A Specific Haplotype Framework Surrounds the Omani Cystic Fibrosis Transmembrane Conductance Regulator ( CFTR ) Mutation S549R

Abstract

Cystic Fibrosis (CF) is an autosomal recessive disorder affecting the chloride transport in mucus-producing epithelial cells. The disease is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR), which is responsible for trans-epithelial chloride transport. Approximately 1900 mutations and gene variants of the CFTR have been described. The spectrum of major White-European mutations includes F508del, G542X, G551D and N1303K. F508del is the most common CF-causing mutation, found in approximately 70% of all CF patients worldwide. The spectrum of CF mutations of Arab populations is under-investigated. However, initial molecular-epidemiological studies indicate the existence of specific CF mutation clusters within geographical regions in the Middle East, suggesting specific distributions of CF mutation carrying chromosomes in this part of the world. We showed that the worldwide rare CF mutation S549R is the predominant disease causing mutation in the Omani population. We reported that S549R, together with two other identified mutations, F508del and the rare private mutation V392G, are genetically linked to the exonic methionine polymorphism c.1408A>G; p.Met470Val at exon 10 and the intronic dimorphic 4-bp GATT 6-repeat at intron 6, c.744_33GATT[6_8]. We detected three haplotypes in 28 alleles of the Omani CF cohort and 408 alleles of our control cohort of unrelated and unaffected Omani volunteers. The CF disease associated haplotype consisting of an M allele and a 6-repeat expansion, occurred with an allele frequency of only 0.174 in the normal Omani population. The discriminative power of the haplotype was attributed to the intronic dimorphic 4-bp GATT 6-repeat. Furthermore, we found only one mutation, c.1733_1734delTA in the Omani CF cohort which deviated from the rule and shared the most common haplotype, a V allele and a 7-repeat extension, with the normal population.

Spectrum of mutations of cystic fibrosis in the 22 Arab countries: A systematic review

“…In Egypt, similar clinical manifestations have been reported, in addition to hepatic diseases and sinusitis. In the United Arab Emirates (UAE) and Oman, c.1521_1523delCTT and c.1645A>C/G account for 95% and 89%, respectively, of the affected families with CF, and homozygosity is observed in most of the patients harbouring c.1645A>C/c.1647T>G mutations . Conversely, the c.1521_1523delCTT mutation was found to account for less than 8% of CF patients in Bahrain …”

“…Due to the wide variation in socioeconomic status among the Arab populations of the 22 Arab countries, the care and diagnosis of CF vary significantly from country to country. In most countries, the disease is diagnosed based on the clinical features of the patient and a sweat chloride test of 60 mmol/L or higher . However, some Arab countries have adopted the use of certain molecular diagnostic techniques for disease confirmation, including multiplex heteroduplex shift analysis, denaturing high‐pressure liquid phase chromatography (DHPLC), denaturing gradient gel electrophoresis (DGGE), and high‐resolution melting curve analysis, as well as sequencing techniques including Sanger sequencing and next‐generation sequencing …”