A method to delineate de novo missense variants across pathways prioritizes genes linked to autism

2021 ◽  
Vol 13 (594) ◽  
pp. eabc1739
Author(s):  
Amanda Koire ◽  
Panagiotis Katsonis ◽  
Young Won Kim ◽  
Christie Buchovecky ◽  
Stephen J. Wilson ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Protein Function ◽  
De Novo ◽  
Autism Spectrum ◽  
Homologous Gene ◽  
Fitness Effect ◽  
Missense Variants ◽  
Whole Exome ◽  
New Gene ◽  
The Impact

Genotype-phenotype relationships shape health and population fitness but remain difficult to predict and interpret. Here, we apply an evolutionary action method to de novo missense variants in whole-exome sequences of individuals with autism spectrum disorder (ASD) to unravel genes and pathways connected to ASD. Evolutionary action predicts the impact of missense variants on protein function by measuring the fitness effect based on phylogenetic distances and substitution odds in homologous gene sequences. By examining de novo missense variants in 2384 individuals with ASD (probands) compared to matched siblings without ASD, we found missense variants in 398 genes representing 23 pathways that were biased toward higher evolutionary action scores than expected by random chance; these pathways were involved in axonogenesis, synaptic transmission, and neurodevelopment. The predicted fitness impact of de novo and inherited missense variants in candidate genes correlated with the IQ of individuals with ASD, even for new gene candidates. Taking an evolutionary action method, we detected those missense variants most likely to contribute to ASD pathogenesis and elucidated their phenotypic impact. This approach could be applied to integrate missense variants across a patient cohort to identify genes contributing to a shared phenotype in other complex diseases.

scholarly journals New pathogenic variants and insights into pathogenic mechanisms in GRK1-related Oguchi disease

2020 ◽  
Author(s):  
James A. Poulter ◽  
Molly S. C. Gravett ◽  
Rachel L. Taylor ◽  
Kaoru Fujinami ◽  
Julie De Zaeytijd ◽  
...  
Keyword(s):  
Protein Function ◽  
Kinase Domain ◽  
Missense Variants ◽  
Pathogenic Variants ◽  
Oguchi Disease ◽  
Whole Exome ◽  
Novel Variants ◽  
Variation Database ◽  
Biallelic Mutations ◽  
The Impact

AbstractPurposeBiallelic mutations in G-Protein coupled receptor kinase 1 (GRK1) cause Oguchi disease, a rare subtype of congenital stationary night blindness (CSNB). The purpose of this study was to identify pathogenic GRK1 variants and use in-depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity.MethodsPatients’ genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Pathogenic variants, published and novel, were compared to nondisease associated missense variants. The impact of GRK1 missense variants at the protein level were then predicted using a series of computational tools.ResultsWe identified eleven previously unpublished cases with biallelic pathogenic GRK1 variants, including seven novel variants, and reviewed all GRK1 pathogenic variants. Further structure-based scoring revealed a hotspot for missense variants in the kinase domain. Additionally, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate pathogenic from non-pathogenic variants.ConclusionWe identified new GRK1 pathogenic variants in Oguchi disease patients and investigated how disease-causing variants may impede protein function, giving new insights into the mechanisms of pathogenicity. All pathogenic GRK1 variants described to date have been collated into a Leiden Open Variation Database (http://dna2.leeds.ac.uk/GRK1_LOVD/genes/GRK1).

scholarly journals Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

2021 ◽  
Author(s):  
Felix Marbach ◽  
◽  
Georgi Stoyanov ◽  
Florian Erger ◽  
Constantine A. Stratakis ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Global Developmental Delay ◽  
Missense Variants ◽  
Large Patient ◽  
Significant Enrichment

Abstract Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.

scholarly journals Evolutionary Action of de novo Missense Variants across Pathways Prioritizes Genes Linked to Autism and Predicts Patient Phenotypic Severity

2017 ◽  
Author(s):  
Amanda Koire ◽  
Christie Buchovecky ◽  
Panagiotis Katsonis ◽  
Young Won Kim ◽  
Stephen J. Wilson ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Synaptic Transmission ◽  
De Novo ◽  
Missense Variant ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Integrative Approach ◽  
Missense Mutations ◽  
Functional Impact ◽  
Missense Variants

AbstractThe pathogenicity of individual de novo missense mutations in autism spectrum disorder remains difficult to validate. Here we asked in 2,384 probands whether these variants exhibited collective functional impact biases across pathways. As measured with Evolutionary Action (EA) in 368 gene groupings, we found significant biases in axonogenesis, synaptic transmission, and other neurodevelopmental pathways. Strikingly, both de novo and inherited missense variants in prioritized genes correlated with patient IQ. This general integrative approach thus detects missense variants most likely to contribute to autism pathogenesis and is the first, to our knowledge, to link missense variant impact to autism phenotypic severity.

scholarly journals Whole exome sequencing reveals inherited and de novo variants in autism spectrum disorder: a trio study from Saudi families

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Bashayer Al-Mubarak ◽  
Mohamed Abouelhoda ◽  
Aisha Omar ◽  
Hesham AlDhalaan ◽  
Mohammed Aldosari ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Whole Exome

scholarly journals Whole Exome Sequencing Identifies Novel De Novo Variants Interacting with Six Gene Networks in Autism Spectrum Disorder

Genes ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 1
Author(s):  
Namshin Kim ◽  
Kyoung Hyoun Kim ◽  
Won-Jun Lim ◽  
Jiwoong Kim ◽  
Soon Ae Kim ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Factors ◽  
De Novo ◽  
Genetic Network ◽  
Autism Spectrum ◽  
Network Analyses ◽  
Functional Relationships ◽  
Whole Exome

Autism spectrum disorder (ASD) is a highly heritable condition caused by a combination of environmental and genetic factors such as de novo and inherited variants, as well as rare or common variants among hundreds of related genes. Previous genome-wide association studies have identified susceptibility genes; however, most ASD-associated genes remain undiscovered. This study aimed to examine rare de novo variants to identify genetic risk factors of ASD using whole exome sequencing (WES), functional characterization, and genetic network analyses of identified variants using Korean familial dataset. We recruited children with ASD and their biological parents. The clinical best estimate diagnosis of ASD was made according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5TM), using comprehensive diagnostic instruments. The final analyses included a total of 151 individuals from 51 families. Variants were identified and filtered using the GATK Best Practices for bioinformatics analysis, followed by genome alignments and annotation to the reference genome assembly GRCh37 (liftover to GRCh38), and further annotated using dbSNP 154 build databases. To evaluate allele frequencies of de novo variants, we used the dbSNP, gnomAD exome v2.1.1, and genome v3.0. We used Ingenuity Pathway Analysis (IPA, Qiagen) software to construct networks using all identified de novo variants with known autism-related genes to find probable relationships. We identified 36 de novo variants with potential relations to ASD; 27 missense, two silent, one nonsense, one splice region, one splice site, one 5′ UTR, and one intronic SNV and two frameshift deletions. We identified six networks with functional relationships. Among the interactions between de novo variants, the IPA assay found that the NF-κB signaling pathway and its interacting genes were commonly observed at two networks. The relatively small cohort size may affect the results of novel ASD genes with de novo variants described in our findings. We did not conduct functional experiments in this study. Because of the diversity and heterogeneity of ASD, the primary purpose of this study was to investigate probable causative relationships between novel de novo variants and known autism genes. Additionally, we based functional relationships with known genes on network analysis rather than on statistical analysis. We identified new variants that may underlie genetic factors contributing to ASD in Korean families using WES and genetic network analyses. We observed novel de novo variants that might be functionally linked to ASD, of which the variants interact with six genetic networks.

scholarly journals Molecular Dysregulation in Autism Spectrum Disorder

2021 ◽  
Vol 11 (9) ◽  
pp. 848
Author(s):  
Pritmohinder S. Gill ◽  
Jeffery L. Clothier ◽  
Aravindhan Veerapandiyan ◽  
Harsh Dweep ◽  
Patricia A. Porter-Gill ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Genomic Analysis ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Nucleotide Polymorphisms ◽  
Common Variants ◽  
Treatment And Prevention ◽  
Whole Exome ◽  
Number Variation

Autism Spectrum Disorder (ASD) comprises a heterogeneous group of neurodevelopmental disorders with a strong heritable genetic component. At present, ASD is diagnosed solely by behavioral criteria. Advances in genomic analysis have contributed to numerous candidate genes for the risk of ASD, where rare mutations and s common variants contribute to its susceptibility. Moreover, studies show rare de novo variants, copy number variation and single nucleotide polymorphisms (SNPs) also impact neurodevelopment signaling. Exploration of rare and common variants involved in common dysregulated pathways can provide new diagnostic and therapeutic strategies for ASD. Contributions of current innovative molecular strategies to understand etiology of ASD will be explored which are focused on whole exome sequencing (WES), whole genome sequencing (WGS), microRNA, long non-coding RNAs and CRISPR/Cas9 models. Some promising areas of pharmacogenomic and endophenotype directed therapies as novel personalized treatment and prevention will be discussed.

scholarly journals Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

2020 ◽  
Author(s):  
Felix Marbach ◽  
Georgi Stoyanov ◽  
Florian Erger ◽  
Jill A. Rosenfeld ◽  
Erin Torti ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
In Vivo Studies ◽  
Global Developmental Delay ◽  
Missense Variants ◽  
Significant Enrichment

Purpose: We characterize the phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder, who carry heterozygous missense-variants of the PRKAR1B gene. Methods: Variants of PRKAR1B were identified by single-exome or trio-exome analysis. We contacted the families and physicians of the six individuals in order to collect clinical and phenotypic information. Results: PRKAR1B encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA), and is predominantly expressed in the central nervous system. Recent studies of patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B, and in vivo studies of the murine ortholog demonstrated altered hippocampal function and reduced neurogenic inflammation and long-term nociceptive pain in R1β-deficient mice. In our study, de novo origin of the PRKAR1B-variants could be confirmed in five out of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p. Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia has been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. Conclusion: Our study provides strong evidence for a novel, PRKAR1B-related neurodevelopmental disorder.

Family-based Whole Exome Sequencing of Autism Spectrum Disorder Reveals Novel De Novo Variants in Korean Population

2017 ◽  
Vol 41 (S1) ◽  
pp. S309-S309 ◽  
Author(s):  
H. Yoo ◽  
S.A. Kim ◽  
M. Park ◽  
J. Kim ◽  
W.J. Lim ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Korean Population ◽  
De Novo Mutation ◽  
Whole Exome ◽  
Family Based

ObjectivesThe objective of this family-based whole exome sequencing (WES) is to examine genetic variants of autism spectrum disorder (ASD) in Korean population.MethodsThe probands with ASD and their biological parents were recruited in this study. We ascertained diagnosis based on DSM-5™ criteria, using Autism Diagnostic Observation Schedule and Autism Diagnostic Interview–Revised. We selected probands with typical phenotypes of ASD both in social interaction/communication and repetitive behaviour/limited interest domains, with intellectual disability (IQ < 70), for attaining homogeneity of the phenotypes. First, we performed WES minimum 50× for 13 probands and high-coverage pooled sequencing for their parents. We performed additional WES for 38 trio families, at least 100× depth. De novo mutations were confirmed by Sanger sequencing. All the sequence reads were mapped onto the human reference genome (hg19 without Y chromosome). Bioinformatics analyses were performed by BWA-MEM, Picard, GATK, and snpEff for variant annotation. We selected de novo mutation candidates from probands, which are neither detected in two pooled samples nor both parents.ResultsFifty-one subjects with ASD (5 females, 40∼175 months, mean IQ 42) and their families were included in this study. We discovered 109 de novo variants from 46 families. Twenty-nine variants are expected to be amino acid changing, potentially causing deleterious effects. We assume CELSR3, MYH1, ATXN1, IDUA, NFKB1, and C4A/C4B may have adverse effect on central nerve system.ConclusionsWe observed novel de novo variants which are assumed to contribute to development of ASD with typical phenotypes and low intelligence in WES study.Disclosure of interestThis work has been supported by Healthcare Technology R&D project (No: A120029) by Ministry of Health and Welfare, Republic of Korea.

scholarly journals Whole-Exome Sequencing Identifies One De Novo Variant in the FGD6 Gene in a Thai Family with Autism Spectrum Disorder

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Chuphong Thongnak ◽  
Areerat Hnoonual ◽  
Duangkamol Tangviriyapaiboon ◽  
Suchaya Silvilairat ◽  
Apichaya Puangpetch ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Bioinformatics Pipeline ◽  
Whole Exome ◽  
De Novo Variant ◽  
Genetic Analyzer

Autism spectrum disorder (ASD) has a strong genetic basis, although the genetics of autism is complex and it is unclear. Genetic testing such as microarray or sequencing was widely used to identify autism markers, but they are unsuccessful in several cases. The objective of this study is to identify causative variants of autism in two Thai families by using whole-exome sequencing technique. Whole-exome sequencing was performed with autism-affected children from two unrelated families. Each sample was sequenced on SOLiD 5500xl Genetic Analyzer system followed by combined bioinformatics pipeline including annotation and filtering process to identify candidate variants. Candidate variants were validated, and the segregation study with other family members was performed using Sanger sequencing. This study identified a possible causative variant for ASD, c.2951G>A, in the FGD6 gene. We demonstrated the potential for ASD genetic variants associated with ASD using whole-exome sequencing and a bioinformatics filtering procedure. These techniques could be useful in identifying possible causative ASD variants, especially in cases in which variants cannot be identified by other techniques.

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