Objective FMF has traditionally been considered an autosomal recessive disease; however, it has been observed that a substantial quantity of patients with clinical FMF possess only one demonstrable mutation. non-FMF patients with active inflammation. Testing of genes encoding pyrin-interacting proteins identified rare variants in a small number of patients, suggesting the possibility of digenic inheritance. Conclusion Our data underscore the presence of a significant subset of FMF patients who are carriers of only one mutation and demonstrate that total sequencing is not likely Etizolam IC50 to yield a second mutation. Screening for the set of most common mutations appears sufficient in the presence of clinical symptoms to diagnose FMF and initiate a trial of colchicine. Introduction Familial Mediterranean fever (FMF, OMIM 249100) is an autosomal recessive autoinflammatory disease characterized by episodic, self-limiting attacks of fever along with abdominal pain, pleurisy, arthritis, and a distinctive rash (1). Systemic amyloidosis is the most severe manifestation of the disease, commonly affecting the kidneys (11% of cases), and sometimes the adrenals, intestine, spleen, lung and testis (2). Of the known Etizolam IC50 hereditary periodic fevers, FMF is the most prevalent and best characterized. FMF is usually common in Middle Eastern populations, including Sepharadi and Ashkenazi Jews, Turks, Armenians, and Arabs and is not uncommon in other Mediterranean Etizolam IC50 populations such as Italians, Spanish, Portuguese, French, and Greeks. FMF cases have also been explained in many other populations, including Northern Europeans and Japanese (1). The carrier frequency for mutations is quite high in the four classically affected populations, ranging from 37C39% in Armenians and Iraqi Jews, to 20% in Turks, North African and Ashkenazi Jews, and Arabs. The high prevalence of carriers in multiple Middle Eastern and Mediterranean populations suggests that heterozygosity may confer a selective advantage. Despite high carrier frequencies in these populations, the prevalence of FMF is usually less than expected, indicating that the disease is usually either underdiagnosed or that disease-associated mutations have reduced penetrance. The gene responsible for FMF, designated mutations (usually E148Q in exon 2 and M680I, M694I, M694V, and V726A in exon 10) may account for as much Etizolam IC50 as 80% of FMF cases in classically affected populations (11); however, it has been observed that a substantial quantity of patients with clinical FMF (up to 30% depending on the populace) possess only one demonstrable mutation despite sequencing of the entire coding region (12C16). These single-variant patients often have a typical disease history and respond well to colchicine, the standard treatment for FMF. One explanation for this phenomenon is usually a lack of sensitivity in screening techniques. The majority of FMF patients in classically affected populations are screened for a limited quantity of mutations, which account for a majority of carrier chromosomes in a given populace. This approach typically targets only the most prevalent mutations in a specific populace, thus rare or novel variants can be overlooked. Another possibility is that the second disease-associated mutation may reside in the non-coding (intronic) or regulatory regions of transcript is usually 15 kb in size, thus it is not practical for diagnostic sequencing using standard techniques. Although most disease-associated mutations are missense nucleotide changes, the possibility of genomic re-arrangements (e.g. deletions, or copy number variations) cannot be excluded as another mechanism of disease. However, a recent study using multiplex ligation-dependent probe amplification (MLPA) failed to identify any copy number variations (CNV) in a large cohort of 216 FMF patients, suggesting that CNVs do not contribute to FMF pathogenesis (17). Two recent reports have raised the question of dominant inheritance in FMF. Booth et al. explained GADD45BETA a single mutation associated.