The M694V mutation in Armenian‐Americans: a 10‐year retrospective study of MEFV mutation testing for familial Mediterranean fever at UCLA

Familial Mediterranean fever (FMF), inherited in an autosomal recessive manner, is a systemic auto‐inflammatory disorder characterized by recurrent attacks of fever with peritonitis, pleuritis, synovitis and erysipeloid rash. The marenostrin‐encoding fever (MEFV) gene, located on chromosome 16p13.3, is the only gene in which mutations are currently known to cause FMF. To correlate specific genotypes with adverse phenotypes of affected populations residing in the Western United States, a retrospective case series review was conducted of all MEFV gene mutation testing completed at UCLA Clinical Molecular Diagnostic Laboratory between February 2002 and February 2012, followed by clinical chart review of all subjects who either have a single or double mutation. All 12 common mutations in the MEFV gene were analyzed and the M694V variant was found to be associated with an adverse FMF clinical outcome in the Armenian‐American population, manifested by earlier onset of disease, increased severity of disease, and renal amyloidosis.     

Misdiagnosis of familial Mediterranean fever in patients with Anderson–Fabry disease

Fabry disease (FD) is an underdiagnosed pathology due to its symptomatology that overlaps with various systemic and rheumatic disorders, including familial Mediterranean fever (FMF). We examined the Mediterranean fever (MEFV) and α‐galactosidase A (GLA) genes, whose mutations are responsible for FMF and FD, respectively, in 42 unrelated patients diagnosed with FMF, which revealed significant ambiguity regarding some of the symptoms which are also present in FD. The objective of this study was to determine the spectrum of mutations present in these genes, in order to identify cases of mistaken diagnosis of FMF and/or missed diagnosis of FD. Ten out of 42 patients had one mutation in homozygosis or two different mutations in heterozygosis in the MEFV gene; 20/42 had a single heterozygous mutation, and 12/42 did not have genetic alterations in MEFV. The analysis of the GLA gene conducted on all the samples revealed that three subjects, and some members of their families, had two different exonic mutations associated with FD. Family studies allowed us to identify eight other cases of FD, bringing the total undiagnosed subjects to 11/53. Analyzing the MEFV and GLA genes in patients with clinical diagnoses of FMF proved to be fundamentally important for the reduction of diagnostic errors.     

Familial Mediterranean Fever Associated with MEFV Mutations in a Large Cohort of Cypriot Patients

Familial Mediterranean fever (FMF) is caused by mutations in the MEFV gene and the spectrum of mutations among Greek–Cypriots with FMF‐related symptoms was examined. Sequence analysis for exons 2, 3, 5, and 10 of the MEFV gene was performed in a cohort of 593 patients. A total of 70 patients carried mutations in the homozygote or compound heterozygote state, 128 were identified with one MEFV mutation and 395 had no mutations. Of the 268 identified alleles, p.Val726Ala (27.61%) was the most frequent followed by p.Met694Val (19.40%). The missense mutations p.Arg761His (3.73%) and p.Ala744Ser (2.24%) were identified as the rarest. An interesting finding is the high frequency (18.28%) of the complex p.Phe479Leu–p.Glu167Asp that was identified in 49 of the mutated alleles. The MEFV genotypes did not follow a binomial distribution and proved not to satisfy the HWE (P < 0.001). The high percentage (66.61%) of patients with unidentified mutations could be due to mutations in the rest of the coding or noncoding MEFV gene or due to mutations in other genes that are also causing Hereditary Recurrent Fevers. Results from this work indicate the high incidence of FMF in Cyprus and describe the spectrum of the mutations which occur in the country.     

Increased prevalence of MEFV exon 10 variants in Japanese patients with adult-onset Still’s disease

Autoinflammatory diseases include a large spectrum of monogenic diseases, e.g. familial Mediterranean fever (FMF), as well as complex genetic trait diseases, e.g. adult-onset Still''s disease (AOSD). In populations where FMF is common, an increased MEFV mutation rate is found in patients with rheumatic diseases. The aim of this study was to examine MEFV mutations in Japanese patients with AOSD. Genomic DNA was isolated from 49 AOSD patients and 105 healthy controls, and exons 1, 2, 3 and 10 of the MEFV gene genotyped by direct sequencing. MEFV mutation frequencies in AOSD patients were compared with controls. We found no significant difference in overall allele frequencies of MEFV variants between AOSD patients and controls. However, MEFV exon 10 variants (M694I and G632S) were significantly higher in AOSD patients than controls (6·1 versus 0%). In addition, there was no significant difference between MEFV variant carriers and non-carriers with clinical manifestations, but the monocyclic clinical course of the AOSD disease phenotype was observed less frequently in patients without MEFV variants. AOSD patients had significantly higher frequencies of MEFV exon 10 mutations, suggesting that low-frequency variants of MEFV gene may be one of the susceptibility factors of AOSD.     

The spectrum of Familial Mediterranean Fever gene (MEFV) mutations and genotypes in Iran,and report of a novel missense variant (R204H)

BackgroundFamilial Mediterranean Fever (FMF) is an autosomal recessive disorder, characterized by recurrent and self-limited episodes of fever, abdominal pain, synovitis and pleuritis. FMF as the most common inherited monogenic autoinflammatory disease mainly affects ethnic groups of the Mediterranean basin, Arab, Jewish, Turkish, Armenian North Africans and Arabic descent.Materials and methodsIn the present study, we selected 390 unrelated FMF patients according to the Tel-Hashomer criteria, and analyzed all patients for 12 most common mutations of MEFV gene by reverse hybridization assay (FMF strip assay). We also investigated exon 2 and 10 of MEFV gene in 78 patients by Sanger sequencing.ResultsAccording to strip assay results, at least one mutation was found in 234 patients (60%), and no mutation was found in other 156 patients (40%). The five most common mutations and allelic frequencies were M694V (13.6%), E148Q (10.4%), M694I (6.5%), V726A (4.1%), and M680I (3.8%). Moreover, we detected a novel missense variant (R204H, c.611 G > A) (SCV000297822) and following rare mutations among sequenced samples; R202Q, P115T, G304R, and E230K.ConclusionThis study describes the MEFV mutations spectrum and distribution in Iranian population, and shows different mutation patterns among Iranian ethnicities. Moreover, M694V is the most common MEFV mutation in Iran.     

The rate of MEFV gene mutations in hematolymphoid neoplasms

The aim of this study was to determine the rate of MEFV gene mutations, the gene responsible for familial Mediterranean fever (FMF), in patients with hematolymphoid neoplasm. The rate of the five most common MEFV gene mutations (M694V, M680I, V726A, M694I and E148Q) was determined in 46 patients with hematolymphoid neoplasm. We found a high frequency of carriers in patients with multiple myeloma (60%) and acute lymphocytic leukaemia (33.3%), whereas patients with chronic lymphocytic leukaemia (9%) and non-Hodgkin lymphoma (5%) had a low mutation carrier rate. There is no MEFV gene mutation in patients with Hodgkin lymphoma. Furthermore, the statistically significant predominance of strong heterozygous mutations such as M694V and M680I in patients with hematolymphoid neoplasm; none had own and/or family history compatible with FMF, is interesting. In conclusion, we found a high frequency of carriers for MEFV gene in patients with multiple myeloma and acute lymphocytic leukaemia. The data of our study may provide some new insights in understanding of individual genetic differences in susceptibility to these neoplasms.     

Common MEFV mutations among Jewish ethnic groups in Israel: High frequency of carrier and phenotype III states and absence of a perceptible biological advantage for the carrier state*

Familial Mediterranean fever (FMF) is an autosomal recessive disease, characterized by recurrent attacks of fever and inflammation of serosal membranes and gradual development of nephropathic amyloidosis. The recent cloning of the FMF gene (MEFV) and identification of disease‐associated mutations in most patients made the direct determination of FMF carrier frequency feasible. The aim of the present study was to investigate the carrier rate of the most common MEFV mutations among different Jewish ethnic groups in Israel. Further, an attempt was made to elucidate the possible biological advantage that the heterozygote state may confer. Three hundred Ashkenazi, 101 Iraqi, and 120 Moroccan Jews were screened for the E148Q, V726A, and M694V mutations (at least two most common mutations per group), with a resulting overall carrier frequency in the respective ethnic group of 14%, 29%, and 21%. No difference in morbidity between Ashkenazi carriers and non‐carriers of MEFV mutations was discerned, although an excess of febrile episodes in carriers of the V726A and in carriers of either V726A or E148Q was evident (P < 0.02 and P < 0.05, respectively). The frequency of subjects with two MEFV mutations but not expressing FMF (phenotype III) was 1:300 in Ashkenazi Jews and 1:25 in Iraqi Jews, exceeding the reported rate of overt FMF in these ethnic groups by 40–240 fold. These results affirm the high carrier rate among the studied Jewish ethnic groups in Israel and suggest that most subjects with FMF mutations are unaffected. © 2001 Wiley‐Liss, Inc.     

The Population Genetics of Familial Mediterranean Fever: A Meta‐Analysis Study

Our aim was to construct a Familial Mediterranean Fever (FMF) cumulative database and to propose a MEFV based phylogenetic tree. Data were collected from published studies. A meta‐analysis based on 16,756 chromosomes from FMF patients and normal individuals from 14 affected populations was performed. Arlequin 2.0 and Phylip 3.2 software were used for population genetics analysis and phylogenetic tree construction. We have shown that MEFV mutations are distributed non‐uniformly along the Mediterranean Sea area. The most frequent mutations detected in FMF patients are M694V (39.6%), V726A (13.9%), M680I (11.4%), E148Q (3.4%), and M694I (2.9%), while 28.8% of chromosomes carry unidentified or no mutations, especially in Western Europeans. The mean overall carrier rate is 0.186 with peak values in Arabs, Armenians, Jews, and Turks. Only V726A obeys the Hardy‐Weinberg law in FMF patients implying that this mutation is the most ancient. Jews present the most intense genetic isolation and drift; thus they might have nested de novo mutations and accelerated evolution. Besides Jews, three population groups might follow distinct evolutionary lines (Asia Minor, Eastern European, and Western European). In conclusion, the MEFV mutation pattern is non‐uniform regarding distribution, phenotypic expression, neutrality and population genetics characteristics. Jews are the candidate population for founder effects in MEFV.     

Familial Mediterranean Fever: The First Adult Case in Korea

Familial Mediterranean fever (FMF) is known to be a genetic disorder that prevalent among populations surrounding the Mediterranean Sea. Since Mediterranean fever gene (MEFV) was discovered at 1997, some cases have been reported in countries not related or close to this area like Japan. In addition it has been generally accepted that the clinical onset of FMF begins before 20 yr of age in most patients. Onset of the disease at an older age may occur but is rare. Adult-onset FMF may be a form of disease with distinct clinical, demographic and molecular characteristics. We describe a case of adult-onset FMF confirmed by DNA analysis of the MEFV gene in a Korean patient. A 32-yr-old man, who has no family history of FMF, presented with periodic fever, abdominal pain and vomiting. Though several various tests were thoroughly performed to evaluate the cause of his symptoms, there was no evidence of infectious, autoimmune or neoplastic diseases. Several gene analysis of periodic fever syndrome was finally performed and two point mutations (p.Leu110Pro, p.Glu148Gln) were identified. We confirmed the first adult case of FMF through detection of MEFV gene mutations in Korea and describe his clinical characteristics.     

The M694I/M694I genotype: A genetic risk factor of AA-amyloidosis in a group of Algerian patients with familial Mediterranean fever

Familial Mediterranean fever (FMF, OMIM 249100) is the most common hereditary fever, resulting from mutations in MEFV. FMF is characterized by episodic febrile attacks and polyserositis. Renal AA-amyloidosis is a major complication, which often leads to end-stage renal disease in untreated patients. The data about the renal AA-amyloidosis secondary to FMF are scarce in North African countries and non-existent in Algeria. We aimed to investigate the MEFV mutations associated with this complication in an Algerian patient cohort. Molecular analysis included 28 unrelated Algerian FMF patients with ascertained amyloidosis, 23 of them were symptomatic and 5 were asymptomatic. For this study, a group of 20 FMF patients without renal amyloidosis were selected as controls according to their age, disease onset and disease duration. The mutations were detected by sequencing exon 10 of MEFV. A total of 87.5% (49/56) mutant alleles were identified in 27/28 analyzed patients; p.M694I was predominant and appeared with an allele frequency of 62.5%, followed by p.M694V (17.85%), p.M680I (5.35%) and p.I692Del (1.78%). Remarkably, only p.M694I mutation was observed among the asymptomatic patients. The M694I/M694I genotype, identified in 14/27 (52%) patients, was significantly associated with the development of amyloidosis compared to group of controls (p = 0.022). This study did not link the M694V/M694V genotype to the renal complication despite the fact that it has been observed only in the patients with amyloidosis (3/27; 11%) (p = 0.349). The association of other identified genotypes to this complication was statistically insignificant. The progression of amyloidosis led to end-stage renal disease in 14 patients with 6 deaths. This study shows that p.M694I homozygosity is a potential genetic risk factor for the development of renal AA-amyloidosis in Algerian FMF patients.     

Genetic epidemiology of familial Mediterranean fever through integrative analysis of whole genome and exome sequences from Middle East and North Africa

Familial Mediterranean fever (FMF), an autosomal recessive and rare autoinflammatory disease is caused by genetic mutations in the MEFV gene and is highly prevalent in the Mediterranean basin. Although the carrier frequency of specific disease variants in the MEFV gene has been reported from isolated studies, a comprehensive view of variants in the Mediterranean region has not been possible due to paucity of data. The recent availability of whole‐genome and whole‐exome datasets prompted us to study the genetic epidemiology of MEFV variants in the region. We assembled data from 5 datasets encompassing whole‐genome and whole‐exome datasets for 2115 individuals from multiple subpopulations in the region and also created a compendium for MEFV genetic variants, which were further systematically annotated as per the American College of Medical Genetics and Genomics (ACMG) guidelines. Our analysis points to significant differences in allele frequencies in the subpopulations, and the carrier frequency for MEFV genetic variants in the population to be about 8%. The MEFV gene appears to be under natural selection from our analysis. To the best of our knowledge, this is the most comprehensive study and analysis of population epidemiology of MEFV gene variants in the Middle East and North African populations.     

Clinical and Genetic Profile of Children with Periodic Fever Syndromes from a Single Medical Center in South East Michigan

Objective

To report a cohort of children with periodic fever syndromes (PFS) from Southeast Michigan.

Methods

A retrospective review of medical records for patients referred for periodic fever over 5 years.

Results

Sixty-six patients including 21 FMF, 15 PFAPA, four TRAPS and one patient with combined HIDS and FMF were included. In addition, 25 patients were categorized as clinical PFS (cPFS) based on their clinical features however their genetic workup was either negative or inconclusive. Majority of the patients with FMF were from Middle Eastern background (88 %), but positive family history was noted in only 55 % of cases. Mean age at diagnosis was 40.8 months with a mean delay in diagnosis of 24 months. Most common MEFV mutations were p.M694V and p.M694I. Four patients with TRAPS were from mixed European descent and age at onset of symptoms was 6, 12, 12, and 84 months respectively. TNFRSF1A sequence variants in the TRAPS patients included p.R121Q (R92Q) and p.C99G (C70G); one patient had a rare occurrence of a concurrent p.V726A/-MEFV mutation. One patient with HIDS and FMF presented with atypical overlapping PFS clinical manifestations and genetic evaluation showed a unique combination of p.I268T/p.V377I MVK mutations and p.E230K/-MEFV variant. All patients with PFAPA group were from mixed European descent, symptoms started at a mean age of 34.6 months with a mean delay in diagnosis of 23.3 months. Symptoms started during infancy in six patients. All patients fulfilled the diagnostic criteria for PFAPA. The mean age of onset of symptoms in cPFS group was 17.2 months. Empiric colchicine and glucocorticosteroids controlled flares in majority of patients with cPFS. No evidence of amyloidosis was found in this entire cohort of 66 patients after a mean of 29.2 months of follow-up.

Conclusion

PFS can present with atypical manifestations and should not be excluded based on a negative family history. Concomitant mutations in different autoinflammatory disorders genes can be present and possibly explain atypical manifestations. Various therapies may be considered even if genetic testing is inconclusive or negative.     

Familial Mediterranean fever and microRNAs

Familial Mediterranean fever (FMF) is an inherited disorder caused by the gain of function mutations in MEFV (MEditerranean FeVer) gene loci. FMF affects more than 100,000 people worldwide and generally seen in the eastern Mediterranean region and causes the lifelong diseases which have a significant effect on the patient's life quality and health systems. The identification of low penetrant or heterozygous MEFV gene mutations in clinically diagnosed FMF patients was considered that epigenetic or environmental factors may display a role in FMF pathogenesis. Epigenetics might be defined as heritable changes that affect gene expression without any changes in the genome. MicroRNAs (miRNAs) are the main group of small noncoding RNAs, and an important element of epigenetic mechanisms and their discoveries revolutionized our knowledge about biological processes, such as malignant, infectious and autoimmune mechanisms, and contributed to the development of the epigenetic areas. In this review, the studies focusing on the roles of miRNAs in FMF pathogenesis in the last decades were examined and the importance of miRNAs as therapeutic agents which are promising for diagnosis and treatment was discussed.     

Hereditary Autoinflammatory Syndromes: A Brazilian Multicenter Study

Objective

To evaluate the prevalence of genetic defects in clinically suspected autoinflammatory syndromes (AIS) in a Brazilian multicenter study.

Methods

The study included 102 patients with a clinical diagnosis of Cryopyrin Associated Periodic Syndromes (CAPS), TNF Receptor Associated Periodic Syndrome (TRAPS), Familial Mediterranean Fever (FMF), Mevalonate Kinase Deficiency (MKD) and Pediatric Granulomatous Arthritis (PGA). One of the five AIS-related genes (NLRP3, TNFRSF1A, MEFV, MVK and NOD2) was evaluated in each patient by direct DNA sequencing, based on the most probable clinical suspect.

Results

Clinical diagnoses of the 102 patients were: CAPS (n?=?28), TRAPS (n?=?31), FMF (n?=?17), MKD (n?=?17) and PGA (n?=?9). Of them, 27/102 (26?%) had a confirmed genetic diagnosis: 6/28 (21?%) CAPS patients, 7/31 (23?%) TRAPS, 3/17 (18?%) FMF, 3/17 (18?%) MKD and 8/9 (89?%) PGA.

Conclusion

We have found that approximately one third of the Brazilian patients with a clinical suspicion of AIS have a confirmed genetic diagnosis.     

The pyrin inflammasome and the Yersinia effector interaction

Pyrin is a cytosolic pattern-recognition receptor that normally functions as a guard to trigger capase-1 inflammasome assembly in response to bacterial toxins and effectors that inactivate RhoA. The MEFV gene encoding human pyrin is preferentially expressed in phagocytes. Key domains in pyrin include a pyrin domain (PYD), a linker region, and a B30.2 domain. Binding of ASC to pyrin by a PYD-PYD interaction triggers inflammasome assembly. Pyrin is held in an inactive conformation by negative regulation mechanisms to avoid premature inflammasome assembly. One mechanism of negative regulation involves phosphorylation of the linker by PRK kinase which in turn is positively regulated by active RhoA. The B30.2 domain also negatively regulates pyrin. Gain of function mutations in MEFV responsible for the autoinflammatory disease Familial Mediterranean Fever (FMF) map to exon 10 encoding the B30.2 domain. Insights into pyrin regulation have come from studies of several Yersinia effectors, which are injected into phagocytes and interact with the RhoA-PRK-pyrin axis during infection. Two effectors, YopE and YopT, inactivate RhoA to disrupt phagocytic signaling. To counteract an effector-triggered immune response, a third effector, YopM, binds to and inhibits pyrin by hijacking PRK and RSK and directing linker phosphorylation. Inhibition of pyrin by YopM is required for virulence of Yersinia pestis, the agent of plague. Recent results from infection studies with human phagocytes and mice producing pyrin B30.2 FMF variants show that gain of function MEFV mutations bypass inhibition by YopM. Population genetic data suggest that MEFV mutations were selected for in individuals of Mediterranean decent during historic plague pandemics. This review discusses current concepts of pyrin regulation and its interaction with Yersinia effectors.     

High prevalence of germline <Emphasis Type="Italic">STK11</Emphasis>mutations in Hungarian Peutz-Jeghers Syndrome patients

Background  

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominantly inherited disease characterized by gastrointestinal hamartomatous polyposis and mucocutaneous pigmentation. The genetic predisposition for PJS has been shown to be associated with germline mutations in the STK11/LKB1 tumor suppressor gene. The aim of the present study was to characterize Hungarian PJS patients with respect to germline mutation in STK11/LKB1 and their association to disease phenotype.     

Common Mediterranean Fever (MEFV) Gene Mutations Associated with Ankylosing Spondylitis in Turkish Population

Ankylosing spondylitis (AS) is a common inflammatory rheumatic disease. Mediterranean fever (MEFV) gene, which has already been identified as being responsible for familial Mediterranean fever (FMF), is also a suspicious gene for AS because of the clinical association of these two diseases. The aim of this study was to explore the frequency and clinical significance of MEFV gene mutations (M694V, M680I, V726A, E148Q and P369S) in a cohort of Turkish patients with AS. Genomic DNAs of 103 AS patients and 120 controls were isolated and genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. There was a statistically significant difference of the MEFV gene mutation carrier rates between AS patients and healthy controls (p = 0.004, OR: 2.5, 95% CI: 1.32–4.76). This association was also observed in allele frequencies (p = 0.005, OR: 2.3, 95% CI: 1.27–4.2). A relatively higher frequency was observed for M694V mutation in AS patients than controls (10.7% versus 4.2% , p = 0.060). There were no significant differences between MEFV mutation carriers and non-carriers with respect to the clinical and demographic characteristics. The results of this study suggest that MEFV gene mutations are positively associated with a predisposition to develop AS.     

MEFV gene polymorphisms and TNFRSF1A mutation in patients with inflammatory myopathy with abundant macrophages

Inflammatory myopathy with abundant macrophages (IMAM) has recently been proposed as a new clinical condition. Although IMAM shares certain similarities with other inflammatory myopathies, the mechanisms responsible for this condition remain unknown. Patients with familial Mediterranean fever (FMF) and tumour necrosis factor receptor-associated periodic syndrome (TRAPS) also often develop myalgia. We therefore investigated the polymorphisms or mutations of MEFV and TNFRSF1A genes in patients with IMAM to identify their potential role in this condition. We analysed the clinical features of nine patients with IMAM and sequenced exons of the MEFV and TNFRSF1A genes. The patients with IMAM had clinical symptoms such as myalgia, muscle weakness, erythema, fever and arthralgia. Although none of the patients were diagnosed with FMF or TRAPS, seven demonstrated MEFV polymorphisms (G304R, R202R, E148Q, E148Q-L110P and P369S-R408Q), and one demonstrated a TNFRSF1A mutation (C43R). These results suggest that MEFV gene polymorphisms and TNFRSF1A mutation are susceptibility and modifier genes in IMAM.     

Effective quantitative real-time polymerase chain reaction analysis of the parkin gene (<Emphasis Type="Italic">PARK2</Emphasis>) exon 1–12 dosage

Background  

One of the causes of Parkinson's disease is mutations in the PARK2 gene. Deletions and duplications of single exons or exon groups account for a large proportion of the gene mutations. Direct detection of these mutations can be used for the diagnosis of Parkinson's disease.