Abstract
PurposeMonogenic 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. MethodsWe 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. ResultsWe 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. ConclusionWe 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.
Highlights
In many rare genetic disorders, individuals with the same affected gene still present with widely heterogeneous symptoms or phenotypes.[1,2] The clinical heterogeneity across individuals with variants affecting the same gene is not fully understood
To explore the genome-wide distribution of LOF-intolerant genes and identify regions of the genome that may be prone to oligogenic deletion disorders, we investigated the number of neighboring genes (1) around every human gene in each interval and (2) across the genome in nonoverlapping sliding windows (Figure 1A)
We investigated the correlation between LOF-intolerant genes and pathogenic and likely pathogenic (P/LP) ClinVar deletions or deletions found in 171,825 individuals from the general population (UK Biobank).[13]
Summary
In many rare genetic disorders, individuals with the same affected gene still present with widely heterogeneous symptoms or phenotypes.[1,2] The clinical heterogeneity across individuals with variants affecting the same gene is not fully understood. Genes with currently no established human disease phenotype, including genes known to be intolerant for lossof-function (LOF) variants (LOF-intolerant genes),[5] ie, likely to cause haploinsufficiency disorders, are typically ignored. Because such LOF-intolerant genes could contribute to the phenotype, the current practice may lead to incomplete genetic testing results in some individuals and exacerbate knowledge gaps. We assessed the frequency of potential digenic and oligogenic disorders in >143,000 individuals referred to genetic testing for a suspected monogenic disorder.[6] We investigated ClinVar,[7] focusing on epilepsy, an established disorder with many known disease-associated LOF-intolerant genes and reported causal deletions
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