These authors contributed equally.
Exome sequencing in a family segregating for celiac disease
Article first published online: 21 JUN 2011
© 2011 University Medical Center Groningen, NL
Special Issue: Exome Sequencing
Volume 80, Issue 2, pages 138–147, August 2011
How to Cite
Szperl, A., Ricaño-Ponce, I., Li, J., Deelen, P., Kanterakis, A., Plagnol, V., van Dijk, F., Westra, H., Trynka, G., Mulder, C., Swertz, M., Wijmenga, C. and Zheng, H. C. (2011), Exome sequencing in a family segregating for celiac disease. Clinical Genetics, 80: 138–147. doi: 10.1111/j.1399-0004.2011.01714.x
- Issue published online: 12 JUL 2011
- Article first published online: 21 JUN 2011
- Accepted manuscript online: 31 MAY 2011 05:56AM EST
- Received 9 May 2011, revised and accepted for publication 24 May 2011
- complex disease;
- exome sequencing;
- linkage study;
- rare variants
Szperl AM, Ricaño-Ponce I, Li JK, Deelen P, Kanterakis A, Plagnol V, van Dijk F, Westra HJ, Trynka G, Mulder CJ, Swertz M, Wijmenga C, Zheng H Ch. Exome sequencing in a family segregating for celiac disease.
Celiac disease is a multifactorial disorder caused by an unknown number of genetic factors interacting with an environmental factor. Hence, most patients are singletons and large families segregating with celiac disease are rare. We report on a three-generation family with six patients in which the inheritance pattern is consistent with an autosomal dominant model. To date, 27 loci explain up to 40% of the heritable disease risk. We hypothesized that part of the missing heritability is because of low frequency or rare variants. Such causal variants could be more prominent in multigeneration families where private mutations might co-segregate with the disease. They can be identified by linkage analysis combined with whole exome sequencing. We found three linkage regions on 4q32.3-4q33, 8q24.13-8q24.21 and 10q23.1-10q23.32 that segregate with celiac disease in this family. We performed exome sequencing on two affected individuals to investigate the positional candidate regions and the remaining exome for causal nonsense variants. We identified 12 nonsense mutations with a low frequency (minor allele frequency <10%) present in both individuals, but none mapped to the linkage regions. Two variants in the CSAG1 and KRT37 genes were present in all six affected individuals. Two nonsense variants in the MADD and GBGT1 genes were also present in 5 of 6 and 4 of 6 individuals, respectively; future studies should determine if any of these nonsense variants is causally related to celiac disease.