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Absolute quantification reveals the stable transmission of a high copy number variant linked to autoinflammatory disease
Karolinska Inst, Rheumatol Unit, Dept Med, Stockholm, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2016 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 17, 299Article in journal (Refereed) Published
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Abstract [en]

Background: Dissecting the role copy number variants (CNVs) play in disease pathogenesis is directly reliant on accurate methods for quantification. The Shar-Pei dog breed is predisposed to a complex autoinflammatory disease with numerous clinical manifestations. One such sign, recurrent fever, was previously shown to be significantly associated with a novel, but unstable CNV (CNV_16.1). Droplet digital PCR (ddPCR) offers a new mechanism for CNV detection via absolute quantification with the promise of added precision and reliability. The aim of this study was to evaluate ddPCR in relation to quantitative PCR (qPCR) and to assess the suitability of the favoured method as a genetic test for Shar-Pei Autoinflammatory Disease (SPAID). Results: One hundred and ninety-six individuals were assayed using both PCR methods at two CNV positions (CNV_14.3 and CNV_16.1). The digital method revealed a striking result. The CNVs did not follow a continuum of alleles as previously reported, rather the alleles were stable and pedigree analysis showed they adhered to Mendelian segregation. Subsequent analysis of ddPCR case/control data confirmed that both CNVs remained significantly associated with the subphenotype of fever, but also to the encompassing SPAID complex (p < 0.001). In addition, harbouring CNV_16.1 allele five (CNV_16.1 vertical bar 5) resulted in a four-fold increase in the odds for SPAID (p < 0.001). The inclusion of a genetic marker for CNV_16.1 in a genome-wide association test revealed that this variant explained 9.7 % of genetic variance and 25.8 % of the additive genetic heritability of this autoinflammatory disease. Conclusions: This data shows the utility of the ddPCR method to resolve cryptic copy number inheritance patterns and so open avenues of genetic testing. In its current form, the ddPCR test presented here could be used in canine breeding to reduce the number of homozygote CNV_16.1 broken vertical bar 5 individuals and thereby to reduce the prevalence of disease in this breed.

Place, publisher, year, edition, pages
2016. Vol. 17, 299
Keyword [en]
Copy number variation, Autoinflammation, Droplet digital PCR, Quantitative PCR
National Category
Medical Genetics Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:uu:diva-297362DOI: 10.1186/s12864-016-2619-0ISI: 000374945200001PubMedID: 27107962OAI: oai:DiVA.org:uu-297362DiVA: diva2:941859
Funder
Swedish Research Council Formas, 221-2012-1531
Available from: 2016-06-23 Created: 2016-06-22 Last updated: 2017-11-28Bibliographically approved

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Kierczak, MarcinKarlsson, ÅsaLindblad-Toh, KerstinMeadows, Jennifer

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