Comment on: Pyrin variant E148Q potentiates inflammasome activation and the effect of pathogenic mutations in <i>cis</i>

et al. [1] on the potential pathogenic role of the E148Q variant in FMF.I was particularly intrigued by the conclusion that the presence of E148Q in cis with M694I may contribute to the autosomal dominant inheritance of the disease.I want to share a recent case I encountered, with the journal readers, which raises some concerns about the study's conclusions.A 10-year-old boy presented with recurrent fever, arthralgia, skin rash and angioedema.These episodes lasted for 3 days and occurred about twice a month.Despite the atypical symptoms (skin rash and angioedema) and the patient's Ashkenazi Jewish ancestry, a diagnosis of FMF was proposed.Genetic testing revealed the patient carried two pyrin variants: V726A and E148Q.A therapeutic trial with colchicine was ineffective.He was then referred to my clinic for further evaluation.The patient's family history revealed similar symptoms in his brother, father and paternal grandmother, while his mother was completely asymptomatic.This suggested an autosomal dominant pattern, which is unusual for FMF.Wholegenome sequencing showed that the symptomatic father did not carry any MEFV mutation, while the asymptomatic mother and brother both carried V726A and E148Q.Given that both children shared the same genotype as their mother, and the father did not carry any mutation, we concluded that the variants were on the same allele in cis (complex allele).This case illustrates a scenario of a recurrent fever syndrome inherited in an autosomal dominant manner, where some patients carry two mutations (V726A and E148Q) in cis that are not associated with the disease.The mother, who carried both mutations, remained asymptomatic, whereas the father, who had similar symptoms, did not carry any MEFV variant.Therefore, the genetic test results in this case were a 'red herring'.Several lessons from this case are relevant to the study by Reygaerts et al.