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

Rossou, Elena; Kouvatsi, Anastasia; Aslanidis, Charalampos; Deltas, Constantinos

doi:10.1373/clinchem.2005.050344

Cited by 5 publications

(6 citation statements)

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“…Neocleous et al published on 3 Cypriot patients with clinically diagnosed familial Mediterranean fever (FMF), the most common hereditary autoinflammatory disease. For yet unclear reasons, it is not unusual for a variable percentage of patients to be heterozygous for mutations in the MEFV gene, thus raising the probability of co‐inheriting other contributory mutations under DI . The authors screened 128 MEFV heterozygous patients with FMF‐like disease.…”

Section: True Non‐mendelian Digenic Inheritancementioning

confidence: 99%

“…49 The genes for mutations in the MEFV gene, thus raising the probability of coinheriting other contributory mutations under DI. 50,51 The authors screened 128 MEFV heterozygous patients with FMF-like disease. In addition to the previously found MEFV mutation, 2 patients cosegregated heterozygous mutations in the NLRP3 gene and another patient in the TNFRSF1A gene.…”

Section: Selected Recent Publications On True Digenic Inheritancementioning

confidence: 99%

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Digenic inheritance and genetic modifiers

Deltas

2018

Clinical Genetics

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Digenic inheritance (DI) concerns pathologies with the simplest form of multigenic etiology, implicating more than 1 gene (and perhaps the environment). True DI is when biallelic or even triallelic mutations in 2 distinct genes, in cis or in trans, are necessary and sufficient to cause pathology with a defined diagnosis. In true DI, a heterozygous mutation in each of 2 genes alone is not associated with a recognizable phenotype. Well-documented diseases with true DI are so far rare and follow non-Mendelian inheritance. DI is also encountered when by serendipity, pathogenic mutations responsible for 2 distinct disease entities are co-inherited, leading to a mixed phenotype. Also, we can consider many true monogenic Mendelian conditions, which show impressively broad spectrum of phenotypes due to pseudo-DI, as a result of co-inheriting genetic modifiers (GMs). I am herewith reviewing examples of GM and embark on presenting some recent notable examples of true DI, with wider discussion of the literature. Undeniably, the advent of high throughput sequencing is bound to unravel more patients suffering with true DI conditions and elucidate many important GM, thus impacting precision medicine.

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Section: True Non‐mendelian Digenic Inheritancementioning

confidence: 99%

Section: Selected Recent Publications On True Digenic Inheritancementioning

confidence: 99%

Digenic inheritance and genetic modifiers

Deltas

2018

Clinical Genetics

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“…This disease is also found in other populations including Greeks (17–19), Cypriots (20, 21), Italians (22), Spanish (23) and Japanese (24), although at a lower prevalence (25). While the frequency of FMF of Greek Cypriots was thought to be low, recent results showed that the carrier rate is high (approximately 1 in 25 is a carrier of a high‐penetrance MEFV mutation and 1 in 12 of the low‐penetrance E148Q) (21). Data from a variety of ethnic groups suggest that five founding mutations, M694V, V726A, M694I, M680I and E148Q (in order of decreasing frequency), account for the 74% of FMF chromosomes, while others are prevalent in particular ethnic groups, i.e.…”

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confidence: 95%

Familial Mediterranean Fever in Crete: a genetic and structural biological approach in a population of ‘intermediate risk’

et al. 2007

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Familial Mediterranean Fever (FMF) is an autosomal, recessively inherited disease, characterized by recurrent and short attacks of fever with serosal inflammation that are caused by mutations in MEFV gene that encodes pyrin protein. To date, more than 70 disease-associated mutations have been identified, almost all of them representing missense nucleotide changes. FMF is very common among patients with Mediterranean ancestry, although the exact prevalence is not yet known, Greeks are considered to be at 'intermediate risk'. In the present study, we studied FMF patients in natives of Crete, a population sharing a common genetic and cultural background. The spectrum of MEFV gene mutations in 71 patients as well as 158 healthy controls was studied by performing a molecular analysis focused on the 12 most frequent FMF-associated mutations. We found that 59 of 71 (83.1%) FMF patients had at least one MEFV mutation, five patients were homozygotes and 54 heterozygotes for FMF-associated mutations. No mutations were detected in 12 patients (16.9%). As in high-risk populations, common MEFV mutations were found in Cretan FMF patients, with the M694V being the most penetrant. M694V and M694I mutations were associated with severe phenotypes, with many patients presenting with uncommon clinical manifestations such as erysipelas-like erythema or renal disturbances. Of interest, 20 (37%) of our heterozygous FMF patients presented with a severe phenotype. Population genetics analysis showed an FMF carrier frequency in healthy Cretan population of approximately 6% (1:17) and places Cretans closer to the Western rather than Eastern populations of the Mediterranean basin. Finally, we constructed a three-dimensional model showing the interaction of the PRYSPRY domain of pyrin with caspase-1 onto which we mapped MEFV mutations, classified according to disease severity. In this model, the 'flexible loops' of caspase-1 appear to have no access to some positions that have been previously associated with mild disease, suggesting that alternative pathogenic pathways leading to FMF need to be explored.

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“…The carrier rate in these populations reaches up to 1=5 (Aksentijevich et al, 1999;Gershoni-Baruch et al, 2002;Majeed et al, 2005). The disease is also found at a lower prevalence in other Mediterranean populations such as Greeks (Konstantopoulos et al, 2003;Ritis et al, 2004;Giaglis et al, 2007;Fragouli et al, 2008), Greek Cypriots (Deltas et al, 2002;Rossou et al, 2005), Italians (La Regina et al, 2003), and Spaniards (Aldea et al, 2004). Reports from different ethnic groups suggest that five mutations, M694V, V726A, M694I, M680I, and E148Q, account for 74% of FMF cases.…”

Section: Resultsmentioning

confidence: 96%

“…FMF is also reported in other populations of the Mediterranean basin (Deltas et al, 2002;La Regina et al, 2003;Aldea et al, 2004;Rossou et al, 2005), as well as in a Japanese population (Suzuki et al, 2005). In the Greek population, however, FMF has not been thoroughly studied.…”

Section: Introductionmentioning

confidence: 95%

Screening for Familial Mediterranean Fever M694V and V726A Mutations in the Greek Population

Gkretsi

Deltas

Yapijakis

et al. 2009

Genetic Testing and Molecular Biomarkers

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Familial Mediterranean Fever (FMF) is an autosomal recessive genetic disease that primarily affects populations surrounding the Mediterranean basin. FMF patients suffer from recurrent episodes of fever accompanied by abdominal pain, pleuritis, and arthritis. Missense mutations in the gene for FMF (MEFV) have been shown to be responsible for the disease, while more than 70 mutations have been identified to date. The aim of the present study was to determine the carrier rates of two of the most common MEFV mutations, M694V and V726A, in the general Greek population. A cohort of 220 healthy and unrelated individuals of Greek descent was screened for the two MEFV mutations using the Amplification Refractory Mutation System. Our results showed that none of the healthy individuals tested were carriers of any of the two mutations. In conclusion, our study independently confirms that the carrier rate for the MEFV mutations M694V and V726A is extremely low in the general Greek population.

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

Cited by 5 publications

References 20 publications

Digenic inheritance and genetic modifiers

Digenic inheritance and genetic modifiers

Familial Mediterranean Fever in Crete: a genetic and structural biological approach in a population of ‘intermediate risk’

Screening for Familial Mediterranean Fever M694V and V726A Mutations in the Greek Population

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