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Cystic fibrosis gene mutations and polymorphisms in Saudi men with infertility.

ABSTRACT: BACKGROUND:Some mutations of the cystic fibrosis transmembrane regulator (CFTR) gene may impair spermatogenesis or cause a congenital absence of the vas deferens that manifests as isolated male infertility. OBJECTIVE:Assess the frequency and analyze the spectrum of CFTR gene variations in Saudi men with primary infertility. DESIGN:Prospective, cross-sectional. SETTING:Tertiary care specialist hospital in Jeddah. PATIENTS AND METHODS:Genomic DNA was extracted from peripheral blood samples of Saudi men who presented with primary infertility to the outpatient andrology clinic with either azoospermia or oligoasthenoteratozoospermia. Polymerase chain reaction and direct sequencing were used to identify all variants of the CFTR gene. MAIN OUTCOME MEASURES:Proportion of the patients with a mutant CFTR gene and the spectrum of CFTR gene variations. SAMPLE SIZE:50 infertile Saudi men. RESULTS:This study identified 10 CFTR gene variants in 7 (14%) subjects (100 chromosomes). The detected variants and polymorphisms were: c.1408G>A, c.4389G>A, c.2562T>G, c.869+11C>T, c.2909-92G>A, c.3469-65C>A, c.1210-6delT, c.1210-6T>A, c.2988+1G>A, and c.1210-13GT>TG. CONCLUSION:We demonstrated that 14% of the study subjects had one or more CFTR mutations and these were compounded in most of the affected patients. The spectrum of CFTR gene mutations in these subjects was similar to the mutations reported in other studies throughout the world. LIMITATIONS:Small sample size and the lack of a control group. CONFLICTS OF INTEREST:None.

SUBMITTER: AlMaghamsi T

PROVIDER: S-EPMC7410224 | biostudies-literature | 2020 Jul-Aug

REPOSITORIES: biostudies-literature

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Cystic fibrosis gene mutations and polymorphisms in Saudi men with infertility.

AlMaghamsi Talal T Iqbal Naeem N Al-Esaei Nabil Abdullrahman NA Mohammed Muhsina M Eddin Kamel Zein KZ Ghurab Fatima F Moghrabi Nabil N Heaphy Emily E Junaid Islam I

Annals of Saudi medicine 20200701 4

<h4>Background</h4>Some mutations of the cystic fibrosis transmembrane regulator (<i>CFTR</i>) gene may impair spermatogenesis or cause a congenital absence of the vas deferens that manifests as isolated male infertility.<h4>Objective</h4>Assess the frequency and analyze the spectrum of <i>CFTR</i> gene variations in Saudi men with primary infertility.<h4>Design</h4>Prospective, cross-sectional.<h4>Setting</h4>Tertiary care specialist hospital in Jeddah.<h4>Patients and methods</h4>Genomic DNA w ...[more]

PMID: 32757986

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Project description:BACKGROUND:Cystic fibrosis (CF) occurs in populations in Saudi Arabia and the Gulf area. Approximately 2000 known variants have been identified for the CF transmembrane conductance regulator (CTFR) gene. Screening for ten of the most common variants can detect 80% of alleles. OBJECTIVE:Determine the pattern of CFTR variants in the CF population of Saudi Arabia. DESIGN:A retrospective, descriptive. SETTING:Tertiary care center. PATIENTS AND METHODS:We examined the medical records of 396 confirmed CF patients of all age groups that were positive for a CFTR variant from the period of 1 January 1998 to 1 December 2017. MAIN OUTCOME MEASURES:Zygosity, morbidity and mortality patterns of different types of CFTR variants. SAMPLE SIZE:312 families that included 396 patients. RESULTS:Of 48 variants identified, 6 were novel, having not been described in the medical literature. A homozygous state was found in 283 families (90.7%) and compound heterozygosity in 23 (7.4%). Six families were heterozygous (1.9%). Median age (interquartile range) was 10.2 months (4.4 months to 5.7 years) at diagnosis and 9.7 (5.4-16.5) years at follow up. Of 396 patients, 378 patients (95.5%) survived and 18 (4.5%) died. The ten most common variants identified in descending frequency were: p.Gly473GlufsX54 in 98 alleles (16%), p.Ile1234Val in 66 alleles (11%), F508del in 64 alleles (11%), 711+1G>T in 62 alleles (10%), 3120+1G>A in 62 alleles (11%), p.His139Leuin 38 alleles (6.4%), p.Gln637Hisfs in 30 alleles (5.2%), p.Ser549Arg in 27 alleles (4.5%), p.Asn1303Lys in 14 alleles (2.3%), delExon19-21in 10 alleles (1.6%). This analysis identified 79.2% of our CFTR variants. CONCLUSION:CFTR mutational patterns in our CF population are characterized by a high allelic heterogeneity. The high prevalence of homozygous variants reflects the high level of consanguinity between parents. LIMITATIONS:Our CFTR screening reflected only about 80% of CF patients in Saudi Arabia. CONFLICT OF INTEREST:None.

Project description:Variability in pulmonary disease severity is found in patients with cystic fibrosis (CF) who have identical mutations in the CF transmembrane conductance regulator (CFTR) gene. We hypothesized that one factor accounting for heterogeneity in pulmonary disease severity is variation in the family of genes affecting the biology of interleukin-1 (IL-1), which impacts acquisition and maintenance of Pseudomonas aeruginosa infection in animal models of chronic infection.We genotyped 58 single nucleotide polymorphisms (SNPs) in the IL-1 gene cluster in 808 CF subjects from the University of North Carolina and Case Western Reserve University (UNC/CWRU) joint cohort. All were homozygous for DeltaF508, and categories of "severe" (cases) or "mild" (control subjects) lung disease were defined by the lowest or highest quartile of forced expired volume (FEV(1)) for age in the CF population. After adjustment for age and gender, genotypic data were tested for association with lung disease severity. Odds ratios (ORs) comparing severe versus mild CF were also calculated for each genotype (with the homozygote major allele as the reference group) for all 58 SNPs. From these analyses, nine SNPs with a moderate effect size, OR < or =0.5 or >1.5, were selected for further testing. To replicate the case-control study results, we genotyped the same nine SNPs in a second population of CF parent-offspring trios (recruited from Children's Hospital Boston), in which the offspring had similar pulmonary phenotypes. For the trio analysis, both family-based and population-based associations were performed.SNPs rs1143634 and rs1143639 in the IL1B gene demonstrated a consistent association with lung disease severity categories (P < 0.10) and longitudinal analysis of lung disease severity (P < 0.10) in CF in both the case-control and family-based studies. In females, there was a consistent association (false discovery rate adjusted joint P-value <0.06 for both SNPs) in both the analysis of lung disease severity in the UNC/CWRU cohort and the family-based analysis of affection status.Our findings suggest that IL1beta is a clinically relevant modulator of CF lung disease.

Project description:IntroductionMeconium ileus (MI) is one of the most common causes of intestinal obstruction in newborns. It is the earliest clinical manifestation of cystic fibrosis (CF). MI is suspected if a baby fails to pass meconium shortly after birth and develops symptoms of bowel obstruction, such as distention of the abdomen or vomiting. MI can lead to bowel perforation, a twisting of the bowel, or inflammation and infection of the abdominal cavity.ObjectivesTo find the incidence and prevalence of meconium ileus in cystic fibrosis patients and to report on the most common gene mutation of MI in CF patients.MethodologyRetrospective review of the medical documentations of all MI patients during the period of 1989-2018.ResultsA total of 40 CF confirmed patients were presented with MI. Twenty-nine patients (71%) are alive and 11 patients (29%) died or lost to follow-up. The following CFTR mutations were found: Eight patients (20%) with c.2988+1G>A; Intron 18. Seven patients (17.5%) with c.1418delG; Exon 11. Five patients (12.5%) with c.579+1G>T; Intron 5. Four patients (10%) with c.1911delG; Exon 14. Four patients (10%) with c.1521_1523delCTT; Exon 11. Four patients (10%) with c.416A>T; Exon 13. Three patients (7.5%) with c.2421A>G; Exon 14. Two patients (5%) with c.3908A>C; Exon 21. One patient (2.5%) with c.3889dupT; Exon 24. One patient (2.5%) with c.1657C>T; Exon 12. One patient (2.5%) with c.2547C>A; Exon 14a. Eighteen patients (45%) were presented with vomiting, 38 patients (95%) had postnatal radiological findings, 7 patients (17.5%) had electrolytes imbalance. Five patients (12.5%) had cholestasis and 4 patients (10%) developed chronic liver disease. Thirty-five patients (79.5%) underwent surgical repair and 9 patients (20.5%) were treated medically. Mean age of operation was 2.25 (2) days. Of 9 patients, 6 (66.6%) were treated with gastrograffin enema, 2 patients (22.2%) with oral N-acetylcysteine and 1 patient (11.1%) with saline rectal wash. Thirteen patients (31.5%) required TPN. Five patients had recurrent operation.ConclusionCF and meconium ileus are commonly present in CF patients in Saudi Arabia. Prognosis is similar to other CFs without MI, if treated early. Thirty percent of our CF/MI patients have intronic mutations.

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Cystic fibrosis gene mutations and polymorphisms in Saudi men with infertility.

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Cystic fibrosis gene mutations and polymorphisms in Saudi men with infertility.

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