Project Details

Confirming Mendelian Genetic Causes of Pediatric Food Allergy

Jeffrey SoRelle, MD

Summary

BACKGROUND: Food allergies affect 7.5% of children in the US with more than 40% experiencing severe reactions including life-threatening anaphylaxis. The cause of allergy has been strongly linked to genetics, yet several superficial, population based, genetic studies have failed to identify any genetic cause. GAP: Comprehensive DNA sequencing (whole exome sequencing), has never been performed on children with food allergy. This method can detect Mendelian causes of allergy that have not been detected to this point. HYPOTHESIS: Recently, we performed a genetic allergy screen in mice and found dozens of genes that regulate allergies in mice. We hypothesize mutations in these newly discovered genes that cause allergy in mice will also cause allergy in humans. METHODS: Comprehensive DNA sequencing was performed on children with multiple, severe food allergies and close relatives to pinpoint genes causing allergy. Children with multiple food allergies and a strong family history of allergy are more likely to have a genetic cause for their food allergy, so we collected their DNA by blood or saliva sample. RESULTS: We performed whole exome sequencing on 60 individuals (18 families) with >98% of the genome covered at least 20x sequencing depth. These results were mapped to the human genome and analyzed by pedigree analysis, which demonstrated many possible causative variants. The most promising occurred in a family with two affected children carrying rare, compound heterozygous mutations in an AT-hook transcription gene. The children had either celiac disease or eosinophilic esophagitis in addition to multiple food allergies. This was the only family with variants in this gene and further studies will be required to replicate the findings. IMPACT: Discovery of novel genes associated with allergic disease will help identify people at increased risk of allergies. This will allow personalized treatments based on biological pathways affected. Furthermore, this can lead to discovery of novel pathways that can be therapeutically targeted for a broader population of pediatric patients affected by food allergies. Website Link: https://mutagenetix.utsouthwestern.edu/home.cfm