously, we studied Kirrel3 loss-of-function using knockout mice and showed that Kirrel3 is a synaptic adhesion molecule necessary to form one specific type of hippocampal synapse in vivo. Here, we developed a new gain-of-function assay for Kirrel3 and find that wild-type Kirrel3 induces synapse formation selectively between Kirrel3-expressing cells via homophilic, trans-cellular binding. We tested six disease-associated Kirrel3 missense variants and find that five attenuate this synaptogenic function. All variants tested traffic to the cell surface and localize to synapses similar to wild-type Kirrel3. Two tested variants lack homophilic trans-cellular binding, which likely accounts for their reduced synaptogenic function. Interestingly, we also identified variants that bind in trans but cannot induce synapses, indicating Kirrel3 trans-cellular binding is necessary but not sufficient for its synaptogenic function. Collectively, these results suggest Kirrel3 functions as a synaptogenic, cell-recognition molecule, and this function is attenuated by missense variants associated with autism spectrum disorder and intellectual disability. Thus, we provide critical insight to Kirrel3 function in typical brain development and the consequences of missense variants associated with autism spectrum disorder and intellectual disability.SIGNIFICANCE STATEMENTHere, we advance our understanding of mechanisms mediating target-specific synapse formation by providing evidence that Kirrel3 trans-cellular interactions mediate contact recognition and signaling to promote synapse development. Moreover, this is the first study to test the effects of disease-associated Kirrel3 missense variants on synapse formation, and thereby, provides a framework to understand the etiology of complex neurodevelopmental disorders arising from rare missense variants in synaptic genes.

Exome sequencing reveals three homozygous missense variants inSNRPAin two sisters with syndromic intellectual disability

2018 ◽  
Vol 93 (6) ◽  
pp. 1229-1233 ◽  
Author(s):  
M.M. Rangel-Sosa ◽  
L.E. Figuera-Villanueva ◽  
I.A. González-Ramos ◽  
Y.X. Pérez-Páramo ◽  
L.A. Martínez-Jacobo ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Missense Variants

scholarly journals Novel Missense Variants in ADAT3 as a Cause of Syndromic Intellectual Disability

2019 ◽  
Vol 08 (04) ◽  
pp. 244-251 ◽  
Author(s):  
Elizabeth Thomas ◽  
Andrea M. Lewis ◽  
Yaping Yang ◽  
Sirisak Chanprasert ◽  
Lorraine Potocki ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Birth Defects ◽  
Augmentative And Alternative Communication ◽  
Ductus Arteriosus ◽  
Failure To Thrive ◽  
Small Subset ◽  
Compound Heterozygous ◽  
Feeding Problems ◽  
Missense Variants ◽  
Individualized Educational Programs

AbstractAutosomal recessive variants in the adenosine deaminase, tRNA specific 3 (ADAT3) gene cause a syndromic form of intellectual disability due to a loss of ADAT3 function. This disorder is characterized by developmental delay, intellectual disability, speech delay, abnormal brain structure, strabismus, microcephaly, and failure to thrive. A small subset of individuals with ADAT3 deficiency have other structural birth defects including atrial septal defect, patent ductus arteriosus, hypospadias, cryptorchidism, and micropenis. Here, we report a sibling pair with novel compound heterozygous missense variants that affect a conserved amino acid in the deaminase domain of ADAT3. These siblings have many of the features characteristic of this syndrome, including, intellectual disability, hypotonia, esotropia, failure to thrive, and microcephaly. Both had gastroesophageal reflux disease (GERD), feeding problems, and aspiration requiring thickening of feeds. Although they have no words, their communication abilities progressed rapidly when they began to use augmentative and alternative communication (AAC) devices. One of these siblings was born with an anterior congenital diaphragmatic hernia, which has not been reported previously in association with ADAT3 deficiency. We conclude that individuals with ADAT3 deficiency should be monitored for GERD, feeding problems, and aspiration in infancy. They may also benefit from the use of AAC devices and individualized educational programs that take into account their capacity for nonverbal language development. Additional studies in humans or animal models will be needed to determine if ADAT3 deficiency predisposes to the development of structural birth defects.

De novo DDX3X missense variants in males appear viable and contribute to syndromic intellectual disability

2019 ◽  
Vol 179 (4) ◽  
pp. 570-578 ◽  
Author(s):  
Pantelis Nicola ◽  
Patrick R. Blackburn ◽  
Kristen J. Rasmussen ◽  
Nicole L. Bertsch ◽  
Eric W. Klee ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
De Novo ◽  
Missense Variants

scholarly journals Further delineation of BCAP31-linked intellectual disability: description of 17 new families with LoF and missense variants

2021 ◽  
Author(s):  
Sandra Whalen ◽  
◽  
Marie Shaw ◽  
Cyril Mignot ◽  
Delphine Héron ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Missense Variants
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