Chia-Ti Tsai1, Chia-Shan Hsieh2, Sheng-Nan Chang3, Eric Y Chuang2, Jyh-Ming Jimmy Juang4, Lian-Yu Lin4, Ling-Ping Lai4, Juey-Jen Hwang4, Fu-Tien Chiang5, Jiunn-Lee Lin4. 1. Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan. 2. Genome and Systems Biology Degree Program, Department of Life Science, National Taiwan University, Taipei, Taiwan Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan. 3. Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan. 4. Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan. 5. Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan Department of Laboratory Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.
Abstract
BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Genome-wide association studies (GWAS) have identified common variants in nine genomic regions associated with AF (KCNN3, PRRX1, PITX2, WNT8A, CAV1, C9orf3, SYNE2, HCN4 and ZFHX3 genes); however, the genetic variability of these risk variants does not explain the entire genetic susceptibility to AF. Rare variants missed by GWAS may also contribute to genetic risk of AF. METHODS: We used an extreme trait design to sequence carefully selected probands with extreme phenotypes and their unaffected parents to identify rare de novo variants or mutations. Based on the hypothesis that common and rare variants may colocate in the same disease susceptibility gene, we used next-generation sequencing to sequence these nine published AF susceptibility genes identified by GWAS (a total of 179 exons) in 20 trios, 200 unrelated patients with AF and 200 non-AF controls. RESULTS: We identified a novel mutation in the 5' untranslated region of the PITX2 gene, which localised in the transcriptionally active enhancer region. We also identified one missense exon mutation in KCNN3, two in ZFHX3 and one in SYNE2. None of these mutations were present in other unrelated patients with AF, healthy controls, unaffected parents and are thus novel and de novo (p<10(-4)). Functional study showed that the mutation in the 5' untranslated region of the PITX2 gene significantly downregulated PITX2 expression in atrial myocytes, either in basal condition or during rapid pacing. In silico analysis showed that the missense mutation in ZFHX3 results in damage of the ZFHX3 protein structure. CONCLUSIONS: The genetic architecture of subjects with extreme phenotypes of AF is similar to that of rare or Mendelian diseases, and mutations may be the underlying cause. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
BACKGROUND:Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Genome-wide association studies (GWAS) have identified common variants in nine genomic regions associated with AF (KCNN3, PRRX1, PITX2, WNT8A, CAV1, C9orf3, SYNE2, HCN4 and ZFHX3 genes); however, the genetic variability of these risk variants does not explain the entire genetic susceptibility to AF. Rare variants missed by GWAS may also contribute to genetic risk of AF. METHODS: We used an extreme trait design to sequence carefully selected probands with extreme phenotypes and their unaffected parents to identify rare de novo variants or mutations. Based on the hypothesis that common and rare variants may colocate in the same disease susceptibility gene, we used next-generation sequencing to sequence these nine published AF susceptibility genes identified by GWAS (a total of 179 exons) in 20 trios, 200 unrelated patients with AF and 200 non-AF controls. RESULTS: We identified a novel mutation in the 5' untranslated region of the PITX2 gene, which localised in the transcriptionally active enhancer region. We also identified one missense exon mutation in KCNN3, two in ZFHX3 and one in SYNE2. None of these mutations were present in other unrelated patients with AF, healthy controls, unaffected parents and are thus novel and de novo (p<10(-4)). Functional study showed that the mutation in the 5' untranslated region of the PITX2 gene significantly downregulated PITX2 expression in atrial myocytes, either in basal condition or during rapid pacing. In silico analysis showed that the missense mutation in ZFHX3 results in damage of the ZFHX3 protein structure. CONCLUSIONS: The genetic architecture of subjects with extreme phenotypes of AF is similar to that of rare or Mendelian diseases, and mutations may be the underlying cause. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: Tudor Groza; Sebastian Köhler; Dawid Moldenhauer; Nicole Vasilevsky; Gareth Baynam; Tomasz Zemojtel; Lynn Marie Schriml; Warren Alden Kibbe; Paul N Schofield; Tim Beck; Drashtti Vasant; Anthony J Brookes; Andreas Zankl; Nicole L Washington; Christopher J Mungall; Suzanna E Lewis; Melissa A Haendel; Helen Parkinson; Peter N Robinson Journal: Am J Hum Genet Date: 2015-06-25 Impact factor: 11.025