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Identification and quantification of oligogenic loss-of-function disorders

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dc.contributor.authorStefanski, Arthur
dc.contributor.authorPérez, Eduardo
dc.contributor.authorMrdjen, Marko
dc.contributor.authorMcHugh, Megan
dc.contributor.authorLeu, Costin
dc.contributor.authorLal, Dennis
dc.date.accessioned2023-03-31T18:04:21Z
dc.date.available2023-03-31T18:04:21Z
dc.date.issued2021
dc.description.abstractPurpose: Monogenic disorders can present clinically heterogeneous symptoms. We hypothesized that in patients with a monogenic disorder caused by a large deletion, frequently additional loss-of-function (LOF)-intolerant genes are affected, potentially contributing to the phenotype. Methods: We investigated the LOF-intolerant gene distribution across the genome and its association with benign population and pathogenic classified deletions from individuals with presumably monogenic disorders. For people with presumably monogenic epilepsy, we compared Human Phenotype Ontology terms in people with large and small deletions. Results: We identified LOF-intolerant gene dense regions that were enriched for ClinVar and depleted for population copy number variants. Analysis of data from >143,000 individuals with a suspected monogenic disorder showed that 2.5% of haploinsufficiency disorder-associated deletions can affect at least 1 other LOF-intolerant gene. Focusing on epilepsy, we observed that 13.1% of pathogenic and likely pathogenic ClinVar deletions <3 megabase pair, covering the diagnostically most relevant genes, affected at least 1 additional LOF-intolerant gene. Those patients have potentially more complex phenotypes with increasing deletion size. Conclusion: We could systematically show that large deletions frequently affected admditional LOF-intolerant genes in addition to the established disease gene. Further research is needed to understand how additional potential disease-relevant genes influence monogenic disorders to improve clinical care and the efficacy of targeted therapies.
dc.description.versionVersión publicada
dc.identifier.citationStefanski A, Pérez-Palma E, Mrdjen M, McHugh M, Leu C, Lal D. Identification and quantification of oligogenic loss-of-function disorders. Genet Med. 2022 Mar;24(3):729-735. doi: 10.1016/j.gim.2021.10.026
dc.identifier.doihttps://doi.org/10.1016/j.gim.2021.10.026
dc.identifier.urihttps://repositorio.udd.cl/handle/11447/7225
dc.language.isoen
dc.subjectCNV
dc.subjectEpilepsy
dc.subjectLoss-of-function
dc.subjectMonogenic
dc.subjectOligogenic
dc.titleIdentification and quantification of oligogenic loss-of-function disorders
dc.typeArticle
dcterms.accessRightsAcceso abierto
dcterms.sourceGenetics in medicine : official journal of the American College of Medical Genetics
dspace.entity.typePublication

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