Exome sequencing reveals rare loss-of-function mutations in FLG and immune genes in patients with multiple food allergies.

Abstract

Studies of twins, parents, and families have demonstrated a strong heritable role in allergy and food allergy in particular (60%-80%). However, genetic loci identified in previous genome-wide association studies focused on common variants, have not withstood validation, are not located inside protein coding exons, do not explain familial allergy, or have a low effect size. We sought to apply forward genetics of families and exome sequencing to identify the frequency of Mendelian gene mutations for food allergy with emphasis on rare coding high-risk variants. To enrich the probability of detecting Mendelian genetic variants, we included probands who had at least 2 food allergies confirmed by a food allergist. Family history of eczema, asthma, or food allergy was preferred but not required. Exome sequencing and analysis of DNA samples from probands, siblings, and parents was conducted to detect inheritance and enrichment of specific genes. Of 28 full trio families and 28 singletons, we found that 39.3% probands (n = 22/56) had a loss-of-function (LoF) mutation in FLG, a gene known to cause food allergy. We further found genes suspected of causing Mendelian food allergy: SMAD3 LoF mutation (n = 1) and dominant inheritance of LoF mutations in IFIH1 (MDA5) (n = 3 independent probands). FLG LoF mutations were significantly enriched in our non-Hispanic White cohort compared with 1100 non-Hispanic White controls (P_LoF = 4.28 × 10^-4; odds ratio 3.38 [95% CI 1.72-6.67]). Notably, exome sequencing improved detection of FLG LoF mutations by 58% compared with previously used FLG genotyping methods, especially for people of non-European ancestry. Furthermore, we found FLG LoF variants in most subjects of African (55%, 5/9) ancestry with food allergy, but this observation could be limited by low sample size. A Mendelian cause for food allergy may be present in 39.3% of patients with multiple food allergies. Expanded genomic studies of ethnically diverse groups and validation cohorts are warranted to uncover the variety of LoF variants from FLG present and confirm a potential role for MDA5.