Imbalanced expression for predicted high-impact, autosomal-dominant variants in a cohort of 3,818 healthy samples

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract Background One of the growing problems in genome diagnostics is the increasing number of variants that get identified through genetic testing but for which it is unknown what the significance for the disease is (Variants of Unknown Significance - VUS) 1,2 . When these variants are observed in patients, clinicians need to be able to determine their relevance for causing the patient’s disease. Here we investigated whether allele-specific expression (ASE) can be used to prioritize disease-relevant VUS and therefore assist diagnostics. In order to do so, we conducted ASE analysis in RNA-seq data from 3,818 blood samples (part of the the Dutch BIOS biobank consortium), to ascertain how VUS affect gene expression. We compared the effect of VUS variants to variants that are predicted to have a high impact, and variants that are predicted to be pathogenic but are either recessive or autosomal-dominant with low penetrance. Results For immune and haematological disorders, we observed that 24.7% of known pathogenic variants from ClinVar show allelic imbalance in blood, as compared to 6.6% of known benign variants with matching allele frequencies. However, for other types of disorders, ASE information from blood did not distinguish (likely) pathogenic variants from benign variants. Unexpectedly, we identified 5 genes ( ALOX5, COMT, PRPF8, PSTPIP1 and SH3BP2 ) in which seven population-based samples had a predicted high impact, autosomal-dominant variant. For these genes the imbalanced expression of the major allele compensates for the lower expression of the minor allele. Conclusions Our analysis in a large population-based gene expression cohort reveals examples of high impact, autosomal-dominant variants that are compensated for by imbalanced expression. Additionally, we observed that ASE analyses in blood are informative for predicting pathogenic variants that are associated with immune and haematological conditions. We have made all our ASE results, including many ASE calls for rare variants (MAF < 1%), available at https://molgenis15.gcc.rug.nl/ .

Authors 12

1. Niek de Klein

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands

2. Freerk van Dijk

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Genomics Coordination Center, University of Groningen, University Medical Center Groningen, the Netherlands

   University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands

3. Patrick Deelen

   University Medical Center Groningen · University of Groningen · University Medical Center Utrecht

   Affiliation as printed

   Department of Genetics, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA, Utrecht, the Netherlands

   Genomics Coordination Center, University of Groningen, University Medical Center Groningen, the Netherlands

   University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands

4. Carlos G. Urzúa-Traslaviña

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands

5. Annique Claringbould

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands

6. Urmo Võsa

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands

7. Joost Verlouw

   Erasmus MC

   Affiliation as printed

   Dept. of Internal Medicine, Erasmus Medical Center Rotterdam, the Netherlands

8. Ramin Monajemi Aachen Department of Biomedical Data Sciences

   Leiden University Medical Center

   Affiliation as printed

   Dept. of Biomedical Data Sciences, Leiden University Medical Center, the Netherlands

9. Peter A.C. ’t Hoen Aachen Department of Human Genetics

   Leiden University Medical Center · Radboud University Medical Center

   Affiliation as printed

   Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, the Netherlands

   Dept. of Human Genetics, Leiden University Medical Center, the Netherlands

10. Richard J. Sinke

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands

11. Morris A. Swertz

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    Genomics Coordination Center, University of Groningen, University Medical Center Groningen, the Netherlands

    University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands

12. Lude Franke corresponding

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands