Autosomal dominant polycystic kidney disease is one of the most common genetic renal diseases in adults and occurs in 1.2% to 10% of ESKD patients in several ME communities. ^{, ,} Autosomal recessive polycystic disease (ARPKD; Online Mendelian Inheritance in Man [OMIM] catalogue number 263200) occurs with a proposed incidence of 1/20,000 to 1/40,000. Mortality during the first month of life is particularly high among those born with severe oligohydramnios leading to pulmonary hypoplasia. Its principal manifestations include fusiform dilation of the renal collecting ducts and distal tubules and dysgenesis of the hepatic portal triad. ARPKD is associated with mutations in the PKHD1 gene on chromosome 6p21.1-p12, encoding fibrocystin, a membrane protein located on the primary cilium. More than 700 mutations in the PKHD1 gene have been reported. Several mutations were reported in Turkish and Israeli children who participated in a large international study. ^, One of these variants (c.3761_3762delCCinsG) was found to be a founder mutation among Ashkenazi Jews.

Meckel-Gruber syndrome (MKS) is a lethal, recessively inherited ciliopathy characterized by multiple congenital anomalies, including polycystic kidneys, occipital encephalocele, and polydactyly. At least 13 genes have been reported to date to underlie MKS. The incidence of this relatively rare disorder in Qatar has been reported as 1 in 500 live births for a population with over 40% consanguineous marriages. The underlying genetic cause was identified in 11 of 12 Arab families residing in a distinct region in Israel, comprising mutations in 7 different genes and revealing high genetic heterogeneity. Likewise, other ciliopathies including various forms of nephronophthisis (including the infantile type) with mutations in NPHP1 , NPHP2 (INVS) , and NPHP3 , encoding nephrocystin 1, inversin, and nephrocystin 3, respectively, have been reported in several ME countries ( Table 76.5 ). Cases of Joubert syndrome, characterized by cerebellar vermis hypoplasia, developmental delay, seizures, retinal dystrophy, and kidney involvement, have been reported in the ME. There is genetic heterogeneity with pathogenic mutations in 33 distinct genes responsible for this disorder. Founder mutations have been identified in Iranian families and in Ashkenazi Jews.

A substantial number of patients in the ME with kidney disease have familial glomerular diseases whose spectrum includes familial hematuria, Alport syndrome, IgA nephropathy, and familial SRNS with histologic findings consistent with FSGS. ^{, , ,} A recessive form of SRNS has been shown to be associated with mutations in the NPHS2 gene, which encodes the glomerular barrier protein podocin. The most common phenotype is a nephrotic syndrome that is resistant to immunosuppressive treatment in early childhood, and most patients will develop ESKD by the end of their second decade of life. In a group of children from two consanguineous families of Israeli Arab descent, mutation analysis of the NPHS2 gene revealed homozygosity for the C412T nonsense mutation (R138X). The same mutation was subsequently found in additional children who presented with SRNS from the same ethnic background, which points to the possibility of a founder effect. Interestingly, cardiac anomalies, especially left ventricular hypertrophy, pulmonary stenosis, and discrete subaortic stenosis, were detected in a high proportion of the children with NPHS2 mutations. Frishberg and associates have speculated that podocin may have a role in normal cardiac development because podocin messenger RNA is reported to be expressed in the human fetal heart.

At least 53 NPHS2 mutations have also been found in Turkish children with familial and “sporadic” SRNS. ^, In this context, the term sporadic is a misnomer. As a recessively inherited disease, both parents are obligatory carriers of pathogenic mutations, and the lack of positive family history may merely represent the first case in a given nuclear family. Among Turkish patients with NPHS2 mutations, the proportion of patients with CKD or ESKD was significantly higher (19 of 73) than that of patients without these mutations (28 of 222). Furthermore, the mean time for progression to ESKD was significantly shorter in patients with mutations compared with those without mutations. ^, The prevalence of NPHS2 mutations among 49 children with SRNS and 50 children with steroid-sensitive nephrotic syndrome from Iran was 31% and 4%, respectively. Of these children, 33% experienced recurrence of primary disease after kidney transplantation, none of whom had an NPHS2 mutation.

The NPHS1 gene encodes nephrin, an essential protein for maintaining the normal structure and function of the slit diaphragm of the visceral glomerular epithelial cell. Three mutations in the NPHS1 gene were reported in 12 children with congenital nephrotic syndrome of the Finnish type from a large consanguineous Israeli Arab family. Steroid-sensitive nephrotic syndrome is rarely reported to have a familial pattern. However, a familial pattern associated with this condition has been reported in Israeli Bedouin families with a high rate of consanguinity, and the authors of the report proposed that the increased incidence of steroid-sensitive nephrotic syndrome resulted from selective enrichment of susceptibility genes in this population. Whereas multiple genes, in their mutated form, have been associated with SRNS, there has not been a single monogenic disease leading to steroid-sensitive nephrotic syndrome.

A study has evaluated causative mutations related to childhood nephrotic syndrome in 49 families from Saudi Arabia; 62 patients were screened for mutations in genes associated with congenital, infantile, or childhood nephrotic syndrome, such as NPHS1, NPHS2, LAMB2 (laminin-β ₂ ), PLCE1 (phospholipase Cε ₁ ) , CD2AP (CD2-associated protein), MYO1E (myosin 1E) , WT1 (Wilms’ tumor suppressor gene 1), PTPRO (protein tyrosine phosphatase receptor type O), and NEIL1 (Nei endonuclease VII-like 1). A homozygous mutation in the NPHS2 gene was found in 11 families (22%) and was the most common cause of nephrotic syndrome. Other mutations were found in NPHS1 (12%) , PLCE1 (8%), and MYO1E (6%) genes. FSGS was the most common pattern of histopathologic injury and a significant proportion of patients developed kidney failure requiring KRT.

The Podonet Consortium, an international registry for congenital nephrotic syndrome and childhood SRNS, has analyzed the data retrieved from 1655 patients, 9.2% of whom were from the ME (Syria, Lebanon, Iran, and the UAE). Pathogenic mutations were detected in 23.6% of the screened patients. A cohort of children with SRNS from a single center in Saudi Arabia was tested for causal mutations in NPHS1, NPHS2, and WT1 . All 44 children were older than 1 year, and presumably pathogenic mutations were identified in 5 children (11.4%), 3 in NPHS2 and the remaining 2 in NPHS1 . None of those with an identified genetic cause showed any response to immunosuppressive treatment.

In Turkey, 25 children with SRNS underwent mutation screening in TRPC6, a dominantly inherited form of SRNS. Positive family history was found in nine children. The results showed a variant in one patient, intronic nucleotide substitution in six patients, and previously described missense and synonymous amino acid variants in nine patients. Although the pathogenicity of all these genetic variants remains to be proven, the authors concluded that TRPC6 mutations may play a significant role in childhood SRNS.

Galloway-Mowat syndrome (GAMOS) is an autosomal recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Recessive mutations in OSGEP, TP53RK, TPRKB, and X-linked mutations in LAGE3 genes encoding the four subunits of the KEOPS complex have been detected in 37 individuals from 32 families with GAMOS, 6 of whom are from the ME (Iran, Turkey, Jordan, and Egypt).

Coenzyme Q10 (CoQ10), also known as ubiquinone, is a lipid-soluble component of virtually all cell membranes and plays a critical role in transporting electrons along the respiratory chain of the mitochondrial inner membrane. ADCK4 encoding CoQ8B plays a role in CoQ10 biosynthesis; mutations in ADCK4 may cause SRNS and/or CKD of presumably unknown cause. A total of 146 index patients aged 10 to 18 years from Turkey, with newly diagnosed non-nephrotic proteinuria, nephrotic syndrome, or CKD of varying severity, were screened for ADCK4 mutations. In this study, 28 individuals with a biallelic mutation were identified, and CoQ10 supplementation appeared efficacious in reducing proteinuria in a subgroup of this cohort.

The Rat sarcoma homolog gene family of small guanosine triphosphate (GTP)-ases (Rho GTPases) is associated with actin remodeling and podocyte migratory ability. Alterations in Rho GTPases signaling interfere with podocyte motility and cause proteinuria. Rho guanosine diphosphate (GDP) dissociation inhibitor 1, a regulator of Rho GTPases, is a protein that is encoded in humans by the ARHGDIA gene and is also expressed in podocytes. ARHADIA mutations, associated with SRNS progressing to ESKD during the first decade of life, have been reported in three siblings from a family of Ashkenazi Jews and in a Moroccan infant.

The primary hyperoxalurias (PHs) are a group of rare autosomal recessive inborn errors of glyoxylate metabolism that result in the excessive production of oxalate. ^, Currently, three types of PH have been characterized genetically and phenotypically. The more frequently identified PH type 1 (OMIM number 259900) is caused by the absence, deficiency, or mistargeting to the mitochondria of the liver-specific peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. Accumulating glyoxylate diffuses from the peroxisome into the cytosol, where it is oxidized to oxalate, a reaction catalyzed by lactate dehydrogenase (LDH). Excessive oxalate synthesis and massive urinary excretion of the insoluble calcium oxalate crystals result in nephrocalcinosis, kidney stones, and declining kidney function. As the glomerular filtration rate (GFR) declines, the oxalate load, produced by the liver, can no longer be cleared by the kidneys, plasma oxalate level increases, and calcium oxalate crystals are deposited in almost all tissues in a devastating process termed “systemic oxalosis.” PH type 2 (OMIM number 260000) is caused by a deficiency of the mitochondrial enzyme glyoxylate reductase/hydroxypyruvate reductase (GRHPR), which catalyzes the reduction of glyoxylate to glycolate. In 2010, PH type 3 (OMIM number 613616) was described in a cohort of patients with calcium oxalate nephrolithiasis due to hyperoxaluria in whom PH1 and PH2 were excluded. In affected members of nine unrelated families, Belostotsky and colleagues ^, found biallelic loss-of-function mutations in HOGA1, formerly DHDPSL, which encodes a mitochondrial 4-hydroxy-2-oxoglutarate aldolase that catalyzes the fourth step in the hydroxyproline pathway.

PH1 has the most severe phenotype and therefore is more likely to be diagnosed as reflected in voluntary patients’ registries. ^, However, the prevalence calculated on the basis of publicly available data regarding allele frequency by populations, suggests that all three types of PH are much more common. It is especially underestimated for the less severe type—PH3, which was predicted to be as prevalent as PH1 and twice as common as PH2. Of note, analysis of the gnomAD database reveals a carrier frequency, of one of 4 pathogenic mutations in HOGA1, of 1:36 among Ashkenazi Jews. There is an additional group of patients with undetected mutations in either of the three known genes.

PH types 1 to 3 are relatively prevalent in the ME. Cases of PH1 and isolated cases of type 2 have been reported in Israeli families. In 22 Israeli Arab families with type 1 hyperoxaluria, at least 15 different mutations in the AGT-encoding AGXT gene have been detected. ^, Marked intrafamilial phenotypic variability, with no definite genotype-phenotype correlation, was noted in these families, and the prevalent phenotype was of early onset of disease with progression to ESKF in the first decade of life. The diagnosis of PH1 was confirmed in 15 of 19 children tested in a single tertiary center in Egypt. Two-thirds of this cohort reached ESKD, with one-third during infancy. A similar phenotype among PH1 patients, namely early onset with a high portion of individuals presenting with kidney failure, has been described in a more recent report from Egypt and in a cohort from Syria. ^, A large European study of 155 patients from 129 families with type 1 hyperoxaluria, including a large proportion of ME individuals, has shown that the most common mutation, among European families, is p.Gly170Arg (allelic frequency, 21.5%). This mutation results in mistargeting of AGT into mitochondria while the catalytic activity of the enzyme remains intact. A subgroup of these patients will respond to vitamin B ₆ treatment, a precursor of pyridoxal phosphate, which is a known active cofactor in all aminotransferase reactions and therefore may have a better long-term prognosis. Unfortunately, mutations in AGXT that are amenable to pyridoxine treatment are quite rare in the ME.

Hyperoxaluria manifesting as kidney stone disease and/or progressive CKD has been described in the following reports from the ME. Although systematic genetic analysis has not been performed, it is likely that PH accounts for the disease in a substantial number of individuals. For example, among 260 adult patients with recurrent nephrolithiasis from a tertiary center in Israel, hyperoxaluria was detected in 24.2%. Hyperoxaluria was found among 10.7% of 84 patients with CKD, treated conservatively or by hemodialysis, in the Jenin district of the PA. PH1 is the probable cause of hyperoxaluria in most of these cases. In a retrospective report from a single center in Amman, Jordan, 70 children with suspected PH were identified. At the time of initial presentation, 15.7% were in ESKF and an additional 25% had impaired kidney function. Although not tested at the time of this report, PH1 may be responsible for hyperoxaluria in many of these children, particularly in those with compromised kidney function. Similarly, a high prevalence of hyperoxaluria was demonstrated among Turkish children with kidney stone disease. Hyperoxaluria causing nephrolithiasis, nephrocalcinosis, and kidney failure was reported in children from other ME countries in western North Africa, Saudi Arabia, and Kuwait. ^{, ,} Primary hyperoxaluria is probably underdiagnosed because, by the time of diagnosis, advanced CKD or early graft dysfunction in isolated kidney transplant recipients may have already developed.

Until recently, there was no approved treatment for patients with PH, and conservative management including increased water intake and crystallization inhibitors such as citrate were recommended. Intensive hemodialysis was implemented once they reached kidney failure, and the only cure has been combined liver-kidney transplantation.

Lumasiran (Oxlumo) is the first approved drug for patients with PH1. It was approved by the FDA and EMA in November 2020 for treating PH1 patients of all age groups and subsequently in many sites around the globe including Israel. Lumasiran is a small interfering RNA therapeutic (siRNA) targeting glycolate oxidase (GO), harnessing a naturally occurring mechanism for regulating gene expression by selective depletion of mRNA molecules that encode for target proteins. GO is exclusively expressed in hepatocytes and is likely playing a role in glyoxylate metabolism only. GO catalyzes the oxidation of glycolate to glyoxylate, which is the substrate for oxalate synthesis. Following preclinical studies, the safety of GO suppression in humans was supported by the incidental discovery of GO deficiency in an 8-year-old boy with asymptomatic glycolic aciduria, associated with normal kidney and hepatic functions. Targeted delivery of siRNAs to the liver was obtained by conjugation to N-acetylgalactosamine (GalNAc). This allows direct uptake of the drug by asialoglycoprotein receptors, which are almost exclusively expressed by hepatocytes. The 6-month double-blind phase of a randomized, placebo-controlled phase 3 study evaluating lumasiran in 39 patients with PH1 enrolling children older than age 6 and adults, with genetically PH1 and eGFR >30 mL/min per 1.73 m ² . Lumasiran was administered subcutaneously at 3 mg/kg monthly for 3 months, followed by quarterly doses. The least squares mean change from baseline in 24-hour urinary oxalate (Uox) excretion was 65.4% in the lumasiran group and 11.8% in the placebo group. The proportion of lumasiran-treated patients who achieved normalization or near normalization of 24-hour Uox excretion at 6 months was 84%, compared with 0% in placebo-treated patients. There were no serious or severe adverse events. The most common adverse event was a mild and transient injection site reaction in 38% of lumasiran-treated patients. Significant decrease in Uox levels associated with a decline in the rate of stone events and improvement in nephrocalcinosis, assessed by sequential kidney sonographic studies, have been shown in long-term studies (12 months) of all age groups (including infants and toddlers). In PH1 patients with CKD G3b-5 and those treated with hemodialysis, plasma oxalate was used as an endpoint since urinary oxalate excretion decreases with declining GFR. Similar trend of a decrease in plasma oxalate was recorded in patients in all age groups treated with lumasiran. Small case series showed that isolated kidney transplantation combined with lumasiran therapy may be a fair substitution for combined liver-kidney transplantation, although larger studies with long-term follow-up are required.

Nedosiran, a siRNA targeting the lactate dehydrogenase A (LDHA) enzyme, has been developed. Similarly to lumasiran, conjugation with GalNAc allows selective silencing of LDHA in the liver, preventing off-target effects in other tissues, especially in muscles.

Since LDHA mediates the final enzymatic reaction of oxalate production, nedosiran can potentially be beneficial in all types of PH. Whereas nedosiran has been shown to be beneficial in patients with PH1 by lowering Uox levels with a favorable safety profile, preliminary results in patients with PH2 and PH3 did not demonstrate the expected beneficial effect. ^,

Cystinuria is a recessively inherited kidney stone disease, prevalent in various ethnic groups in ME countries. ^{, ,} Cystinuria is caused by biallelic mutations in either one or both of two genes:

• 1.

  The SLC3A1 gene on chromosome 2p16.3-p21 encodes rBAT, a protein required for normal trafficking of the amino acid transporter to its appropriate location in the apical membrane of affected epithelia. In its mutated form, it leads to impairment of cystine and dibasic amino acid (e.g., ornithine, lysine, and arginine) transport.

• 2.

  The SLC7A9 gene located on chromosome 19q12-13.1 encodes an amino acid transporter, b ^0,+ AT. When this protein is defective, its appearance at the apical membrane, assuming that rBAT is normal, does not lead to normal amino acid reabsorption.

Both proteins together form a heterodimer that mediates sodium-independent transport of cystine and dibasic amino acids (ornithine, arginine, and lysine) in the apical membrane of the proximal tubule and small intestine.

Because parents of patients with cystinuria due to SLC7A9 mutations have increased levels of urinary cystine excretion, they may sometimes form stones if the urine volume is low or if animal protein intake is high. Otherwise, disease manifestations caused by either mutation are similar. Some patients may bear heterozygous digenic mutations, and they do not tend to form cystine stones unless there are mutations in two copies of a single gene. Mutations in SCL3A1 have been detected in Turks, Muslim Arabs, Druze, Ashkenazi, and Sephardic Jews of Persian and Yemenite origin. The disease is also common among Libyan Jews, in whom the estimated prevalence is 1/2500 and the corresponding carrier rate is 1/25. In this population, the disease is caused by a single founder mutation, V170M, in the SLC7A9 gene.

Cystinosis is a recessively inherited lysosomal transport defect leading to the accumulation of cystine. It presents with renal Fanconi syndrome and results in CKD with various extrarenal manifestations (see Table 76.5 ). The prevalent causes of mutations in a few countries of the ME have been summarized. A founder mutation among Jews of Moroccan ancestry has been identified (Y. Frishberg, personal communication).

Fabry disease is a rare X-linked inborn error of the glycosphingolipid metabolic pathway caused by deficiency of α-galactosidase A. A mutation in the gene encoding this enzyme results in insufficient breakdown of lipids, which accumulate to harmful levels in the eyes, kidneys, autonomic nervous system, and cardiovascular system. In untreated patients, the accumulation of globotriaosylceramide (Gb3) in lysosomes may result in multiple organ damage that includes the development of kidney failure between the fourth and fifth decades of life. Histologic evidence of Fabry disease has been detected in graft biopsy samples many years after successful kidney transplantation. ^, Although most disease features have been reported in adults, a pediatric disease phenotype that includes acroparesthesias, skin manifestations, and glomerular alterations has been described. ^, Fabry disease has been diagnosed in families in Israel and Turkey. The disease may be underdiagnosed in other ME countries because of phenotypic variability of the disease, with often nonspecific signs and symptoms or insufficient awareness. However, screening of adult patients with kidney failure undergoing dialysis in Turkey and in Lebanon has yielded an extremely low prevalence rate of Fabry disease. ^, Similarly, screening adults from Turkey with left ventricular hypertrophy yielded 1.58% with genetically proven Fabry disease, mostly males with severe hypertrophy.

Bartter syndrome and Gitelman syndrome belong to a group of inherited salt-losing tubulopathies with distinct phenotypes; they are caused by inherited defects in ion transporters in the loop of Henle and distal convoluted tubule, respectively. Most cases of the variants of Bartter syndrome in the ME have been reported in Israeli Arabs, in large Bedouin communities living in southern and northern Israel, and in Kuwaiti children. ^{, ,}

Congenital anomalies of the kidney and urinary tract (CAKUT) comprise the most common cause of CKD in childhood. To understand the underlying pathogenetic mechanisms better, Vivante and associates have identified 20 Israeli pedigrees with isolated nonsyndromic renal hypodysplasia and screened for mutations in genes known to be involved in kidney development. Two brothers were found to have a heterozygous PAX2 nonsense mutation, responsible for renal coloboma syndrome, which includes kidney dysplasia, eye coloboma, and hearing impairment. Nine affected subjects from two unrelated families were found to harbor heterozygous HNF1B mutations, encoding the hepatocyte nuclear factor-1β. These mutations are associated with variable renal phenotypes, maturity-onset diabetes of the young (MODY5), hypomagnesemia, and hyperuricemia. In one family, two affected brothers were heterozygous for a missense mutation in WNT4 . Functional analysis of this variant in different cell lines revealed both agonistic and antagonistic canonical WNT stimuli. In primary cultures of human fetal kidney cells, this mutation causes loss of function, resulting in diminished canonical WNT/β-catenin signaling. These findings were interpreted as suggestive of a role for heterozygous WNT4 variants in renal hypodysplasia. A three-generation Yemenite Jewish family with seven individuals who had CAKUT was investigated by whole-exome sequencing. Renal hypoplasia-dysplasia was the predominant phenotype (six individuals), together with vesicoureteral reflux (VUR; four individuals) and/or ectopia (two individuals). A heterozygous truncating mutation of the nuclear receptor interacting protein 1 gene (NRIP1) was identified in all seven affected members. NRIP1 encodes a nuclear receptor transcriptional cofactor that directly interacts with the retinoic acid receptors (RARs) to modulate retinoic acid transcriptional activity.

Some rare genetic kidney diseases that have been reported in ME communities are listed in Table 76.5 . Other nonrenal genetic diseases may cause glomerular and tubulointerstitial complications; an example is sickle cell anemia, a hemoglobinopathy that is prevalent in the ME countries in western North Africa and the Arabian Peninsula. ^{, , , ,} Inherited diseases of the kidney are discussed further in Chapter 44 , Chapter 45 , Chapter 71 .

FMF is the most common of the hereditary periodic fever syndromes and is a prevalent recessively inherited disease in the ME. FMF is an autoinflammatory disease that is characterized by recurrent attacks of fever, serositis, arthritis, and erysipelas-like skin lesions. The disease affects several ethnic groups in the ME, including Sephardic Jews, Armenians, Turks, and Arabs. The most significant complication of FMF is renal amyloidosis that progresses to nephrotic syndrome and kidney failure. Renal amyloidosis is occasionally diagnosed in patients without a typical history of FMF attacks.

In the 1990s, two groups identified the MEFV gene by positional cloning as the underlying genetic cause of FMF. ^, At least 370 mutations in the MEFV gene have been reported, and more than 195 of these mutations have been found to be associated with FMF. The MEFV gene encodes the protein pyrin (or marenostrin). The gene is located on the short arm of chromosome 16 (16p13.3) and includes 10 exons that encode 781 amino acids. Pyrin is expressed predominantly in polymorphonuclear cells (PMNCs), eosinophils, and monocytes, but not in lymphocytes. It is also expressed in dendritic cells and fibroblasts from the synovium, peritoneum, and skin. Pyrin has an important role in the innate immune system, which constitutes a primary defense against external pathogens and other noxious agents. Its exact role and mechanism of action appear to be in sensing changes in the Rho GTPases. Rho proteins are involved in controlling GTPase activity, which in turn are important in the regulation of actin and tubulin dynamics. Actin-tubulin interactions contribute to neutrophil motility and chemotaxis. Bacterial toxins (e.g., Clostridium difficile toxin) may modify the effect of Rho proteins on GTPases, thereby inhibiting actin-tubulin activity and neutrophil chemotaxis. Pyrin does not directly recognize Rho modification but probably senses an event downstream of Rho modification in the actin cytoskeleton pathway and forms a caspase-1–activating inflammasome. ^, Therefore pyrin-mediated innate immunity is unique in that it senses bacterial virulence rather than microbial molecules.

In patients with FMF, the mutations in the MEFV gene lead to the production of pyrin protein, which is capable of constructing the inflammasome, even in the absence of a known external trigger such as a toxin or infectious agent. This possibility suggests that the mutations in MEFV gene cause gain of function of pyrin protein so that it acts without a known provocation. The outcome of this process is the secretion of interleukin (IL)-1, IL-18, and other mediators of inflammation, which enhance chemotaxis and neutrophilia and induce an attack of FMF.

The carrier frequency of mutant alleles is high, as much as 1:5 to 1:3, in certain populations of the ME countries (Armenians, Jews, and Turks). The most commonly reported mutations are M694V, V726A, M680I, and M694I in exon 10 and E148Q in exon 2. ^, The first four mutations are believed to be pathogenic, with the M694V homozygotes having the most severe phenotype. Although the E1489Q homozygotes are asymptomatic in 50% of cases, this variant may be associated with other systemic inflammatory diseases, including Behçet disease, vasculitis, ulcerative colitis, rheumatoid arthritis, and multiple sclerosis. The most frequent MEFV mutations in the ME populations are listed in Table 76.6 . Data from five databases encompassing whole-genome and whole-exome datasets for 2115 individuals from multiple subpopulations in the ME were available for analysis. A compendium for MEFV genetic variants was also created. The carrier frequency for genetic variants in MEFV was found to be 8%, with differences in allele frequency among subpopulations. Also, three pathogenic variants were added to the four popular studied variants. The former include c.1261-11T>G, Y688X, and E148V. Mutations in the MEFV gene have also been reported in Spanish, Italian, Greek, Portuguese, Indian, Chinese, and Japanese populations. ^, Most MEFV mutations are single amino acid substitutions (missense), and some patients with FMF have a single MEFV mutation. The latter may imply a dominantly inherited trait, which may go along with a gain of function of the gene product. Alternatively, additional genes or immune factors may modulate the innate immune response in FMF.

Table 76.6

Genotype-Phenotype Correlations in Several Patient Populations With Familial Mediterranean Fever

Population, Community	Frequent Mutations	Phenotype	Amyloidosis (% of Patients)	Associated Syndromes and Diseases	Reference
Israeli Jews and Arabs	M680I, M694V, M694I, V726A	Arthritis, fever, serositis, vasculitis	1.4% (associated with mutation in M694V )	NR	Brik et al
Israeli Jews and Arabs	M694V (very common in Jews), M694I (exclusive in Arabs), M680I, V726A, E148Q	Arthritis, fever, serositis, vasculitis	NR	NR	Ben-Chetrit et al
Israeli Arabs	M694V (associated with severe disease), V726A (most common)	Arthritis, fever, serositis, vasculitis	NR	NR	Shinawi et al
Israeli Jews of North African origin and Arabs a	M694I, M694V (common in North African Jews), E148Q	Synovitis, pleuritis, abdominal pain, skin rash	95% a	Focal glomerulosclerosis	Ben-Chetrit and Backenroth
Israeli Jews of North African origin, Ashkenazi Jews, Jews of Iraqi origin, Israeli Arabs, and Druze	E148Q, M694V (common in North African Jews), V726A	FMF criteria	4.6% (most common in M694V homozygous)	NR	Zaks et al
Israeli Jews (Ashkenazi and non-Ashkenazi), Arabs, and Druze	M694V (common in Jews), E148Q, M694V, V726A (equally common in Arabs), E148Q (most common in Druze)	Fever, serositis	NR	NR	Sharkia et al
Turks	M680I, M694V, M694I, V726A, E148Q	Abdominal pain, fever, arthralgia, chest pain, skin rash	3% (mostly associated with M694V )	NR	Solak et al
Turks	M680I, M694V, V726A	Abdominal pain, fever, arthralgia, pleuritis, muscle pain, skin rash	12.9%; 0.9% as the main disease manifestation (phenotype II, associated with M694V )	Nonamyloid renal disease, Henoch-Schönlein purpura, polyarteritis nodosa, Behçet syndrome, rheumatic fever, uveitis, inflammatory bowel disease	Tunca et al
Turks b	M680I, M694V (most common), V726A, E148Q	Abdominal pain, fever, arthralgia, chest pain, erysipelas-like lesion, vomiting, family history of renal failure	0%	NR	Caglayan et al
Turks	M680I, M694V (most common), M694I, V726A E148Q (common)	Abdominal pain, fever, arthritis, pleuritis, erysipelas-like erythema, peritonitis	NR	NR	Ozdemir et al
Turks	M680I, M694V (most common), V726A, E148Q	Fever, arthritis, pleuritis, erysipelas-like erythema, peritonitis, vasculitis	8.6% (most common in M694V homozygous)	NR	Kasifoglu et al
Azeri Turks	M680I, M694V (most common), M694I, V726A E148Q	Fever, serositis, synovitis, kidney failure	NR	NR	Mohammadnejad and Farajnia
Jordanian Arabs Palestinian Arabs	M680I, M694V, M694I, V726A, E148Q	Abdominal pain, fever, arthralgia, myalgia, skin rash	1% (associated with M694V )	Protracted fever, myalgia syndrome; 42% homozygous for M694V	Langevitz et al; Majeed et al
Jordanian Arabs	M680I, M694V, V726A, E148Q	Abdominal pain, fever, arthralgia	9% ( M694V in 1 patient, V726A/M680I in 2 patients)	Celiac disease, folliculitis	Medlej-Hashim et al
Palestinian Arabs	M680I, M694V, V726A, E148Q	NR	NR	NR	Ayesh et al
Arabs from Jordan, Egypt, Syria, Iraq, and Saudi Arabia	M694V, V726A, E148Q	NR	NR	NR	Al-Alami et al
Iranian Azeris who live in Turkey	M680I, M694V, M694I, V726A, E148Q	Abdominal pain, fever, arthralgia, pleuritis, skin rash	7%	NR	Esmaeili et al
Iranians (72% Azeri)	M680I (most common), M694V, V726A	Fever, peritonitis, arthralgia, pleuritis, skin rash	5.6%	NR	Bidari et al
Egyptian Arabs	M680I, M694V, V726A	Abdominal pain, chest pain, fever, arthritis, myalgia	NR	NR	Settin et al
Egyptian Arabs	M680I, M694I (most common), M694V, V726A, E148Q	Fever, serositis	Mostly associated with M694V	NR	el Gezery et al
Egyptian Arabs	V726A (most common), M694V (common), M680I, M694I, E148Q	Abdominal pain, fever, arthralgia, pleuritis, skin rash, myalgia	2.9% (associated with M694V )	NR	el Garf et al
Syrian Arabs	M680I, M694V, M694I, V726A, E148Q, A744S, R761H	Serositis, fever, arthritis, pleuritis	5%	NR	Mattit et al
Lebanese Arabs	M680I, M694V (frequent), M694I, V726A, E148Q (frequent); minor alleles also detected	Serositis, fever, arthritis, chest pain	NR	NR	Sabbagh et al
Algerian, Moroccan, and Tunisian Arabs	M694V, M694I (most common), M680l, M680I, A744S, V726A, E148Q	Serositis, fever, arthritis, chest pain	NR	NR	Belmahi et al
Algerians	M694I (most common), M694V, E148Q, A744S, M680I	Abdominal pain, fever, arthritis, chest pain, erythema	8%	NR	Ait-Idir et al
Tunisian Arabs	M680I (most common), M694V, M694I, V726A, E148Q, A744S, R761H, 1692del	FMF criteria	3.5%	NR	Chaabouni et al

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