Identification of pathogenic MEFV variants in Korean patients with familial Mediterranean fever via whole-genome sequencing: a case report

Abstract

Familial Mediterranean fever (FMF) is an autoinflammatory disorder characterized by recurrent episodes of fever, serositis, and arthritis. It is caused by variants in the MEFV gene, which encodes the pyrin protein. FMF primarily affects individuals of Mediterranean and Middle Eastern descent, and six cases have been reported in the Korean population to date. However, the pathogenicity of the MEFV gene variants identified in previous Korean cases remains uncertain. Here, we report two cases of Korean patients with FMF, confirmed to have pathogenic variants in the MEFV gene through whole-genome sequencing. A 43- and 42-year-old male presented with intermittent fever, abdominal pain, and chest pain, which began in their teenage years. Whole-genome sequencing revealed the M694I and R761H variants in exon 10 of the MEFV gene in each patient, both recognized as pathogenic for FMF. Following the genetic confirmation of FMF, both patients were treated with colchicine. To our knowledge, this is the first report of Korean FMF cases with confirmed pathogenic variants in the MEFV gene.

INTRODUCTION

Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory disease, characterized by recurrent episodes of fever, peritonitis, pleuritis, and arthritis [1]. FMF primarily affects populations from the Mediterranean and Middle East, including non-Ashkenazi Jews, Armenians, Turks, and Arabs [1]. The highest prevalence is among Turks, ranging from 1 in 400 to 1 in 1,000 individuals [1]. In FMF-prevalent countries, the diagnosis is based on clinical symptoms, with the Tel-Hashomer clinical criteria being one of the most widely used tools [1]. The most significant long-term complication of FMF is secondary amyloidosis [1]. Colchicine remains the cornerstone of treatment, aimed at preventing acute flare-ups and reducing the risk of amyloidosis. Recent advancements in understanding FMF pathogenesis have highlighted the role of interleukin-1 inhibitors as an alternative therapy for colchicine-resistant cases [1].

In 1997, the MEFV gene on chromosome 16 was identified as the causative gene for FMF [1]. The MEFV gene encodes pyrin, a protein composed of 781 amino acids, mainly found in innate immune cells such as granulocytes and monocytes [2]. When pyrin detects upstream modifications by pathogen virulence factors, the pyrin inflammasome assembles to activate caspase-1 and release interleukin-1β and interleukin-18 [2]. Pathogenic variants of MEFV promote pyrin’s active state, resulting in the release of proinflammatory cytokines and triggering pyroptosis [2]. While clinical findings are usually sufficient for a presumptive diagnosis of FMF in high-prevalence regions, genetic testing for MEFV variations serves as a valuable tool for confirming the diagnosis, especially in atypical cases or in low-prevalence regions.

In Korea, six cases of FMF have been reported to date [3-8]. Each case involved MEFV gene variants, although none were recognized as pathogenic variants for FMF. Here, we report two cases of FMF in Korean patients, in which pathogenic variants responsible for the disease were identified for the first time using whole-genome sequencing (WGS).

CASE REPORT

Case 1

A 43-year-old Korean male patient presented to our outpatient clinic with recurrent episodes of fever accompanied by abdominal pain. At the age of 12, he was suspected of having rheumatic fever but was not treated with long-term antibiotic prophylaxis, as there was no evidence of cardiac involvement. At the age of 17, the patient began experiencing intermittent episodes of abdominal pain accompanied by fever. Each episode initially presented with localized abdominal pain, which progressed to become generalized, causing the entire abdomen to feel firm. The pain was severe, rated 9 to 10 out of 10 on a Numeric Rating Scale. Each episode lasted 2 to 3 days and was accompanied by a fever of 38ºC~39ºC and occasional sharp chest pain. These attacks occurred 1 to 2 times per month over the past 10 years, with the consumption of fatty foods triggering symptom onset. The patient was admitted for further evaluation after experiencing symptoms one day prior to admission. A review of systems, including symptoms suggestive of connective tissue diseases, was unremarkable. None of his parents or siblings had similar symptoms. The patient was not taking any medications before admission and had no known drug allergies. Cardiovascular, pulmonary, and abdominal physical examination findings were unremarkable. Laboratory tests revealed the following: white blood cells (WBCs) 12,690/µL; hemoglobin 13.1 g/dL; platelets 434×10³/µL; C-reactive protein (CRP) 21.46 mg/dL; erythrocyte sedimentation rate (ESR) 87 mm/h; kidney and liver function tests were within normal limits. Rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies were all negative. An abdominal computed tomography (CT) scan with contrast showed diffuse, subtle mesenteric haziness suggesting peritoneal inflammation (Figure 1A). Esophagogastroduodenoscopy and colonoscopy with random biopsies were unremarkable. Allergy tests were negative, including specific immunoglobulin E and the multiple allergen simultaneous test. WGS was conducted to assess for possible genetic etiology of his symptoms. WGS of the patient’s whole blood at 31.1×average depth revealed 4,353,801 single nucleotide variants and indels. We prioritized potentially pathogenic protein-coding variants rare (allele frequency of <1%) in the general population, resulting in 269 rare coding variants. Among these, we identified a heterozygous chr16:3,293,405 C>T (c.2082G>A, p.Met694Ile, M694I) in exon 10, which is recognized as a pathogenic variant for FMF according to the International Study Group for Systemic Autoinflammatory Diseases [9]. The patient was also found to be heterozygous for chr16:3,304,626 C>G (c.442G>C, p.Glu148Gln, E148Q) in exon 2, which is recognized as a variant of uncertain significance (VUS) for FMF [9]. The presence of these variants combined with the patient’s symptoms, confirmed the diagnosis of FMF [10]. The patient was started on colchicine at a dose of 0.6 mg/day, leading to a reduction in the frequency of acute attacks from 1~2 times per month to once every two months over six years of follow-up.

Figure 1.

Abdominal computed tomography scans of familial Mediterranean fever patients during symptomatic fever and abdominal pain episodes. (A) Case 1: diffuse, subtle mesenteric haziness (arrow heads). (B) Case 2: inflammation in the omentum (arrow heads).

Case 2

A 42-year-old Korean male patient presented to our outpatient clinic with recurrent episodes of fever accompanied by chest and abdominal pain, which had begun approximately 25 years earlier. Since his teenage years, episodes of chest and abdominal pain with fever had recurred intermittently. The pain followed a migrating pattern, affecting the anterior chest, upper back, and abdomen, and was accompanied by a fever of 38ºC~39ºC. The symptoms occurred once a year and lasted 3 to 5 days. Physical overexertion occasionally triggered symptom onset. He denied having any other medical history. None of his parents or siblings had similar symptoms, but his nephew did. Laboratory tests conducted during a symptom-free period revealed the following: WBC 5,220/µL, hemoglobin 14.9 g/dL, platelets 207×10³/µL, CRP 0.34 mg/dL, and ESR 19 mm/h. An abdominal CT scan performed during a symptomatic period showed inflammation in the omentum (Figure 1B). WGS of the patient’s blood was conducted using the RareVision platform (Inocras Inc., San Diego, CA, USA) to investigate monogenic autoinflammatory diseases. The patient was found to be heterozygous for a single nucleotide variant at chr16:3,254,626 G>A (c.2282G>A, p.Arg761His, R761H) in exon 10 of the MEFV gene, which is a likely pathogenic variant for FMF [9]. He also had a heterozygous variant at chr16:3,243,205 G>C (c.442G>C, p.Glu148Gln, E148Q) in exon 2 of the MEFV gene [9]. Based on the patient’s symptoms and the presence of these variants, he was diagnosed with FMF [10]. The patient was started on colchicine at a dose of 1.2 mg/day, and experienced no recurrence of symptoms for approximately three years. Despite continued colchicine therapy, the patient subsequently began experiencing recurrent episodes of fever and abdominal pain every 1 to 3 months, leading to the consideration of interleukin-1 inhibitors.

This study was approved by the Institutional Review Board (IRB) of Seoul National University Hospital (IRB no. H-1606-116-771) and written informed consent was obtained from both patients.

DISCUSSION

We report two cases of Korean patients who experienced repeated episodes of fever accompanied by abdominal and chest pain, ultimately diagnosed as FMF. M694I and R761H variants in the MEFV gene were identified through WGS, making this the first case report to confirm pathogenic MEFV gene variants in the Korean population.

Sequence variants are classified as pathogenic, likely pathogenic, of uncertain significance, likely benign, and benign according to the American College of Medical Genetics and Genomics (ACMG) [11]. Recently, a consensus classification adhering to ACMG recommendations was developed by experts for assessing the pathogenicity of MEFV gene variants [9]. Based on this consensus, the M694I and R761H variants identified in our cases are classified as pathogenic and likely pathogenic for FMF, respectively (Table 1) [3-8]. The identification of pathogenic variants, along with clinical symptoms, supported the diagnosis of FMF [10]. Identifying the MEFV variant also had prognostic value in Case 1. The patient experienced typical FMF attacks—early onset, short episode duration, high fever, peritonitis, and pleuritis—and responded well to colchicine. This aligns with Japanese studies that have linked M694I to classic FMF features [12-14], as well as a favorable colchicine response [12]. Our findings in Case 1 highlight M694I as a useful diagnostic and prognostic marker for Korean FMF patients. In contrast, the patient in Case 2 experienced atypical FMF attacks with a longer episode duration and responded poorly to colchicine, requiring an interleukin-1 inhibitor. Data on the phenotype of R761H remain limited. Whether it predicts a poor prognosis, as observed in Case 2, warrants further investigation.

Table 1.

Reports of familial Mediterranean fever patients in the Korean population

Reference	MEFV variant	Clinical significance	Sex	Onset age (yr)	Clinical symptom
Lim et al. [3]	L110P E148Q	VUS VUS	Male	29	Fever, abdominal pain
Koo et al. [4]	P369S R408Q	VUS VUS	Male	7	Fever, abdominal pain, renal amyloidosis
Joo et al. [5]	E148Q P369S R408Q	VUS VUS VUS	Male	22	Fever, arthralgia, abdominal pain, venous thrombosis
Lee et al. [6]	L110P E148Q	VUS VUS	Male	21	Fever, abdominal pain, urticarial eruption
Kim et al. [7]	L110P E148Q	VUS VUS	Female	21	Fever, abdominal pain
Lee et al. [8]	E148Q R202Q	VUS Benign	Male	17	Fever
Our case 1	M694I E148Q	Pathogenic VUS	Male	12	Fever, abdominal pain
Our case 2	R761H E148Q	Likely pathogenic VUS	Male	17	Fever, abdominal pain, chest pain

Japan, a neighboring country to Korea, has a relatively higher number of FMF cases among non-prevalent regions. Given the potential genetic similarity between Koreans and Japanese, reviewing Japanese FMF cases may provide valuable insights into the genetic and clinical characteristics of FMF in Korean patients. In Japanese patients, 40% present with atypical FMF based on the Tel-Hashomer criteria, and 80% lack a family history of periodic fever [13,15]. Although FMF is conventionally known as an autosomal recessive disorder, the majority of Japanese patients present with heterozygous variants (Table 2) [12,13,15]. While M694V, M694I, V726A, M680I, and E148Q are the five most common mutations in FMF among individuals of Mediterranean descent, accounting for approximately 90% of sequence variants, E148Q and M694I are the two most common variants found in approximately 50%~60% of the Japanese patients [12,13,15]. Moreover, various mutations that are relatively rare in the Mediterranean population account for 40% of cases in Japanese patients. Although data on Korean FMF patients are currently limited, similar features—such as atypical presentations and genetic variations—have also been observed in Korean patients (Table 1) [3-8]. These findings suggest the possibility of a population-specific genetic and phenotypic spectrum of FMF in non-prevalent regions, distinct from that observed in Mediterranean populations. As a result, relying solely on traditional diagnostic criteria developed and validated in Mediterranean populations may lead to underdiagnosis or misclassification of FMF in countries such as Japan and Korea [12, 13]. In these regions, high clinical awareness and comprehensive genetic testing are necessary in suspected FMF cases.

Table 2.

Frequency of MEFV gene variants in familial Mediterranean fever patients in the Japanese population

	Kishida et al. [12] (n=116)	Migita et al. [13] (n=311)	Migita et al. [15] (n=192)
Patient number
Homozygote	2 (1.7)	10 (3.2)	13 (6.8)
Compound heterozygote	67 (57.8)	179 (57.6)	104 (54.2)
Heterozygote	47 (40.5)	97 (31.2)	64 (33.3)
Normal	0 (0)	25 (8.0)	11 (5.7)
Allele frequency*
E148Q	90 (38.8)	258 (41.5)	150 (39.1)
M694I	47 (20.3)	135 (21.7)	52 (13.5)
L110P	42 (18.1)	117 (18.8)	45 (11.7)
P369S	12 (5.2)	38 (6.1)	33 (8.6)
R408Q	12 (5.2)	37 (5.9)	31 (8.1)
E84K	5 (2.2)	30 (4.8)	12 (3.1)
R202Q	10 (4.3)	11 (1.8)	17 (4.4)
G304R	2 (0.9)	10 (1.6)	11 (2.9)
S503C	4 (1.7)	5 (0.8)	0 (0)
R410H	0 (0)	2 (0.3)	1 (0.3)
R354Q	0 (0)	1 (0.2)	1 (0.3)
E225K	0 (0)	1 (0.2)	1 (0.3)
M680I	0 (0)	1 (0.2)	0 (0)
P715L	0 (0)	1 (0.2)	0 (0)
I740V	0 (0)	1 (0.2)	0 (0)
W750R	0 (0)	1 (0.2)	0 (0)
P751L	0 (0)	0 (0)	1 (0.3)
G632S	0 (0)	0 (0)	1 (0.3)

Values are presented as number (%). *Allele frequency is calculated based on the total allele number (2n).

SUMMARY

We have identified the first pathogenic and likely pathogenic variants in Korean FMF patients, confirmed through WGS. Our cases contribute to the understanding of the genetic features of FMF in the Korean and East Asian populations.