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Identification of pathogenic variant enriched regions across genes and gene families

View ORCID ProfileEduardo Pérez-Palma, View ORCID ProfilePatrick May, Sumaiya Iqbal, Lisa-Marie Niestroj, Juanjiangmeng Du, Henrike Heyne, Jessica Castrillon, View ORCID ProfileAnne O’Donnell-Luria, Peter Nürnberg, Aarno Palotie, Mark Daly, Dennis Lal
doi: https://doi.org/10.1101/641043
Eduardo Pérez-Palma
1Cologne Center for Genomics, University of Cologne, Cologne, NRW, Germany
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  • ORCID record for Eduardo Pérez-Palma
Patrick May
2Luxembourg Centre for Systems Biomedicine, University Luxembourg, Esch-sur-Alzette, Luxembourg
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  • ORCID record for Patrick May
Sumaiya Iqbal
3Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Lisa-Marie Niestroj
1Cologne Center for Genomics, University of Cologne, Cologne, NRW, Germany
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Juanjiangmeng Du
1Cologne Center for Genomics, University of Cologne, Cologne, NRW, Germany
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Henrike Heyne
3Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Jessica Castrillon
5Genomic Medicine Institute, Lerner Research Institute Cleveland Clinic, USA
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Anne O’Donnell-Luria
3Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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  • ORCID record for Anne O’Donnell-Luria
Peter Nürnberg
1Cologne Center for Genomics, University of Cologne, Cologne, NRW, Germany
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Aarno Palotie
3Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
6Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
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Mark Daly
3Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
6Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
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Dennis Lal
1Cologne Center for Genomics, University of Cologne, Cologne, NRW, Germany
3Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
5Genomic Medicine Institute, Lerner Research Institute Cleveland Clinic, USA
7Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, USA
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  • For correspondence: lald@ccf.org
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Abstract

Missense variant interpretation is challenging. Essential regions for protein function are conserved among gene family members, and genetic variants within these regions are potentially more likely to confer risk to disease. Here, we generated 2,871 gene family protein sequence alignments involving 9,990 genes and performed missense variant burden analyses to identify novel essential protein regions. We mapped 2,219,811 variants from the general population into these alignments and compared their distribution with 65,034 missense variants from patients. With this gene family approach, we identified 398 regions enriched for patient variants spanning 33,887 amino acids in 1,058 genes. As a comparison, testing the same genes individually we identified less patient variant enriched regions involving only 2,167 amino acids and 180 genes. Next, we selected de novo variants from 6,753 patients with neurodevelopmental disorders and 1,911 unaffected siblings, and observed a 5.56-fold enrichment of patient variants in our identified regions (95% C.I. =2.76-Inf, p-value = 6.66×10−8). Using an independent ClinVar variant set, we found missense variants inside the identified regions are 111-fold more likely to be classified as pathogenic in comparison to benign classification (OR = 111.48, 95% C.I = 68.09-195.58, p-value < 2.2e−16). All patient variant enriched regions identified (PERs) are available online through a user-friendly platform for interactive data mining, visualization and download at http://per.broadinstitute.org. In summary, our gene family burden analysis approach identified novel patient variant enriched regions in protein sequences. This annotation can empower variant interpretation.

Footnotes

  • The authors declare no competing interests

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 17, 2019.
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Identification of pathogenic variant enriched regions across genes and gene families
Eduardo Pérez-Palma, Patrick May, Sumaiya Iqbal, Lisa-Marie Niestroj, Juanjiangmeng Du, Henrike Heyne, Jessica Castrillon, Anne O’Donnell-Luria, Peter Nürnberg, Aarno Palotie, Mark Daly, Dennis Lal
bioRxiv 641043; doi: https://doi.org/10.1101/641043
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Identification of pathogenic variant enriched regions across genes and gene families
Eduardo Pérez-Palma, Patrick May, Sumaiya Iqbal, Lisa-Marie Niestroj, Juanjiangmeng Du, Henrike Heyne, Jessica Castrillon, Anne O’Donnell-Luria, Peter Nürnberg, Aarno Palotie, Mark Daly, Dennis Lal
bioRxiv 641043; doi: https://doi.org/10.1101/641043

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