scholarly journals Rare Pathogenic Variants in Genes Implicated in Glutamatergic Neurotransmission Pathway Segregate with Schizophrenia in Pakistani Families

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1899
Author(s):  
Ambrin Fatima ◽  
Uzma Abdullah ◽  
Muhammad Farooq ◽  
Yuan Mang ◽  
Mana M. Mehrjouy ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Protein Function ◽  
Rare Variants ◽  
Glutamatergic Neurotransmission ◽  
Small Individual ◽  
Complex Disorders ◽  
Pathogenic Variants ◽  
Genetic Components ◽  
Pakistani Origin ◽  
Pakistani Families

Schizophrenia is a disabling neuropsychiatric disorder of adulthood onset with high heritability. Worldwide collaborations have identified an association of ~270 common loci, with small individual effects and hence weak clinical implications. The recent technological feasibility of exome sequencing enables the identification of rare variants of high penetrance that refine previous findings and improve risk assessment and prognosis. We recruited two multiplex Pakistani families, having 11 patients and 19 unaffected individuals in three generations. We performed genome-wide SNP genotyping, next-generation mate pairing and whole-exome sequencing of selected members to unveil genetic components. Candidate variants were screened in unrelated cohorts of 508 cases, 300 controls and fifteen families (with 51 affected and 47 unaffected individuals) of Pakistani origin. The structural impact of substituted residues was assessed through in silico modeling using iTASSER. In one family, we identified a rare novel microduplication (5q14.1_q14.2) encompassing critical genes involved in glutamate signaling, such as CMYA5, HOMER and RasGRF2. The second family segregates two ultra-rare, predicted pathogenic variants in the GRIN2A (NM_001134407.3: c.3505C>T, (p.R1169W) and in the NRG3 NM_001010848.4: c.1951G>A, (p.E651K). These genes encode for parts of AMPA and NMDA receptors of glutamatergic neurotransmission, respectively, and the variants are predicted to compromise protein function by destabilizing their structures. The variants were absent in the aforementioned cohorts. Our findings suggest that rare, highly penetrant variants of genes involved in glutamatergic neurotransmission are contributing to the etiology of schizophrenia in these families. It also highlights that genetic investigations of multiplex, multigenerational families could be a powerful approach to identify rare genetic variants involved in complex disorders.

scholarly journals Exome sequencing identifies novel AD-associated genes.

2020 ◽  
Author(s):  
Henne Holstege ◽  
Marc Hulsman ◽  
Camille Charbonnier ◽  
Benjamin Grenier-Boley ◽  
Olivier Quenez ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Genetic Variants ◽  
Rare Variants ◽  
Mendelian Inheritance ◽  
Loss Of Function ◽  
App Processing ◽  
Complex Disorders ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
The Impact

Background: With the development of next-generation sequencing technologies, it is possible to identify rare genetic variants that influence the risk of complex disorders. To date, whole exome sequencing (WES) strategies have shown that specific clusters of damaging rare variants in the TREM2, SORL1 and ABCA7 genes are associated with an increased risk of developing Alzheimers Disease (AD), reaching odds ratios comparable with the APOE-ε4 allele, the main common AD genetic risk factor. Here, we set out to identify additional AD-associated genes by an exome-wide investigation of the burden of rare damaging variants in the genomes of AD cases and cognitively healthy controls. Method: We integrated the data from 25,982 samples from the European ADES consortium and the American ADSP consortium. We developed new techniques to homogenise and analyse these data. Carriers of pathogenic variants in genes associated with Mendelian inheritance of dementia were excluded. After quality control, we used 12,652 AD cases and 8,693 controls for analysis. Genes were analysed using a burden analysis, including both non-synonymous and loss-of-function rare variants, the impact of which was prioritised using REVEL. Result: We confirmed that carrying rare protein-damaging genetic variants in TREM2, SORL1 or ABCA7 is associated with increased AD-risk. Moreover, we found that carrying rare damaging variants in the microglial ATP8B4 gene was significantly associated with AD, and we found suggestive evidence that rare variants in ADAM10, ABCA1, ORC6, B3GNT4 and SRC genes associated with increased AD risk. High-impact variants in these genes were mostly extremely rare and enriched in AD patients with earlier ages at onset. Additionally, we identified two suggestive protective associations in CBX3 and PRSS3. We are currently replicating these associations in independent datasets. Conclusion: With our newly developed homogenisation methods, we identified novel genetic determinants of AD which provide further evidence for a pivotal role of APP processing, lipid metabolism, and microglia and neuro-inflammatory processes in AD pathophysiology.

Whole‐Exome Sequencing of a Saudi Epilepsy Cohort Reveals Association Signals in Known and Potentially Novel Loci

2021 ◽  
Author(s):  
Amein Kadhem AlAli ◽  
Abdulrahman Al-Enazi ◽  
Ahmed Ammar ◽  
Mahmoud Hajj ◽  
Cyril Cyrus ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
High Rate ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variants ◽  
Unknown Significance ◽  
Rare Genetic Variants

Abstract Background Epilepsy, a serious chronic neurological condition effecting up to 100 million people globally, has clear genetic underpinnings including common and rare variants. In Saudi Arabia the prevalence of epilepsy is high and caused mainly by perinatal and genetic factors. No whole-exome sequencing (WES) studies have been performed to date in Saudi Arabian Epilepsy cohorts. This offers a unique opportunity for the discovery of rare genetic variants impacting this disease as there is a high rate of consanguinity amongst large tribal pedigrees. Results We performed WES on 144 individuals diagnosed with epilepsy, to interrogate known Epilepsy related genes for known and functional novel variants. We also used an American College of Medical Genetics (ACMG) guideline based variant prioritization approach in an attempt to discover putative causative variants. We identified a 32 potentially causative pathogenic variants across 30 different genes in 44/144 (30%) of these Saudi Epilepsy individuals. We also identified 232 variants of unknown significance (VUS) across 101 different genes in 133/144 (92%) subjects. Strong enrichment of variants of likely pathogenicity were observed in previously described epilepsy-associated loci, and a number of putative pathogenic variants in novel loci are also observed. Conclusion Several putative pathogenic variants known to be epilepsy-related loci were identified for the first time in our population, in addition to several potential new loci have been identified which may be prioritized for further investigation.

scholarly journals Diagnostic exome sequencing in non-acquired focal epilepsies highlights a major role of GATOR1 complex genes

2020 ◽  
Vol 57 (9) ◽  
pp. 624-633 ◽  
Author(s):  
Martin Krenn ◽  
Matias Wagner ◽  
Christoph Hotzy ◽  
Elisabeth Graf ◽  
Sandrina Weber ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Rare Variants ◽  
Focal Epilepsy ◽  
Diagnostic Yield ◽  
Mammalian Target Of Rapamycin ◽  
High Rate ◽  
Molecular Heterogeneity ◽  
Pathogenic Variants ◽  
Uncertain Significance

BackgroundThe genetic architecture of non-acquired focal epilepsies (NAFEs) becomes increasingly unravelled using genome-wide sequencing datasets. However, it remains to be determined how this emerging knowledge can be translated into a diagnostic setting. To bridge this gap, we assessed the diagnostic outcomes of exome sequencing (ES) in NAFE.Methods112 deeply phenotyped patients with NAFE were included in the study. Diagnostic ES was performed, followed by a screen to detect variants of uncertain significance (VUSs) in 15 well-established focal epilepsy genes. Explorative gene prioritisation was used to identify possible novel candidate aetiologies with so far limited evidence for NAFE.ResultsES identified pathogenic or likely pathogenic (ie, diagnostic) variants in 13/112 patients (12%) in the genes DEPDC5, NPRL3, GABRG2, SCN1A, PCDH19 and STX1B. Two pathogenic variants were microdeletions involving NPRL3 and PCDH19. Nine of the 13 diagnostic variants (69%) were found in genes of the GATOR1 complex, a potentially druggable target involved in the mammalian target of rapamycin (mTOR) signalling pathway. In addition, 17 VUSs in focal epilepsy genes and 6 rare variants in candidate genes (MTOR, KCNA2, RBFOX1 and SCN3A) were detected. Five patients with reported variants had double hits in different genes, suggesting a possible (oligogenic) role of multiple rare variants.ConclusionThis study underscores the molecular heterogeneity of NAFE with GATOR1 complex genes representing the by far most relevant genetic aetiology known to date. Although the diagnostic yield is lower compared with severe early-onset epilepsies, the high rate of VUSs and candidate variants suggests a further increase in future years.

scholarly journals Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1329
Author(s):  
Julia Doll ◽  
Barbara Vona ◽  
Linda Schnapp ◽  
Franz Rüschendorf ◽  
Imran Khan ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Splice Site ◽  
Genetic Heterogeneity ◽  
Bioinformatics Analysis ◽  
Molecular Genetic ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Syndromic Hearing Loss ◽  
Pakistani Families

The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes.

scholarly journals Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes

2018 ◽  
Author(s):  
Suhas Ganesh ◽  
Ahmed P Husayn ◽  
Ravi Kumar Nadella ◽  
Ravi Prabhakar More ◽  
Manasa Sheshadri ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Exome Sequencing ◽  
Rare Variants ◽  
Association Studies ◽  
Mental Illnesses ◽  
Disease Genes ◽  
Mendelian Disease ◽  
Genome Wide Association Studies ◽  
Complex Disorders ◽  
Family Based

AbstractIntroductionSevere Mental Illnesses (SMI), such as bipolar disorder and schizophrenia, are highly heritable, and have a complex pattern of inheritance. Genome wide association studies detect a part of the heritability, which can be attributed to common genetic variation. Examination of rare variants with Next Generation Sequencing (NGS) may add to the understanding of genetic architecture of SMIs.MethodsWe analyzed 32 ill subjects (with diagnosis of Bipolar Disorder, n=26; schizophrenia, n=4; schizoaffective disorder, n=1 schizophrenia like psychosis, n=1) from 8 multiplex families; and 33 healthy individuals by whole exome sequencing. Prioritized variants were selected by a 4-step filtering process, which included deleteriousness by 5 in silico algorithms; sharing within families, absence in the controls and rarity in South Asian sample of Exome Aggregation Consortium.ResultsWe identified a total of 42 unique rare, non-synonymous deleterious variants in this study with an average of 5 variants per family. None of the variants were shared across families, indicating a ‘private’ mutational profile. Twenty (47.6%) of the variant harboring genes identified in this sample have been previously reported to contribute to the risk of neuropsychiatric syndromes. These include genes which are related to neurodevelopmental processes, or have been implicated in different monogenic syndromes with a severe neurodevelopmental phenotype.ConclusionNGS approaches in family based studies are useful to identify novel and rare variants in genes for complex disorders like SMI. The study further validates the phenotypic burden of rare variants in Mendelian disease genes, indicating pleiotropic effects in the etiology of severe mental illnesses.

scholarly journals Detection of rare disease-related genetic variants using the birthday model

2018 ◽  
Author(s):  
Yael Berstein ◽  
Shane E. McCarthy ◽  
Melissa Kramer ◽  
W. Richard McCombie
Keyword(s):  
Bipolar Disorder ◽  
Exome Sequencing ◽  
Case Control Study ◽  
Rare Variants ◽  
Autism Spectrum ◽  
Case Control ◽  
Supplementary Information ◽  
Complex Disorders ◽  
Link Type ◽  
Control Study

AbstractMotivationExome sequencing is a powerful technique for the identification of disease-causing genes. A number of Mendelian inherited disease genes have been identified through this method. However, it remains a challenge to leverage exome sequencing for the study of complex disorders, such as schizophrenia and bipolar disorder, due to the genetic and phenotypic heterogeneity of these disorders. Although not feasible for many studies, sequencing large sample sizes (>10,000) may improve statistical power to associate more variants, while the aggregation of distinct rare variants associated with a given disease can make the identification of causal genes statistically challenging. Therefore, new methods for rare variant association are imperative to identify causative genes of complex disorders.ResultsHere we propose a method to predict causative rare variants using a popular probabilistic problem: The Birthday Model, which estimates the probability that multiple individuals in a group share the same birthday. We consider the probability and coincidence of samples sharing a variant akin to the chance of individuals sharing the same birthday. We investigated the parameter effects of our model, providing guidelines for its use and interpretation of the results. Using published data on autism spectrum disorder, hypertriglyceridemia in addition to a current case-control study on bipolar disorder, we evaluated this probabilistic method to identify potential causative variants. Several genes in the top results of the case-control study were associated with autism spectrum and bipolar disorder. Given that the core probability based on the birthday model is very sensitive to low recurrence, the method successfully tests the association of rare variants, which generally do not provide enough signal in commonly used statistical tests. Importantly, the simplicity of the model allows quick interpretation of genomic data, enabling users to select gene candidates for further biological validation of specific mutations and downstream functional or other studies.Availabilityhttps://github.com/yberstein/Birthday-Alqorithmhttp://labshare.cshl.edu/shares/mccombielab/www-data/Birthday-Algorithm/[email protected] (or [email protected])Supplementary informationSupplementary data are available online.

scholarly journals Whole-exome Sequencing for the Identification of Rare Variants in Primary Immunodeficiency Genes in Children With Sepsis: A Prospective, Population-based Cohort Study

2020 ◽  
Vol 71 (10) ◽  
pp. e614-e623 ◽  
Author(s):  
Alessandro Borghesi ◽  
Johannes Trück ◽  
Samira Asgari ◽  
Vanessa Sancho-Shimizu ◽  
Philipp K A Agyeman ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
Population Based ◽  
Healthy Children ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Uncertain Significance ◽  
National Cohort ◽  
Pediatric Sepsis

Abstract Background The role of primary immunodeficiencies (PID) in susceptibility to sepsis remains unknown. It is unclear whether children with sepsis benefit from genetic investigations. We hypothesized that sepsis may represent the first manifestation of underlying PID. We applied whole-exome sequencing (WES) to a national cohort of children with sepsis to identify rare, predicted pathogenic variants in PID genes. Methods We conducted a multicenter, population-based, prospective study including previously healthy children aged ≥28 days and <17 years admitted with blood culture-proven sepsis. Using a stringent variant filtering procedure, analysis of WES data was restricted to rare, predicted pathogenic variants in 240 PID genes for which increased susceptibility to bacterial infection has been reported. Results There were 176 children presenting with 185 sepsis episodes who underwent WES (median age, 52 months; interquartile range, 15.4–126.4). There were 41 unique predicted pathogenic PID variants (1 homozygous, 5 hemizygous, and 35 heterozygous) found in 35/176 (20%) patients, including 3/176 (2%) patients carrying variants that were previously reported to lead to PID. The variants occurred in PID genes across all 8 PID categories, as defined by the International Union of Immunological Societies. We did not observe a significant correlation between clinical or laboratory characteristics of patients and the presence or absence of PID variants. Conclusions Applying WES to a population-based cohort of previously healthy children with bacterial sepsis detected variants of uncertain significance in PID genes in 1 out of 5 children. Future studies need to investigate the functional relevance of these variants to determine whether variants in PID genes contribute to pediatric sepsis susceptibility.

scholarly journals Clues for Polygenic Inheritance of Pituitary Stalk Interruption Syndrome From Exome Sequencing in 20 Patients

2017 ◽  
Vol 103 (2) ◽  
pp. 415-428 ◽  
Author(s):  
Nitash Zwaveling-Soonawala ◽  
Marielle Alders ◽  
Aldo Jongejan ◽  
Lidija Kovačič ◽  
Floor A Duijkers ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Rare Variants ◽  
De Novo ◽  
Hypogonadotropic Hypogonadism ◽  
Reference Population ◽  
Pituitary Stalk ◽  
Polygenic Inheritance ◽  
Pathogenic Variants ◽  
Brain Anomalies ◽  
Posterior Pituitary Lobe

Abstract Context Pituitary stalk interruption syndrome (PSIS) consists of a small/absent anterior pituitary lobe, an interrupted/absent pituitary stalk, and an ectopic posterior pituitary lobe. Mendelian forms of PSIS are detected infrequently (<5%), and a polygenic etiology has been suggested. GLI2 variants have been reported at a relatively high frequency in PSIS. Objective To provide further evidence for a non-Mendelian, polygenic etiology of PSIS. Methods Exome sequencing (trio approach) in 20 patients with isolated PSIS. In addition to searching for (potentially) pathogenic de novo and biallelic variants, a targeted search was performed in a panel of genes associated with midline brain development (223 genes). For GLI2 variants, both (potentially) pathogenic and relatively rare variants (<5% in the general population) were studied. The frequency of GLI2 variants was compared with that of a reference population. Results We found four additional candidate genes for isolated PSIS (DCHS1, ROBO2, CCDC88C, and KIF14) and one for syndromic PSIS (KAT6A). Eleven GLI2 variants were present in six patients. A higher frequency of a combination of two GLI2 variants (M1352V + D1520N) was found in the study group compared with a reference population (10% vs 0.68%). (Potentially) pathogenic variants were identified in genes associated with midline brain anomalies, including holoprosencephaly, hypogonadotropic hypogonadism, and absent corpus callosum and in genes involved in ciliopathies. Conclusion Combinations of variants in genes associated with midline brain anomalies are frequently present in PSIS and sustain the hypothesis of a polygenic cause of PSIS.

scholarly journals Identification and Classification of Rare Variants in NPC1 and NPC2 in Quebec

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lahoud Touma ◽  
Marjorie Labrecque ◽  
Martine Tetreault ◽  
Antoine Duquette
Keyword(s):  
Exome Sequencing ◽  
Rare Variants ◽  
Variant Calling ◽  
Allelic Frequency ◽  
Healthy Individuals ◽  
Pathogenic Variants ◽  
Niemann Pick Disease ◽  
Novel Variants ◽  
Uncertain Significance ◽  
Niemann Pick

AbstractNiemann–Pick disease type C (NPC) is a treatable autosomal recessive neurodegenerative condition which leads to a variety of progressive manifestations. Despite most cases being diagnosed at a young age, disease prevalence may be underestimated, especially in adults, and interpretation of NPC1 and NPC2 variants can be difficult. This study aims to identify potential pathogenic variants in a large cohort of healthy individuals and classify their risk of pathogenicity to assist with future interpretation of variants. The CARTaGENE (CaG) cohort was used to identify possible variants of NPC1 and NPC2. Nine-hundred and eleven RNA samples and 198 exome sequencing were screened for genetic variants through a bio-informatic pipeline performing alignment and variant calling. The identified variants were analyzed using annotations for allelic frequency, pathogenicity and conservation scores. The ACMG guidelines were used to classify the variants. These were then compared to existing databases and previous studies of NPC prevalence, including the Tübingen NPC database. Thirty-two distinct variants were identified after running the samples in the RNA-sequencing pipeline, two of which were classified as pathogenic and 21 of which were not published previously. Furthermore, 46 variants were both identified in our population and with the Tübingen database, the majority of which were of uncertain significance. Ten additional variants were found in our exome-sequencing sample. This study of a sample from a population living in Quebec demonstrates a variety of rare variants, some of which were already described in the literature as well as some novel variants. Classifying these variants is arduous given the scarcity of available literature, even so in a population of healthy individuals. Yet using this data, we were able to identify two pathogenic variants within our population and several new variants not previously identified.

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