Allelic and Genotype Frequencies of CYP2B6∗2 (64C > T) and CYP2B6∗3 (777C > A) in Three Dominant Ethnicities of the Iranian Population.

Background: Cytochrome P450 complex plays a key role in drug metabolism. CYP2B6 has an essential part in Cytochrome P450 complex metabolism. This study aims to determine the allelic distribution of CYP2B6∗2 and CYP2B6∗3 in three main Iranian ethnicities: Fars, Turk, and Kurd. Methods: The study was conducted on 174 unrelated healthy volunteers from three main Iranian ethnicities. After DNA extraction from peripheral blood samples, genotyping of CYP2B6∗2 and ∗3 was performed using tetra ARMS and ARMS PCR, respectively. Results: The average age of 174 cases was 40.69 ± 11.87 (mean ± SD) and 39.06 ± 11.63 (mean ± SD) for males and females. In the CYP2B6∗2 variant, the genotyping frequency of wild type (C/C), heterozygous (C/T), and homozygous mutant (T/T) was 8.7%, 86%, and 5.2%, respectively. The CYP2B6∗2 (c.64C > T) allele frequency was 48.2% (95% CI: (37.8-58.6)). In the CYP2B6∗3 variant, the frequency of wild type (C/C), heterozygous (C/T), and homozygous mutant (T/T) was 75.3%, 11%, and 13.6%, respectively. The CYP2B6∗3 (c.777C > A) allelic frequency was 19.1% (95% CI: (17.5-20.7)). Conclusion: Allelic distribution in three main Iranian ethnicities, i.e., Turk, Kurd, and Fars, is remarkably higher than that in other populations, even that in Southern Iran. High frequencies of CYP2B6∗2 and ∗3 in the Iranian population highly affect drug responsiveness. Understanding such variability could help to increase drug efficacy and reduce its toxicity.

Frequency of CYP2B6 Alleles in Major Iranian Ethnicities, Affecting Response to Efavirenz.

Introduction: Efavirenz is an antihuman immunodeficiency virus (HIV) drug metabolized by cytochrome P450 2B6 (CYP2B6) enzyme. Cytochrome P450 2B6 is an enzyme that in humans is encoded by the CYP2B6 gene. Polymorphisms of this gene play a crucial role in the metabolism of drugs such as Efavirenz. This study aims to evaluate the frequency of three clinically significant CYP2B6 polymorphisms (CYP2B6 ∗ 6 (516G > T), CYP2B6 ∗ 4 (785A > G), and CYP2B6 ∗ 5 (1459C > T)) in three major Iranian ethnicities. Methods: One hundred forty-seven participants from three main Iranian ethnicities were included in this study. After DNA extraction, CYP2B6 ∗ 6 (516G > T), CYP2B6 ∗ 4 (785A > G), and CYP2B6 ∗ 5 (1459C > T) were genotyped using tetra-primer amplification refractory mutation system polymerase chain reaction (ARMS-PCR). Results: The frequency of the mutated allele in the Iranian population for CYP2B6 ∗ 6 (516G > T) was 41.50 (95% CI: 35.81, 47.36), which was significantly lower than in Kurds (59.62, 95% CI: 45.10, 72.99). Similarly, Kurds had a higher frequency of mutated allele of CYP2B6 ∗ 5 (1459C > T) (46.15%, 95% CI: 32.23, 60.53) than in Iranians (24.49%, 95% CI: 19.68, 29.82). The frequency of A and G alleles of CYP2B6 ∗ 4 (785A > G) was 62.59% (95% CI: 56.78, 68.13) and 37.41 (95% CI: 31.87, 43.22), respectively. Conclusion: Kurds are at higher risk of adverse drug reactions (ADRs) and insufficient anti-HIV response compared to other Iranians.

Familial hypercholesterolemia in an Iranian family due to a mutation in the APOE gene (first case report).

Familial Hypercholesterolemia is an autosomal, dominant genetic disorder associated with premature cardiovascular disease (CVD). Mutations in the LDLR, APOB, and PCSK9 genes cause the FH phenotype, but in 20% of FH patients, mutations in other genes cause FH. In this regard, we investigated the genetic basis of an Autosomal Dominant Hypercholesterolemia (ADH) phenotype in an Iranian family via next-generation exome sequencing with a panel of hyperlipidemia. We report the first case of FH in an Iranian family due to a mutation in the APOE gene. A 10-year-old female was referred to our genetic clinic with a family history of hypercholesterolemia and high cholesterol level at the age of 3. Evaluation of the lipid profile showed the off total cholesterol of 338 mg/dl, low-density lipoprotein cholesterol (LDL-C of 247 mg/dl(. We identified a mutation in the APOE gene, c.500_502del /p. Leu167del confirmed co-segregation in three individuals of the family from three generations. This in-frame mutation identified here, the first report in Iran, confirms previous reports that ADH can be caused by mutations within the APOE gene and strongly introduces it as the 4th gene that must be checked in the genetic investigating of FH.

First Report of a Known Pathogenic Variant in the FZD6 Gene, in an Iranian Family with Recessive Nail Dysplasia: A Case Report.

Congenital Nail abnormalities are rare ectodermal defects. Autosomal recessive nail dysplasia is much rarer. Recently it has been recognized as a condition resulting in nail dystrophy in the absence of other cutaneous or extracutaneous disorders. Few case reports have identified mutations in the Frizzled 6 (FZD6) gene in families presenting with abnormal nails consistent with Non-Syndromic Congenital Nail Dysplasia. We report a family presenting, they lived in Namin a country of the Ardabil Province, northwestern Iran in 2016, for the first time in Iran in whom we identified mutations in FZD6 with abnormal nails formation.

Effect of inbreeding on intellectual disability revisited by trio sequencing.

In outbred Western populations, most individuals with intellectual disability (ID) are sporadic cases, dominant de novo mutations (DNM) are frequent, and autosomal recessive ID (ARID) is very rare. Because of the high rate of parental consanguinity, which raises the risk for ARID and other recessive disorders, the prevalence of ID is significantly higher in near- and middle-east countries. Indeed, homozygosity mapping and sequencing in consanguineous families have already identified a plethora of ARID genes, but because of the design of these studies, DNMs could not be systematically assessed, and the proportion of cases that are potentially preventable by avoiding consanguineous marriages or through carrier testing is hitherto unknown. This prompted us to perform whole-exome sequencing in 100 sporadic ID patients from Iran and their healthy consanguineous parents. In 61 patients, we identified apparently causative changes in known ID genes. Of these, 44 were homozygous recessive and 17 dominant DNMs. Assuming that the DNM rate is stable, these results suggest that parental consanguinity raises the ID risk about 3.6-fold, and about 4.1 to 4.25-fold for children of first-cousin unions. These results do not rhyme with recent opinions that consanguinity-related health risks are generally small and have been "overstated" in the past.

Exome Sequencing and Linkage Analysis Identified Novel Candidate Genes in Recessive Intellectual Disability Associated with Ataxia.

BACKGROUND: Intellectual disability (ID) is a neuro-developmental disorder which causes considerable socio-economic problems. Some ID individuals are also affected by ataxia, and the condition includes different mutations affecting several genes. METHODS: We used whole exome sequencing (WES) in combination with homozygosity mapping (HM) to identify the genetic defects in five consanguineous families among our cohort study, with two affected children with ID and ataxia as major clinical symptoms. RESULTS: We identified three novel candidate genes, RIPPLY1, MRPL10, SNX14, and a new mutation in known gene SURF1. All are autosomal genes, except RIPPLY1, which is located on the X chromosome. Two are housekeeping genes, implicated in transcription and translation regulation and intracellular trafficking, and two encode mitochondrial proteins. The pathogenesis of these variants was evaluated by mutation classification, bioinformatic methods, review of medical and biological relevance, co-segregation studies in the particular family, and a normal population study. CONCLUSIONS: Linkage analysis and exome sequencing of a small number of affected family members is a powerful new technique which can be used to decrease the number of candidate genes in heterogenic disorders such as ID, and may even identify the responsible gene(s).

Etiological characteristics of people with intellectual disability in Iran.

OBJECTIVE: To describe the etiological characteristics of intellectual disability in one Iranian center. METHODS: In a cross-sectional study, 64 cases with mental retardation (MR) were examined in the Intellectual Rehabilitation & Welfare Care Center of Vardavard, Iran between April and September 2008. Cases were diagnosed with MR or showed delay/regression of developmental milestones. We studied the records of patients and interviewed their families. RESULTS: A total of 64 cases were screened (most were children). The number of male patients was 19 (29.7%) and the females was 45 (70.3%). First degree relatives with mental retardation were found in the families of studied patients, among these relatives 48% were female and 52% were male. Up to 77% of the marriages were between relatives, approximately half between first cousins. The illiteracy rate reached 34% in the families of MR children. Hard labor, hypoxia during labor, mother`s preexisting systemic disease, and maternal and neonatal infection were the most important factors for MR. Furthermore, most of the families were found to have low socioeconomic class. CONCLUSION: Cognitive disabilities in children are multifactorial. Consanguinity was the main risk factor for MR and considering its high rate in our country due to traditional marriages, it should be modified.