Exome sequencing in a family segregating for celiac disease

Clin Genet. 2011 Aug;80(2):138-47. doi: 10.1111/j.1399-0004.2011.01714.x. Epub 2011 Jun 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / genetics
  • Celiac Disease / genetics*
  • Death Domain Receptor Signaling Adaptor Proteins / genetics
  • Exons / genetics*
  • Female
  • Gene Frequency
  • Genetic Linkage
  • Genetic Predisposition to Disease
  • Genome, Human / genetics*
  • Guanine Nucleotide Exchange Factors / genetics
  • Humans
  • Keratins, Hair-Specific / genetics
  • Keratins, Type I / genetics
  • Male
  • Neoplasm Proteins / genetics
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Sequence Analysis, DNA


  • Antigens, Neoplasm
  • CSAG1 protein, human
  • Death Domain Receptor Signaling Adaptor Proteins
  • Guanine Nucleotide Exchange Factors
  • KRT37 protein, human
  • Keratins, Hair-Specific
  • Keratins, Type I
  • MADD protein, human
  • Neoplasm Proteins