ABCMdb

PMID: 25097766

Fass UW, Al-Salmani M, Bendahhou S, Shivalingam G, Norrish C, Hebal K, Clark F, Heming T, Al-Khusaiby S
Defining a mutational panel and predicting the prevalence of cystic fibrosis in oman.
Sultan Qaboos Univ Med J. 2014 Aug;14(3):e323-9. Epub 2014 Jul 24., [PubMed]

Sentences

No. Mutations Sentence Comment

7 ABCC7 p.Ser549Arg Results: S549R and F508del were the major mutations, accounting for 89% of mutations in the patient population. Login to comment 9 ABCC7 p.Ser549Arg Two carriers, one for F508del and another for S549R, were identified by screening of the volunteer cohort, resulting in a predicted prevalence for Oman of 1 in 8,264. Login to comment 12 ABCC7 p.Ser549Arg Conclusion: The mutational panel for the NAB region and the high proportion of S549R mutations emphasises the need for specific screening for CF in Oman. Login to comment 17 ABCC7 p.Ser549Arg S549R is the predominant disease-causing mutation. Login to comment 20 ABCC7 p.Ser549Arg Application to Patient Care - The predominance of only two major disease-causing CF mutations in the population (S549R and F508del) allows for economically efficient detection methods and a fast confirmation of a clinical CF diagnosis in 89% of cases. Login to comment 23 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Other mutations are less frequent and only four, G542X, N1303K, G551D and W1282X, haveallelefrequenciesabove1%inCaucasianpatients.15 Nonetheless, regional and geographical differences of common Caucasian mutations exist in various ethnic subpopulations.15 Similarly comprehensive molecular epidemiological data about CF in Arab populations are missing. Login to comment 52 ABCC7 p.Ser549Arg Restriction digest analysis was used for the screening of the substitution S549R in the volunteer cohort. Login to comment 59 ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Val392Gly ABCC7 p.Val392Gly For the estimation of CF prevalence, the allele Table 1: Mutational panel of cystic fibrosis transmembrane conductance regulator (CFTR) mutations of unrelated patients in the North Al Batinah region (N = 14) cDNA name Protein name Legacy name Location at exon # (legacy nomenclature exon #) Number of alleles Allelic frequency c.1647T>G p.Ser549Arg S549R (T>G) 12 (11) 21 0.75 c.1521-1523delCTT p.Phe508del F508del 11 (10) 4 0.14 ߤc.1733-1734delTA p.Leu578Argfs*10 - 13 (12) 2 0.07 c.1175T>G p.Val392Gly V392G 9 (8) 1 0.04 cDNA = complementary deoxyribonucleic acid. Login to comment 63 ABCC7 p.Ser549Arg However, detailed information about CF allele frequencies are available for the NAB region, as determined by the current study, as well as in the neighbouring UAE.11 These findings allow the prediction of CF prevalence in Oman based on the most commonly observed mutations, S549R and F508del. Login to comment 73 ABCC7 p.Ser549Arg The substitution S549R and the three base pair deletion F508del mutations accounted for 89.2% of all disease-causing mutations in the patient cohort [Table 1]. Login to comment 74 ABCC7 p.Ser549Arg S549R was the predominant mutation followed by F508del, with an allele frequency of 0.75 and 0.14, respectively [Table 1]. Login to comment 75 ABCC7 p.Ser549Arg ABCC7 p.Val392Gly One individual was a compound heterozygote with S549R on one allele and the reported but not yet clinically described alteration c.1175T>G (p.Val392Gly) at exon 9 (or exon 8 using legacy nomenclature) on the other allele.27 The substitution of thymine to guanine results in the amino acid valine being changed to glycine at the position 392. Login to comment 82 ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg The joined allele frequency for F508del and S549R in the NAB region was 0.89, which is very similar to the reported allele frequency of 0.95 for these two mutations in the UAE.11 The total CF allele frequency for F508del and S549R for the whole of Oman is unknown. Login to comment 85 ABCC7 p.Ser549Arg One individual was identified as a carrier for F508del and another individual as a carrier for S549R. Login to comment 86 ABCC7 p.Ser549Arg Applying the average allele frequency for F508del and S549R, the identified mutations accounted for 92% of CF mutations in the population. Login to comment 94 ABCC7 p.Ser549Arg e327 Discussion The substitution S549R and three base pair deletion F508del were found to be the two most common CF mutations in the NAB region of Oman. Login to comment 96 ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg The clinical characteristics were in accordance with recorded homozygote mutations of S549R and F508del in CFTR2, including sweat chloride concentrations above 100 mmol/L, pancreatic insufficiency and diminished pulmonary function.27 The disease liability of S549R was recently confirmed.28 The predominant and characteristic mutation of the current CF cohort was the substitution S549R with an allele frequency of 0.75 [Table 1]. Login to comment 97 ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg The high coverage of CF cases by only two mutations was similar to findings in the UAE, where S549R and F508del were reported to be disease-causing in 95% of the investigated CF cases.27 Concordantly, in all investigated alleles of CF patients in the UAE, the substitution S549R occurred with the highest allele frequency (0.68).29 An explanation for the observed similarity might be the territorial proximity of the two countries and the cultural and historical ties between extended families which may go beyond administrative borders. Login to comment 98 ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg The allele frequency of S549R in an analysis of 27,177 chromosomes from 23 European and three North African countries only accounts for 12 identified chromosomes with S549R, resulting in an allele frequency of 4.4 x 10-4 .15 In addition, to the best of the authors` knowledge, S549R has been reported in six chromosomes of CF patients of Moroccan descent in Israel but in no other Arab epidemiological study of CF.29-31 Therefore, the high allele frequency of S549R in Oman and the UAE might suggest a specific geographical cluster for this substitution. Login to comment 101 ABCC7 p.Ser549Arg ABCC7 p.Glu1104* Other regional mutations occur with higher frequencies, such as 1548delG in Saudi Arabia18 and E1104X in Libya.19 The observed frequency for S549R in Oman follows exactly this pattern. Login to comment 105 ABCC7 p.Ser549Arg The CF patient in the cohort who was compound heterozygote for c.1175G>T and S549R had mild pancreatic insufficiency and sweat chloride levels of above 100 mmol/L. Login to comment 108 ABCC7 p.Ser549Arg It is significant to note that the mutational panel established in this study, with the predominance of the mutations S549R and F508del, emphasises the need for the development of regional laboratory strategies for fast and effective CF mutational screening and molecular genetic diagnoses. Login to comment 109 ABCC7 p.Ser549Arg For S549R, the disruption of the restriction site of the DraIII enzyme can be considered a fast and cost-efficient screening tool. Login to comment 111 ABCC7 p.Ser549Arg The strategy of screening for potential S549R carrier status in volunteer samples was successfully applied in this study and can be readily adapted for clinical use. In addition, this strategy does not exclude other private mutations which might be identified during the screening of future CF patients. Login to comment 112 ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg However, it appears unlikely that the predominance of S549R identified in the Omani mutational panel of this study, with an allele frequency of 0.75, will be replaced by another as yet unidentified mutation because of the very close similarity to the S549R frequency reported in the UAE. Login to comment 123 ABCC7 p.Ser549Arg Third, the CF mutations S549R and F508del were the major mutations in the area and have also been reported in the UAE which shares a border with the NAB region. Login to comment 124 ABCC7 p.Ser549Arg Therefore, the identification of two carriers in the NAB region but not in any other sample might indicate an increased allele frequency for the CF mutations S549R and F508del in the area. Login to comment 126 ABCC7 p.Ser549Arg From these results, it appears that the major CFTR mutations S549R and F508del follow a spatial north-to-south pattern within the Omani population. Login to comment 128 ABCC7 p.Ile1234Val ABCC7 p.Ile1234Val For instance, the most common Saudi mutations 1548delG and I1234V are reported mainly in the central region of the country whereas the mutation 3120+1G࢐A appears to be more predominant in the east.18 Furthermore, the mutation I1234V has been described in 17 families of the same kabilah in Qatar.33 The estimated carrier frequency for CF in Oman of 1/94 appears lower than the reported carrier frequency for the UAE of 1/64.11 However, the context of mutational clusters with increased CF allele frequencies in subpopulations might be an explanation for this difference. Login to comment 131 ABCC7 p.Ser549Arg Conclusion The two predominant CF mutations of S549R and F508del define the mutational panel in Oman. Login to comment 132 ABCC7 p.Ser549Arg The mutation S549R appears to be clustered in one region and occurs with a higher prevalence in the NAB region of Oman. Login to comment