scholarly journals Both rare and common genetic variants contribute to autism in the Faroe Islands

2018 ◽  
Author(s):  
Claire S Leblond ◽  
Freddy Cliquet ◽  
Coralie Carton ◽  
Guillaume Huguet ◽  
Alexandre Mathieu ◽  
...  
Keyword(s):  
Genetic Architecture ◽  
De Novo ◽  
Copy Number Variants ◽  
Snp Array ◽  
Faroe Islands ◽  
Isolated Populations ◽  
Risk Genes ◽  
Common Genetic Variants ◽  
Rare Gene

AbstractThe number of genes associated with autism is increasing, but few studies have been performed on epidemiological cohorts and in isolated populations. Here, we investigated 357 individuals from the Faroe Islands including 36 individuals with autism, 136 of their relatives and 185 non-autism controls. Data from SNP array and whole exome sequencing revealed that individuals with autism compared to controls had a higher burden of copy-number variants (p < 0.05), higher inbreeding status (p < 0.005) and higher load of homozygous deleterious variants (p < 0.01). Our analysis supports the role of several genes/loci associated with autism (e.g. NRXN1, ADNP, 22q11 deletion) and identified new truncating (e.g. GRIK2, ROBO1, NINL and IMMP2L) or recessive deleterious variants (e.g. KIRELL3 and CNTNAP2) affecting autism-risk genes. It also revealed three genes involved in synaptic plasticity, RIMS4, KALRN and PLA2G4A, carrying de novo deleterious variants in individuals with autism without intellectual disability. In summary, our analysis provides a better understanding of the genetic architecture of autism in isolated populations by highlighting the role of both common and rare gene variants and pointing at new autism-risk genes. It also indicates that more knowledge about how multiple genetic hits affect neuronal function will be necessary to fully understand the genetic architecture of autism.

scholarly journals Latest findings in the genetic architecture of schizophrenia: The contribution of genetic studies among Afrikaners

2014 ◽  
Vol 33 (1) ◽  
Author(s):  
Johannes L. Roos
Keyword(s):  
Genetic Architecture ◽  
De Novo ◽  
Disease Risk ◽  
Association Studies ◽  
Copy Number Variants ◽  
Point Mutations ◽  
Risk Variants ◽  
Genome Wide ◽  
Long Time

A genetic component of schizophrenia has been acknowledged for a long time. The underlying architecture of the genetic risk remains a contentious issue. Early linkage and candidate association studies led to largely inconclusive results. More recently powerful technologies became available. This aspect coupled with samples of sufficient sizes, and genome-wide panels of genetic markers facilitated systematic and agnostic scans throughout the genome for either common or rare disease risk variants of small or large effect size, respectively. Although the former had limited success, the role of rare genetic events, such as copy-number variants (CNVs) or rare point mutations, has become increasingly important in gene discovery for schizophrenia. Recent research done among Afrikaner patients with schizophrenia, building upon earlier findings of de novo recurrent CNVs at the 22q11.2 locus, has highlighted a de novo mutational paradigm as a major component of the genetic architecture of schizophrenia. Recent progress in this regard will be reviewed.

scholarly journals Recent Advances in Understanding the Genetic Architecture of Autism

2020 ◽  
Vol 21 (1) ◽  
pp. 289-304 ◽  
Author(s):  
Caroline M. Dias ◽  
Christopher A. Walsh
Keyword(s):  
Genetic Architecture ◽  
De Novo ◽  
Clinical Care ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Recent Advances ◽  
Insight Into

Recent advances in understanding the genetic architecture of autism spectrum disorder have allowed for unprecedented insight into its biological underpinnings. New studies have elucidated the contributions of a variety of forms of genetic variation to autism susceptibility. While the roles of de novo copy number variants and single-nucleotide variants—causing loss-of-function or missense changes—have been increasingly recognized and refined, mosaic single-nucleotide variants have been implicated more recently in some cases. Moreover, inherited variants (including common variants) and, more recently, rare recessive inherited variants have come into greater focus. Finally, noncoding variants—both inherited and de novo—have been implicated in the last few years. This work has revealed a convergence of diverse genetic drivers on common biological pathways and has highlighted the ongoing importance of increasing sample size and experimental innovation. Continuing to synthesize these genetic findings with functional and phenotypic evidence and translating these discoveries to clinical care remain considerable challenges for the field.

Developmental psychopathology: The role of structural variation in the genome

2012 ◽  
Vol 24 (4) ◽  
pp. 1319-1334 ◽  
Author(s):  
Michael Gill
Keyword(s):  
Developmental Disorders ◽  
Developmental Psychopathology ◽  
De Novo ◽  
Copy Number Variants ◽  
Cognitive Disorders ◽  
Comparative Genome Hybridization ◽  
Diagnostic Categories ◽  
Wide Range ◽  
Technological Developments

AbstractA wide range of developmental disorders present with characteristic psychopathologies and behaviors, with diagnoses including, inter alia, cognitive disorders and learning disabilities, epilepsies, autism, and schizophrenia. Each, to varying extent, has a genetic component to etiology and is associated with cytogenetic abnormalities. Technological developments, particularly array-based comparative genome hybridization and single nucleotide polymorphism chips, has revealed a wide range of rare recurrent and de novo copy number variants (CNVs) to be associated with disorder and psychopathology. It is surprising that many apparently similar CNVs are identified across two or more disorders hitherto considered unrelated. This article describes the characteristics of CNVs and current technological restrictions that make accurately identifying small events difficult. It summarizes the latest discoveries for individual diagnostic categories and considers the implications for a shared neurobiology. It examines likely developments in the knowledge base as well as addressing the clinical implications going forward.

scholarly journals Schizophrenia-associated somatic copy number variants from 12,834 cases reveal contribution to risk and recurrent, isoform-specific NRXN1 disruptions

2022 ◽  
Author(s):  
Eduardo A Maury ◽  
Maxwell A Sherman ◽  
Giulio Genovese ◽  
Thomas G. Gilgenast ◽  
Prashanth Rajarajan ◽  
...  
Keyword(s):  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Regulatory Elements ◽  
The Body ◽  
Cryptic Promoter ◽  
Intragenic Deletions ◽  
Allele Specific ◽  
Treatment Responsiveness

While inherited and de novo copy number variants (CNV) have been implicated in the genetic architecture of schizophrenia (SCZ), the contribution of somatic CNVs (sCNVs), present in some but not all cells of the body, remains unknown. Here we explore the role of sCNVs in SCZ by analyzing blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls. sCNVs were more common in cases (0.91%) than in controls (0.51%, p = 2.68e-4). We observed recurrent somatic deletions of exons 1-5 of the NRXN1 gene in 5 SCZ cases. Allele-specific Hi-C maps revealed ectopic, allele-specific loops forming between a potential novel cryptic promoter and non-coding cis regulatory elements upon deletions in the 5' region of NRXN1. We also observed recurrent intragenic deletions of ABCB11, a gene associated with anti-psychotic response, in 5 treatment-resistant SCZ cases. Taken together our results indicate an important role of sCNVs to SCZ risk and treatment-responsiveness.

scholarly journals Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 and ALYREF as new candidate risk genes

2021 ◽  
Author(s):  
Lu Qiao ◽  
Le Xu ◽  
Lan Yu ◽  
Julia Wynn ◽  
Rebecca Hernan ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Rare Variants ◽  
De Novo ◽  
Disease Genes ◽  
Risk Genes ◽  
Association Analyses ◽  
Significant Enrichment ◽  
Coding Variants

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (Lon Peptidase 1, Mitochondrial) and ALYREF (Aly/REF Export Factor) as novel candidate CDH genes based on de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 cases and 11,220 ancestry-matched population controls and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in familial cases. Approximately 3% of our CDH cohort was heterozygous with ultra-rare predicted damaging variants in LONP1 who have a range of clinical phenotypes including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium specific deletion of Lonp1 die immediately after birth and have reduced lung growth and branching that may at least partially explain the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

scholarly journals Genetic architecture influences when and how hybridization contributes to colonization

2019 ◽  
Author(s):  
Bryan Reatini ◽  
Todd J. Vision
Keyword(s):  
Environmental Conditions ◽  
Genetic Architecture ◽  
Genetic Variance ◽  
De Novo ◽  
Dispersal Rate ◽  
Intraspecific Hybridization ◽  
Source Populations ◽  
Second Category ◽  
Do So

AbstractThe role of genetic architecture in adaptation to novel environments has received considerable attention when the source of adaptation variation is de novo mutation. Relatively less is known when the source of adaptive variation is inter- or intraspecific hybridization. We model hybridization between divergent source populations and subsequent colonization of an unoccupied novel environment using individual-based simulations in order to understand the influence of genetic architecture on the timing of colonization and the mode of adaptation. We find that two distinct categories of genetic architecture facilitate rapid colonization but that they do so in qualitatively different ways. For few and/or tightly linked loci, the mode of adaptation is via the recovery of adaptive parental genotypes. With many unlinked loci, the mode of adaptation is via the generation of novel hybrid genotypes. The first category results in the shortest colonization lag phases across the widest range of parameter space, but further adaptation is mutation limited. The second category takes longer and is more sensitive to genetic variance and dispersal rate, but can facilitate adaptation to environmental conditions which exceed the tolerance of parental populations. These findings have implications for understanding the origins of biological invasions and the success of hybrid populations.

High inbreeding in the Faroe Islands does not appear to constitute a risk factor for multiple sclerosis

2014 ◽  
Vol 21 (8) ◽  
pp. 996-1002 ◽  
Author(s):  
S Binzer ◽  
K Imrell ◽  
M Binzer ◽  
K. O Kyvik ◽  
J Hillert ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Risk Factor ◽  
Association Studies ◽  
Large Population ◽  
Genome Wide Association Studies ◽  
Faroe Islands ◽  
Isolated Populations ◽  
Inbreeding Coefficients ◽  
Significant Difference

Background: Large population-based genome-wide association studies have identified several multiple sclerosis (MS) genetic risk variants, but the existing missing heritability warrants different strategies. Isolated populations offer an alternative way of searching for rare genetic variants and evaluating the possible role of consanguinity in the development of MS. Studies of consanguinity and MS risk have yielded conflicting results. Objectives: In this study we investigated the role of consanguinity on MS risk in the relatively isolated Faroe Islands, which have a presumed high level of inbreeding. Methods: A total of 29 cases and 28 matched controls were genotyped and assessed for inbreeding coefficients, number of runs of homozygosity (ROH) at different lengths and observed number of homozygotes as measures of relatedness. Parametric and non-parametric statistical models were applied. Results: Both cases and controls exhibited considerable relatedness demonstrated by very high inbreeding coefficients, large number of observed homozygotes and many long ROH. However, apart from the number of ROH ≥ 2.5 mega base pairs, no significant differences between the two groups were observed. Conclusions: Overall, no significant difference between cases and controls were found, indicating that consanguinity in itself does not appear to be an important risk factor for MS in the population of the Faroe Islands.

Xq28 copy number gain causing moyamoya disease and a novel moyamoya syndrome

2020 ◽  
Vol 57 (5) ◽  
pp. 339-346 ◽  
Author(s):  
Chaker Aloui ◽  
Stéphanie Guey ◽  
Eva Pipiras ◽  
Manoelle Kossorotoff ◽  
Sophie Guéden ◽  
...  
Keyword(s):  
Moyamoya Disease ◽  
Copy Number ◽  
De Novo ◽  
Clinical Care ◽  
Copy Number Variants ◽  
Snp Array ◽  
Copy Number Gain ◽  
Array Data ◽  
Whole Exome ◽  
Large Vessel Disease

BackgroundThe molecular anomalies causing moyamoya disease (MMD) and moyamoya syndromes (MMS) are unknown in most patients.ObjectiveThis study aimed to identify de novo candidate copy number variants (CNVs) in patients with moyamoya.MethodsRare de novo CNVs screening was performed in 13 moyamoya angiopathy trios using whole exome sequencing (WES) reads depth data and whole genome high density SNP array data. WES and SNP array data from an additional cohort of 115 unrelated moyamoya probands were used to search for recurrence of these rare de novo CNVs.ResultsTwo de novo CNVs were identified in two unrelated probands by both methods and confirmed by qPCR. One of these CNVs, located on Xq28, was detected in two additional families. This interstitial Xq28 CNV gain is absent from curated gold standard database of control genomic variants and gnomAD databases. The critical region contains five genes, including MAMLD1, a major NOTCH coactivator. Typical MMD was observed in the two families with a duplication, whereas in the triplicated patients of the third family, a novel MMS associating moyamoya and various systemic venous anomalies was evidenced.ConclusionThe recurrence of this novel Xq28 CNV, its de novo occurrence in one patient and its familial segregation with the affected phenotype in two additional families strongly suggest that it is pathogenic. In addition to genetic counselling application, its association with pulmonary hypertension is of major importance for clinical care. These data also provide new insights into the genomic architecture of this emblematic, non-atherosclerotic, large vessel disease.

scholarly journals Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism

2018 ◽  
Author(s):  
F. Kyle Satterstrom ◽  
Jack A. Kosmicki ◽  
Jiebiao Wang ◽  
Michael S. Breen ◽  
Silvia De Rubeis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Exome Sequencing ◽  
Large Scale ◽  
De Novo ◽  
Regulation Of Gene Expression ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Risk Genes ◽  
Functional Changes ◽  
Multiple Paths

SummaryWe present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.

Posttransplant CMV infection and the role of immunosuppression (Sponsor: Novartis Pharma GmbH, Nürnberg)

2016 ◽  
Vol 04 (01) ◽  
pp. 4-10
Keyword(s):  
Lower Incidence ◽  
Paradigm Shift ◽  
Mtor Inhibitor ◽  
De Novo ◽  
Expert Panel ◽  
Risk Of Infection ◽  
Cmv Infection ◽  
Expert Meeting ◽  
Selection Of

AbstractImmunosuppression permits graft survival after transplantation and consequently a longer and better life. On the other hand, it increases the risk of infection, for instance with cytomegalovirus (CMV). However, the various available immunosuppressive therapies differ in this regard. One of the first clinical trials using de novo everolimus after kidney transplantation [1] already revealed a considerably lower incidence of CMV infection in the everolimus arms than in the mycophenolate mofetil (MMF) arm. This result was repeatedly confirmed in later studies [2–4]. Everolimus is now considered a substance with antiviral properties. This article is based on the expert meeting “Posttransplant CMV infection and the role of immunosuppression”. The expert panel called for a paradigm shift: In a CMV prevention strategy the targeted selection of the immunosuppressive therapy is also a key element. For patients with elevated risk of CMV, mTOR inhibitor-based immunosuppression is advantageous as it is associated with a significantly lower incidence of CMV events.

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