Clinical significance of E148Q heterozygous variant in paediatric FMF
2Paediatric Rheumatology unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer
3The Genomic Unit, Sheba Cancer Research Center , Sheba Medical Center , Tel Hashomer
4Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv
5Department of Genetics,, Sheba Medical Centre , Tel Hashomer
Objectives: Familial Mediterranean Fever (FMF) results from mutations in the Mediterranean fever (MEFV) gene. The p.E148Q is one of the most frequent protein alternations in the MEFV gene, yet the exact E148Q genotype–phenotype correlation remains unclear. The aim of this study was to examine clinical significance of heterozygous E148Q variant in a paediatric FMF cohort.
Methods: Of 646 FMF paediatric patients, we compared the clinical manifestations and disease severity score of four genetic sub-groups: (1) patients harboring a single heterozygous p.E148Q variant (n=6); (2) patients harboring a single p.M694V heterozygous mutation (n=88); (3) patients harboring compound heterozygous p.M694V and p.E148Q variants (n=36); and (4) homozygotes for p.M694V mutation (n=160).
Results: Only 1% (6 patients) of our genetically characterized FMF cohort had a single E148Q variant compared to 8.5% in a controlled population, most presenting with recurrent fevers and abdominal pain. None of the participants were found to harbor homozygous E148Q. Overall, M694V/E148Q compound heterozygosity did not exhibit a more severe phenotype compared with patients with a single M694V mutation. The former group were less likely to have abdominal pain and exertional leg pain (P<0.004 and P<0.001, respectively) and more likely to have chest pain (P<0.01). Both sub-groups showed milder clinical phenotype compared to patients with M694V homozygosity.
Conclusion: Our findings demonstrate that a single heterozygous E148Q variant is unlikely to cause FMF in children and that E148Q/M694V is clinically indistinguishable from a single M694V mutation. Thus, E148Q heterozygosity does not result in clinically meaningful phenotype in children.