Clinical significance of E148Q heterozygous variant in paediatric familial Mediterranean fever

Objectives. FMF results from mutations in the Mediterranean fever (MEFV) gene. The p. E148Q protein alternation is one of the most frequent 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. We compared the clinical manifestations and disease severity score of four genetic subgroups: (group 1) patients harbouring a single heterozygous p. E148Q variant (n=6); (group 2) patients harbouring a single p. M694V heterozygous variant (n=88); (group 3) patients harbouring compound heterozygous p. M694V and p. E148Q variants (n=36); and (group 4) homozygotes for p. M694V variant (n=160). Results. Of 646 FMF children from our centre, only 1% (six patients) of our genetically characterized FMF cohort had a single E148Q variant, most presenting with recurrent fevers and abdominal pain. None of the participants was found to harbour homozygous E148Q. Overall, M694V/E148Q compound heterozygosity did not exhibit a more severe phenotype compared with patients with a single M694V variant. 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 subgroups showed milder clinical phenotype compared with 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 variant. Thus, E148Q heterozygosity does not result in clinically meaningful phenotype in children.