A general framework for identifying oligogenic combinations of rare variants in complex disorders

Pounraja, Vijay Kumar; Girirajan, Santhosh

doi:10.1101/gr.276348.121

Cited by 11 publications

(9 citation statements)

References 65 publications

(81 reference statements)

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“…Next, we studied the contribution of digenic interactions to CHD using the RareComb 17 framework ( see Methods ). Our analysis revealed a total of 2,083 digenic pairs significantly enriched for hcLOF and/or missC variants in CHD cases (aCHD) compared to controls at FDR 1% ( Figure 5a, Supplemental Table 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…Contrasting with the study of monogenic causes of CHD, oligogenic factors underlying the disease have been explored to a lesser extent. We took advantage of a newly developed method to study the contribution of digenic interactions (the simplest form of oligogenic) to CHD, in a case-control setting 17 . Interestingly, we observed a higher proportion of digenic interactions contributing to non-syndromic compared to syndromic CHD.…”

Section: Discussionmentioning

confidence: 99%

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Assessing the contribution of rare variants to congenital heart disease through a large-scale case-control exome study

Audain,

Wilsdon,

Dombrowsky

et al. 2023

Preprint

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Several studies have demonstrated the value of large-scale human exome and genome data analysis, to maximise gene discovery in rare diseases. Using this approach, we have analysed the exomes of 4,747 cases and 52,881 controls, to identify single genes and digenic interactions which confer a substantial risk of congenital heart disease (CHD). We identified both rare loss-of-function and missense coding variants in ten genes which reached genome-wide significance (Bonferroni adjustedP< 0.05) and an additional four genes with a significant association at a false discovery rate (FDR)threshold of 5%. We highlight distinct genetic contributions to syndromic and non-syndromic CHD at both single gene and digenic level, by independently analysing probands from these two groups. In addition, by integrative analysis of exome data with single-cell transcriptomics data from human embryonic hearts, we identified cardiac-specific cells as well as putative biological processes underlying the pathogenesis of CHD. In summary, our findings strengthen the association of known CHD genes, and have identified additional novel disease genes and digenic interactions contributing to the aetiology of CHD.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Assessing the contribution of rare variants to congenital heart disease through a large-scale case-control exome study

Audain,

Wilsdon,

Dombrowsky

et al. 2023

Preprint

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“…In this regard, it is pertinent to cite the examples of the abovementioned PKD1 p.Arg3277Cys and MECP2 p.Pro399Leu variants, both of which should theoretically have been filtered out by reference to the maximum allele frequency expected for a typical pathogenic variant in these disorders. As such, "predisposing' variants, which can potentially include any type of variant (e.g., missense, intronic, regulatory), may not only account for a significant fraction of the unexplained cases of both monogenic and oligogenic disease [100][101][102][103] but may also be relevant to the "missing heritability" problem in complex disease [104,105].…”

Section: Discussionmentioning

confidence: 99%

Validation of the ACMG/AMP guidelines-based seven-category variant classification system

Chen

Masson

Zou

et al. 2023

Preprint

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Background:One shortcoming of employing the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP)-recommended five-category variant classification scheme (″pathogenic″, ″likely pathogenic″, ″uncertain significance″, ″likely benign″ and ″benign″) in medical genetics lies in the schemeprime or minutes inherent inability to deal properly with variants that fall midway between ″pathogenic″ and ″benign″. Employing chronic pancreatitis as a disease model, and focusing on the four most studied chronic pancreatitis-related genes, we recently expanded the five-category ACMG/AMP scheme into a seven-category variant classification system. With the addition of two new classificatory categories, ″predisposing″ and ″likely predisposing″, our seven-category system promises to provide improved classification for the entire spectrum of variants in any disease-causing gene. The applicability and practical utility of our seven-category variant classification system however remains to be demonstrated in other disease/gene contexts, and this has been the aim of the current analysis.Results:We have sought to demonstrate the potential universality of pathological variants that could be ascribed the new variant terminology (′predisposing′) by trialing it across three Mendelian disease contexts (i.e., autosomal dominant, autosomal recessive and X-linked). To this end, we firstly employed illustrative genes/variants characteristic of these three contexts. On the basis of our own knowledge and expertise, we identified a series of variants that fitted well with our ″predisposing″ category, including ″hypomorphic″ variants in thePKD1gene and ″variants of varying clinical consequence″ in theCFTRgene. These examples, followed by reasonable extrapolations, enabled us to infer the widespread occurrence of ″predisposing″ variants in disease-causing genes. Such ″predisposing″ variants are likely to contribute significantly to the complexity of human genetic disease and may account not only for a considerable proportion of the unexplained cases of monogenic and oligogenic disease but also for much of the ″missing heritability″ characteristic of complex disease.Conclusion:Employing an evidence-based approach together with reasonable extrapolations, we demonstrate both the applicability and utility of our seven-category variant classification system for disease-causing genes. The recognition of the new ″predisposing″ category not only has immediate implications for variant detection and interpretation but should also have important consequences for reproductive genetic counseling.

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“…To show statistical support for oligogenic inheritance, a worldwide effort should be established to analyze the complete genome of all FUS -ALS carriers and compare the genomes of the ones with ID to the ones without ID, in the same manner as was done in the study by Pounraja and Girirajan. 38 This group developed a method to establish oligogenic inheritance in specific phenotypes among males on the autism spectrum and was able to identify mutated gene combinations significantly associated with ID phenotypes.…”

Section: Discussionmentioning

confidence: 99%

FUS-P525L Juvenile Amyotrophic Lateral Sclerosis and Intellectual Disability

et al. 2022

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Background and ObjectivesAmyotrophic lateral sclerosis (ALS) is characterized by upper and lower motor neuron degeneration, with juvenile ALS (jALS) defined as disease with age at onset (AAO) before 25 years. We aimed to identify the genetic basis of 2 unrelated patients with jALS with very rapid deterioration and early age intellectual disability (ID) and to assess association of genetic findings with both phenotypes in a large cohort of patients with ALS and controls, and in the literature.MethodsExome sequencing was performed in 2 unrelated probands and their parents. Trio analyses included de novo, rare homozygosity, and compound heterozygosity analyses. A TaqMan genotyping assay was used to genotype ALS cohorts. A systematic literature review was conducted and additional information from authors obtained to assess prevalence of fused in sarcoma (FUS)-ALS associated with ID.ResultsA de novo mutation FUS-P525L was identified in both patients. Additional variations were identified in other genes related to intellectual disabilities. Among 8 additional unrelated juvenile patients, one carried the same FUS mutation and had a similar medical history of mild ID and fulminant ALS, whereas the others did not carry any FUS coding mutations and had no reported learning or intellectual disabilities (p = 0.0083). In addition, 486 patients with ALS with AAO ≥25 years were negative for this mutation. An extensive literature review showed that among all patients with FUS-related ALS with full phenotype reports, 10.3% exhibited additional learning/intellectual disabilities.DiscussionFUS-P525L mutation was identified in 3 among 10 patients with jALS (30%) in our clinical cohort, all with a very aggressive disease course and ID. Together with literature reports, these results support a novel association between mutations in FUS and early life ID. Additional variations identified in genes related to ID and brain development in our patients (GPT2, DNAH10, and SCUBE2) may suggest a complex oligogenic inheritance for this phenotype. We propose that this mutation should be screened in patients with ALS with very early AAO, aggressive disease course, and sporadic occurrence, especially when ALS is accompanied by ID.

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A general framework for identifying oligogenic combinations of rare variants in complex disorders

Cited by 11 publications

References 65 publications

Assessing the contribution of rare variants to congenital heart disease through a large-scale case-control exome study

Assessing the contribution of rare variants to congenital heart disease through a large-scale case-control exome study

Validation of the ACMG/AMP guidelines-based seven-category variant classification system

FUS-P525L Juvenile Amyotrophic Lateral Sclerosis and Intellectual Disability

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