Exome Sequencing Reveals rare Loss-of-Function Mutations in FLG and Immune Genes in Multi-Food Allergic Patients

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 (GWAS) 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.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 have at least 2 food allergies confirmed by a food allergist. Family history of eczema, asthma, or food allergy was preferred but not required. DNA from probands, siblings and parents were exome sequenced and analyzed for inheritance and enrichment of specific genes.Of 28 full trio families and 28 singletons, we found 39.3% probands (n=22/56) have a Loss-of-Function (LoF) mutation in a gene known to cause food allergy: FLG. We further found genes suspicious for causing Mendelian food allergy: SMAD3 LoF mutation (n=1), and dominant inheritance of LoF mutations in IFIH1 (MDA5, n=3 independent probands). FLG LoFs were significantly enriched in our Non-Hispanic White (NHW) cohort compared to 1,100 NHW controls (P_Lof= 4.28E-04 ; OR= 3.38 [1.72-6.67]). Notably, exome sequencing improved detection of LoF FLG mutations by 58% compared to previously used FLG genotyping methods, especially for people of non-European Ancestry. Furthermore, we found LoF FLG variants in most food allergic subjects of African (55%, 5/9) ancestry, but this observation could be limited by low sample size.Therefore, 39.3% of patients with multiple food allergies may have a Mendelian cause for food allergy. Expanded genomic studies of ethnically diverse groups and validation cohorts is warranted to uncover the variety of LoF variants from FLG present and confirm a potential role for MDA5.