non-Ashkenazi Jews Research Articles

Acutely developed elbow arthritis in a patient with Brucellosis: Familial Mediterranean Fever

Familial Mediterranean Fever (FMF) is an autosomal recessive disorder that is prevalent in non-Ashkenazi Jews, Armenians, Turks and Arabs. The characteristic features of FMF is recurrent self-limited attacks of fever, polyserositis (synovitis, peritonitis, and pleuritis), and secondary amyloidosis. Genetic studies have shown that the gene for FMF is located on chromosome 16p is designated MEFV. The diagnosis of FMF is based on a clinical history of typical acute attacks, ethnic background, and family history. Brucellosis is a systemic infectious disease caused by gram-negative bacillus. The prevalence of the disease is higher in developing countries. It is frequently transmitted to humans via consumption of infected unpasteurized dairy products and infected by direct contact with infected animals. In this article, we discussed a patient who was in our follow up with diagnosis of brucellosis, after sudden effusion of elbow; we diagnosed the case FMF together with brucellosis.

Associated Morbidity of Chalazia

Chalazion may be associated with some local and systemic conditions. We studied the prevalence of various conditions among patients with chalazion. A retrospective observational case-control study of all the members who were diagnosed with chalazion in the Central District of Clalit Health Services in Israel (years 2000-2008; n = 9119) and 9119 age- and gender-matched controls randomly selected from the district members. We calculated the prevalence of various ocular, systemic, and demographic conditions as risk factors for chalazion. Demographically, a significant (P < 0.0001) tendency to develop chalazion was found in the population of lower socioeconomic class, in the population living in urban areas, in young females (10-29 years), in older men (older than 60 years), and in non-Ashkenazi Jews. The following risk factors of chalazion were statistically significant: blepharitis [odds ratio (OR), 6.2], rosacea (OR, 2.9), gastritis (OR, 1.4), anxiety (OR, 1.5), irritable bowel syndrome (OR, 1.7), and smoking (OR, 1.2). Diabetes (OR, 0.8) and hypothyroidism (OR, 0.8) were significantly less prevalent among chalazion patients. Some systemic conditions are significantly more prevalent and some are significantly less prevalent among patients with chalazion. Better understanding of the pathophysiological association between those diseases and chalazion may help in its treatment and prevention.

The Spectrum of MEFV Mutations in an Arabic Cohort

Background: Autoinflammatory diseases are a group of disorders characterized by seemingly unprovoked inflammation in the absence of high-titer autoantibodies or antigen-specific T cells. Familial Mediterranean Fever (FMF) is an autosomal recessive disorder. It is characterized by recurrent self-limiting episodes of fever and painful polyserositis. FMF is prevalent in specific ethnic groups—namely, non-Ashkenazi Jews, Armenians, Turks, and Arabs. There seems to be a distinctive clinical picture in Arab patients with FMF, and the range and distribution of MEFV mutations is different from that noted in other commonly affected ethnic groups. Objectives: The aim of this study is to delineate the spectrum and distribution of MEFV mutations amongst an Arabic FMF patient cohort and to assist the genotype-phenotype correlation in these patients. Methods: We have collected DNA samples from 188 FMF patients (from Qatar, Jordan and Palestine) who have been clinically diagnosed with FMF, according to international and validated diagnostic criteria. We have designed primers to cover the entire genomic region of MEFV. As a first tier, mutation detection is done by resequencing the entire coding sequence and splice sites; as a second tier the rest of the genomic region including the promoter are resequenced. Results: In the first tier, we have identified 191 out of 376 mutant alleles (50%) by resequencing the entire coding region and splice sites of MEFV. In addition, resequencing of the entire genomic region of 100 patients who had only one identifiable allele was carried resulting in the identification of specific haplotypes and we are currently investigating the phenotypic significance of these haplotypes. Conclusions: The spectrum of MEFV mutations in Arabs seems different from other ethnic groups commonly affected by FMF. The fraction of the identifiable disease causing alleles is the lowest amongst the commonly affected ethnic groups. The results of the genomic resequencing of MEFV may provide some insight into the role of non-coding sequences and may explain the molecular pathology of FMF. Thereby, we are currently working on the development of a low cost and high throughput technique to facilitate the resequencing of the entire genomic sequence of MEFV using Next Generation sequencing technology.

Improved survival in non-Ashkenazi Jewish ovarian cancer patients with BRCA1 and BRCA2 gene mutations

ObjectivesPrevious studies report a survival advantage in ovarian cancer patients with Ashkenazi Jewish (AJ) breast cancer gene (BRCA) founder mutations. The purpose of this study was to determine if this association exists in patients with non-Ashkenazi Jewish (non-AJ) BRCA mutations. We also sought to account for “survival bias” by minimizing lead time that may exist between diagnosis and genetic testing. MethodsPatients with stage III/IV ovarian cancer and a non-AJ BRCA mutation, seen between January 1996 and July 2007, were identified from eight institutions. Patients with sporadic ovarian cancer were compared to similar cases, matched by age, stage, year of diagnosis, and vital status at time interval to BRCA testing. Progression-free (PFS) and overall survival (OS) were calculated by the Kaplan–Meier method. Multivariate Cox proportional hazards models were calculated for variables of interest. Fisher's exact test and chi-square were also used for analysis. ResultsNinety-five advanced stage ovarian cancer patients with non-AJ BRCA mutations and 183 sporadic controls were analyzed. Compared to sporadic ovarian cancer patients, non-AJ BRCA patients had longer PFS (27.9 months vs. 17.9 months, HR 0.61 [95% CI 0.43–0.86]) and OS (101.7 months vs. 54.3 months, HR 0.43 [95% CI 0.27–0.68]). BRCA status was an independent predictor of PFS and OS. ConclusionsThis multicenter study demonstrates a significant survival advantage in advanced stage ovarian cancer patients with non-AJ BRCA mutations, confirming the previous studies in the Jewish population. This improved survival was evident when accounting for the “survival bias” that coincides with genetic testing.

The spectrum of Mediterranean fever (MEFV) mutations in an Arabic cohort

Abstract Autoinflammatory diseases are a group of disorders characterized by seemingly unprovoked inflammation in the absence of high-titer autoantibodies or antigen-specific T cells. Familial Mediterranean fever (FMF) is an autosomal recessive disorder and the archetypal autoinflammatory disease. It is characterized by recurrent self-limiting episodes of fever and painful polyserositis. FMF is prevalent in specific ethnic groups namely, non-Ashkenazi Jews, Armenians, Turks, and Arabs. The gene responsible for FMF, MEFV, was identified in 1997. There seems to be a distinctive clinical picture in Arab patients with FMF, and the range and distribution of MEFV mutations is different from that noted in other commonly affected ethnic groups. The aim of this study was to delineate the distribution of MEFV mutations amongst an Arabic FMF patient cohort and to assist the genotype-phenotype correlation in these patients. We collected DNA samples from 406 FMF patients (from Qatar, Jordan, Algeria and Palestine) who have been clinically diagnosed with FMF. We designed primers to cover the entire genomic region of MEFV. Mutation detection is done by resequencing the entire coding sequence and splice sites then the rest of the genomic region and the promoter will be sequenced as a second tier. So far we have identified 283 (out of 676) mutant alleles by sequencing exon 10, the main hot spot for MEFV mutations (M694V, V726A, M694I, M680IGC, M680IGA, R653H, A744S and R761H). In addition, four novel variations were identified in our cohort in exons 3, 5, 2 & 10, and we are currently investigating the phenotypic significance of these novel variations. The spectrum of MEFV mutations in Arabs seems different from other ethnic groups commonly affected by FMF. The identifiable disease causing alleles are the lowest amongst the commonly affected ethnic groups. The low number of identified alleles suggests the presence of mutations within unexamined regions, such as conserved intronic sequences or the involvement of modifier genes.

Language in Nationalism: Modern Hebrew in the Zionist Project

This article examines the history of Israel's lingua franca as a constituent of the Zionist project. Based largely on recent scholarship, this work sheds light on the role of language in the educational and political efforts to create a New Hebrew Man who, in contradistinction to the European Jew, was to live ‘as a free man’ in his own land. Reflecting Jewish experience in the Russian Empire, these efforts alienated traditional, particularly non-Ashkenazi Jews. The article addresses the question of the uniqueness of the modern Israeli vernacular that contributes to the historical legitimacy of Zionism and the state of Israel.

No significant association results obtained from significant association evidence: the ongoing uncertainty of TP53 codon 72 polymorphism and breast cancer risk

We have read with great interest the article ‘‘No significant association between the TP53 codon 72 polymorphism and breast cancer risk: a meta-analysis of 21 studies involving 24,063 subjects’’ published online on May 23, 2010 issue of ‘‘Breast Cancer Research And Treatment’’ [1]. In conclusion, this meta-analysis with a large sample size provided strong evidence that TP53 codon 72 polymorphism was not associated with breast cancer risk [1]. The meta-analysis based on currently available evidence by Ma et al. [1] was aimed to derive a more precise assessment of the relationship between TP53 codon 72 polymorphism and breast cancer risk, but some methodological issues need to be addressed concerning this research. Ma et al. [1] concluded that no significant association was found between the TP53 codon 72 polymorphism and breast cancer risk when all the studies were pooled into the meta-analysis (Pro/Arg vs. Pro/Pro: OR 1.063, 95% CI 0.967–1.169; Arg/Arg vs. Pro/Pro: OR 1.245, 95% CI 0.997–1.554; dominant model: OR 1.146, 95% CI 0.979–1.340; recessive model: OR 1.179, 95% CI 1.020–1.362). Actually, the odds ratio of 1.179 and 95% confidence interval for odds ratio of 1.020–1.362 in recessive model demonstrated some evidence of association between TP53 codon 72 polymorphism and breast cancer risk. Similarly, Ma et al. [1] demonstrated that no significant association was observed for any of the genetic models in the stratified analysis by source of controls (Pro/Arg vs. Pro/Pro: OR 1.075, 95% CI 0.974–1.187; Arg/Arg vs. Pro/ Pro: OR 1.283, 95% CI 1.036–1.588; dominant model: OR 1.158, 95% CI 1.007–1.333; recessive model: OR 1.229, 95% CI 1.054–1.433). Obviously, significant associations were observed in the Arg/Arg vs. Pro/Pro, the dominant and the recessive models. Thus, the ongoing uncertainty still existed and the conclusion by Ma et al. [1] was not entirely credible. Importantly, several sizeable eligible studies (7,601 cases and 11,549 controls) have not been included in this meta-analysis [2–16], even though they satisfied the search criteria. Of note, there were 5 studies of Asians [2–6], 8 studies of Caucasians [7–14], and 2 studies of mixed populations [15, 16]. Among these eligible studies, 6 were population-based [2–4, 10, 13, 16], 7 were hospital-based [5, 8, 9, 11, 12, 14, 15], and 2 were not reported [6, 7]. Specifically, the study by Ohayon et al. [8] has provided separate data on among Ashkenazi Jews and non-Ashkenazi Jews subpopulations, and Menzel et al. [10] provided separate data on Tyrol and Prague subpopulations. Ma et al. [1] concluded that no significant association was found between the TP53 codon 72 polymorphism and breast cancer risk when all the studies were pooled into the meta-analysis and same conclusions were obtained in the Pei-Hua Lu, Guo-Qing Tao and Xiao Liu contributed equally to this work and should be considered as co-first authors.

Frequencies of C282Y and H63D alleles in the HFE gene among various Jewish ethnic groups in Israel: A change of concept required

PurposeHereditary hemochromatosis has not been fully evaluated in the non-Ashkenazi population and is considered to be relatively rare. After ascertaining three unrelated hereditary hemochromatosis families of North African Jewish origin with the HFE C282Y/C282Y genotype, we evaluated the C282Y and H63D allele frequencies among the different Jewish ethnic groups in Israel, in particular North African Jews. MethodsData were collected from three Israeli Medical Centers. North African, Oriental, Yemenite, and Sephardic Jewish healthy individuals were assessed for the C282Y and H63D alleles. ResultsThe C282Y allele frequency was 1.02% (6/586 chromosomes), and the H63D allele frequency was 13.82% (81/586 chromosomes) in the North African Jewish group. The C282Y allele was not detected in the other non-Ashkenazi groups. The H63D allele frequency was 12.5% (38/304 chromosomes) in Oriental Jews, 14.9% (14/94 chromosomes) in Yemenite Jews, and 9.3% (11/118 chromosomes) in Sephardic Jews. DiscussionHereditary hemochromatosis is underrecognized among North African Jews, who have carrier frequencies of 1/58 and 1/4 for C282Y and H63D, respectively. HFE-hereditary hemochromatosis is not rare among this population as currently thought and merits increased awareness to prevent endpoint disease. The frequent occurrence of β-thalassemia trait and HFE-H63D in non-Ashkenazi Jews raises the possibility of genetic interactions contributing to iron overload when coinherited and requires further evaluation.

LANGUAGE IN NATIONALISM: MODERN HEBREW IN THE ZIONIST PROJECT

This article examines the history of Israel's lingua franca as a constituent of the Zionist project. Based largely on recent scholarship, this work sheds light on the role of language in the educational and political efforts to create a New Hebrew Man who, in contradistinction to the European Jew, was to live ‘as a free man’ in his own land. Reflecting Jewish experience in the Russian Empire, these efforts alienated traditional, particularly non-Ashkenazi Jews. The article addresses the question of the uniqueness of the modern Israeli vernacular that contributes to the historical legitimacy of Zionism and the state of Israel.

Pemphigus – analysis of epidemiological factors in 155 patients

Pemphigus vulgaris is a chronic autoimmune mucocutaneous blistering disease. Only a few studies have evaluated the epidemiological and aetiological parameters of pemphigus vulgaris in a large group of patients over the long term. The sample included 155 patients with a diagnosis of pemphigus who attended the pemphigus clinic of a major tertiary medical centre from 1976 to 2004. Data were obtained from the patient files and entered into an ad hoc form; patients were contacted by telephone for missing information. The female-to-male ratio was 1.5 : 1. Non-Ashkenazi Jews accounted for 37% of the sample. In only 10% of the patients was a potential aetiologic or precipitating factor identified. Pemphigus vulgaris is characterized by a female predominance, consistent with other autoimmune disease. The gender, age and ethnic distribution of affected patients have not changed in the last 40 years. In the vast majority of cases, the aetiologic or precipitating factor is unknown, although drugs appear to be very rare.

Counting the Founders: The Matrilineal Genetic Ancestry of the Jewish Diaspora

The history of the Jewish Diaspora dates back to the Assyrian and Babylonian conquests in the Levant, followed by complex demographic and migratory trajectories over the ensuing millennia which pose a serious challenge to unraveling population genetic patterns. Here we ask whether phylogenetic analysis, based on highly resolved mitochondrial DNA (mtDNA) phylogenies can discern among maternal ancestries of the Diaspora. Accordingly, 1,142 samples from 14 different non-Ashkenazi Jewish communities were analyzed. A list of complete mtDNA sequences was established for all variants present at high frequency in the communities studied, along with high-resolution genotyping of all samples. Unlike the previously reported pattern observed among Ashkenazi Jews, the numerically major portion of the non-Ashkenazi Jews, currently estimated at 5 million people and comprised of the Moroccan, Iraqi, Iranian and Iberian Exile Jewish communities showed no evidence for a narrow founder effect, which did however characterize the smaller and more remote Belmonte, Indian and the two Caucasus communities. The Indian and Ethiopian Jewish sample sets suggested local female introgression, while mtDNAs in all other communities studied belong to a well-characterized West Eurasian pool of maternal lineages. Absence of sub-Saharan African mtDNA lineages among the North African Jewish communities suggests negligible or low level of admixture with females of the host populations among whom the African haplogroup (Hg) L0-L3 sub-clades variants are common. In contrast, the North African and Iberian Exile Jewish communities show influence of putative Iberian admixture as documented by mtDNA Hg HV0 variants. These findings highlight striking differences in the demographic history of the widespread Jewish Diaspora.

A Mutation Analysis of the Phenylalanine Hydroxylase (PAH) Gene in the Israeli Population

Hyperphenylalaninemia (HPA) is a group of diseases characterized by a persistent elevation of phenylalanine levels in tissues and biological fluids. The most frequent form is phenylalanine hydroxylase deficiency, causing phenylketonuria (PKU). Among 159 Israeli patients (Jews, Muslim and Christian Arabs and Druze) with HPA, in whom at least one of the mutations was characterized, a total of 43 different mutations were detected, including seven novel ones. PKU was very rare among Ashkenazi Jews and relatively frequent among Jews from Yemen, the Caucasian Mountains, Bukhara and Tunisia. The mutations responsible for the high frequency were: exon3del (Yemenite Jews), L48S (Tunisian Jews) and E178G, P281L and L48S (Jews from the Caucasian Mountains and Bukhara). Among the non-Jewish Israeli citizens, the disease was relatively frequent in the Negev and in the Nazareth vicinity, and in many localities a unique mutation was detected, often in a single family. While marked genetic heterogeneity was observed in the Arab and Jewish populations, only one mutation A300S, was frequent in all of the communities. Several of the other frequent mutations were shared by the non-Ashkenazi Jews and Arabs; none were mutual to Ashkenazi Jews and Arabs.

Similar prevalence of founder BRCA1 and BRCA2 mutations among Ashkenazi and non-Ashkenazi men with breast cancer: Evidence from 261 cases in Israel, 1976–1999

To evaluate the potential contribution of mutations in the BRCA1 and BRCA2 genes to male breast cancer (MBC), we expanded a previous study to screen a total of 261 Israeli men diagnosed with breast carcinoma. A total of 21 BRCA2 6174delT and 8 BRCA1 185delAG mutations were found. Similar frequencies of BRCA1 and BRCA2 mutation carriers were found among Ashkenazi (12.8%) and non-Ashkenazi Jews (9.1%). The combined prevalence of BRCA1/ BRCA2 founder mutations among Ashkenazi Jewish men is slightly higher than for women, due to a higher frequency of BRCA2 mutations.

The P1812A and P25TBRCA1and the 5164del4BRCA2Mutations: Occurrence in High-Risk Non-Ashkenazi Jews

Founder mutations in the BRCA1 and BRCA2 genes have been discovered in the Ashkenazic Jewish population, but a founder mutation(s) has not been discovered among non-Ashkenazi Jews (NAJ). Two BRCA1 mutations (P1812A, P25T), and a BRCA2 mutation (5164del4) have been detected in NAJ high-risk families. We studied the prevalence of these three mutations in 270 high-risk NAJ families, including 85 from Iraq/Iran, 67 from North Africa, 27 from Yemen, 50 from the Balkan region, and 41 with mixed ancestry. The three mutations were detected only in individuals related to the original families. We conclude that the P1812A and P25T BRCA1 and 5164del4 BRCA2 mutations are not likely to be founder mutations in NAJ high-risk families. We also assessed the pathogenicity of the BRCA1 P1812A mutation in vitro using reporter gene assays in yeast and mammalian cells. We found that the BRCA1 P1812A variant activity assays yielded a slightly reduced reporter gene activity. Thus, there is some uncertainty as to the pathogenicity of BRCA1 P1812A.

ATM haplotypes and breast cancer risk in Jewish high-risk women

While genetic factors clearly play a role in conferring breast cancer risk, the contribution of ATM gene mutations to breast cancer is still unsettled. To shed light on this issue, ATM haplotypes were constructed using eight SNPs spanning the ATM gene region (142 kb) in ethnically diverse non-Ashkenazi Jewish controls (n=118) and high-risk (n=142) women. Of the 28 haplotypes noted, four were encountered in frequencies of 5% or more and accounted for 85% of all haplotypes. Subsequently, ATM haplotyping of high-risk, non-Ashkenazi Jews was performed on 66 women with breast cancer and 76 asymptomatic. One SNP (rs228589) was significantly more prevalent among breast cancer cases compared with controls (P=4 × 10−9), and one discriminative ATM haplotype was significantly more prevalent among breast cancer cases (33.3%) compared with controls (3.8%), (P⩽10−10). There was no significant difference in the SNP and haplotype distribution between asymptomatic high-risk and symptomatic women as a function of disease status. We conclude that a specific ATM SNP and a specific haplotype are associated with increased breast cancer risk in high-risk non-Ashkenazi Jews.

Familial Mediterranean fever in the Syrian population: gene mutation frequencies, carrier rates and phenotype–genotype correlation

Background Familial Mediterranean fever (FMF) is an autosomal recessive disease mainly affecting particularly Arabs, Non-Ashkenazi Jews, Armenians, and Turks. It is an autoinflammatory periodic disorder characterized by febrile and painful attacks due to inflammation involving the serosal membranes in the abdomen, chest or joints. Over 50 mutations have been identified in the MEFV gene responsible for FMF. Objective To identify the distribution and the frequency of the MEFV gene mutations in Syrian FMF patients and population and perform a genotype/phenotype correlation in the patients' cohort. Patients and methods The study was carried out on 83 clinically diagnosed Syrian FMF patients and 242 healthy subjects. The tested individuals were screened for the most common five MEFV mutations (M694V, M694I, M680I, V726A and E148Q) by restriction fragment length polymorphism. Sequencing of exon 10 was performed only for the patients' DNA where just one or no mutation was detected. Results and discussion Of the 83 patients studied, 74 (89%) were positive either for one, two or three mutations and nine (11%) had no mutations detected. Of those positive for mutations, 25 were homozygous, 30 were compound heterozygotes, three had complex alleles, and 16 patients had only one mutation. The M694V, V726A, M694I, M680I and E148Q mutations accounted for 45.8%, 26%, 13.9%, 4.8% and 6% of the alleles, respectively. The carrier rate in the Syrian population for the tested mutations was 17.5%, E148Q being the most common mutation, followed by V726A and M694V. The severity of the disease and development of amyloidosis seem to have an association with M694V, the most common mutation in Syrian FMF patients.

The Matrilineal Ancestry of Ashkenazi Jewry: Portrait of a Recent Founder Event

Both the extent and location of the maternal ancestral deme from which the Ashkenazi Jewry arose remain obscure. Here, using complete sequences of the maternally inherited mitochondrial DNA (mtDNA), we show that close to one-half of Ashkenazi Jews, estimated at 8,000,000 people, can be traced back to only 4 women carrying distinct mtDNAs that are virtually absent in other populations, with the important exception of low frequencies among non-Ashkenazi Jews. We conclude that four founding mtDNAs, likely of Near Eastern ancestry, underwent major expansion(s) in Europe within the past millennium.

Prevalence and distribution of MEFV mutations among Arabs from the Maghreb patients suffering from familial Mediterranean fever

Familial Mediterranean fever (FMF) is an autosomal recessive inherited disease caused by mutations in MEFV. This disease is characterized by recurrent episodes of fever accompanied with topical signs of inflammation. Some patients can develop renal amyloidosis. We prospectively investigated MEFV mutations in a cohort of 209 unrelated Arab patients from Maghreb (85 Algerians, 87 Moroccans, and 37 Tunisians) with a clinical suspicion of FMF. FMF is the main cause of periodic fever syndrome in Maghreb. The most frequent MEFV mutations in this cohort were M694V and M694I. These mutations account for different proportions of the MEFV mutations in Algeria (5%, 80%), Morocco (49%, 37%), and Tunisia (50%, 25%) patients. M694I mutation is specific to the Arab population from Maghreb. Other rare mutations were observed: M680L, M680I, A744S, V726A, and E148Q. We estimated the frequency of MEFV mutation carriers among the Arab Maghrebian population at around 1%, which is significantly lower than in non-Ashkenazi Jews, Armenians or Turks. To cite this article: L. Belmahi et al., C. R. Biologies 329 (2006).

Colorectal Polyps in Carriers of the APC I1307K Polymorphism

The probability of colorectal cancer is moderately increased among carriers of the APC I1307K polymorphism. However, it is not known if endoscopic surveillance of this high-risk group is warranted. The prevalence of polyps and adenomas in specimens of colorectal cancer who are carriers and noncarriers of the APC I1307K polymorphism is compared. Prevalence of adenomatous polyps in the pathology specimens of the study participants, stratified by their APC I1307K polymorphism status, was studied in 900 consecutive cases of colorectal cancer diagnosed in northern Israel between 1998 and 2002, within the framework of a population-based, case-controlled study (MECC Study). The APC I1307K mutation was detected in 78 colorectal cancer cases (8.7 percent) of the study population. Prevalence was higher among Ashkenazi Jews (11.2 percent) than among non-Ashkenazi Jews (2.7 percent) or Arabs (3.1 percent). After adjustment for age, APC I1307K carriers were significantly more likely than noncarriers to have polyps in their surgical specimen (51.3 percent vs. 32.6 percent, P = 0.002). Adenomas with a tubular component (either tubular adenomas or tubulovillous adenomas), but not villous adenomas, were significantly more frequent among carriers (37.2 percent vs. 23.6 percent, P = 0.005). Together with former evidence of I1307K being a risk factor for colorectal cancer, these data suggest that colonoscopic surveillance for colorectal adenomas and cancer may be warranted in I1307K carriers, even in the absence of other identifiable risk factors.

Multiplex Molecular Diagnosis of MEFV Mutations in Patients with Familial Mediterranean Fever by LightCycler Real-Time PCR

Familial Mediterranean fever (FMF) is an autoinflammatory disease inherited as an autosomal recessive condition and characterized by recurrent episodes of fever, abdominal pain, pleuritis, and arthritis (1)(2). The most dangerous manifestation is renal amyloidosis and end-stage renal failure. Many researchers have associated the M694V mutation (3)(4)(5) as well as the α allele of serum amyloid A protein I with significantly higher risk for amyloidosis (6). FMF is very prevalent in non-Ashkenazi Jews, Armenians, Arabs, and Turks, all of whom have ancestors of Mediterranean origin. The carrier frequency in these populations can reach up to 1:5, rendering it the most frequent autosomal recessive condition. Currently, it is considered frequent in other Mediterranean countries, including Cyprus (7)(8)(9)(10)(11). The gene associated with FMF, MEFV , which encodes pyrin/marenostrin, a protein of 781 amino acids (12)(13), belongs to the pyrin family of genes that play a role in autoinflammatory diseases and inflammatory pathways (14)(15). More than 40 mutations have been identified, but 4–6 mutations usually account for a high percentage of MEFV chromosomes in different ethnic populations, emphasizing the importance of molecular epidemiologic studies for identifying the various molecular defects in the population of interest. The detection of known mutations in MEFV can be accomplished by various methods, including direct DNA sequencing. These methods are time-consuming and prone to carryover PCR contamination because of the repetitive work in a diagnostic setting. Using fluorescence resonance energy transfer (FRET) on a LightCycler® instrument (Roche), we developed a rapid method that detects point mutations and small deletions by use of fluorescent hybridization probes. Because of the close proximity of several mutations on exon 10, we designed a single pair of fluorescent probes with multiplex melting profiles that permits …