Allelic Variants in Established Hypopituitarism Genes Expand Our Knowledge of the Phenotypic Spectrum.

We report four allelic variants (three novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p.Phe 57Leufs*43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A hemizygous SOX3 allelic variant (p.Met304Ile) was found in a male patient with IGHD and hypoplastic anterior pituitary. YASARA, a tool to evaluate protein stability, suggests that p.Met304Ile destabilizes the SOX3 protein (ΔΔG = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C>T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). This variant was previously reported in a patient with severe holoprosencephaly and shown to affect TGIF1 function. A novel heterozygous TGIF1 variant (c.82T>C:p.Ser28Pro) was identified in a patient with CPHD, pituitary aplasia and ectopic posterior lobe. Both TGIF1 variants have an autosomal dominant pattern of inheritance with incomplete penetrance. In conclusion, we have found allelic variants in three genes in hypopituitarism patients. We discuss these variants and associated patient phenotypes in relation to previously reported variants in these genes, expanding our knowledge of the phenotypic spectrum in patient populations.

Metabolizer phenotype prediction in different Peruvian ethnic groups through CYP2C9 polymorphisms.

OBJECTIVES: The CYP2C9 gene have three common alleles, CYP2C9*1, CYP2C9*2 and CYP2C9*3, associated with different homozygous (*1/*1, *2/*2 and *3/*3) and heterozygous (*1/*2 and *1/*3) genotypes, which in turn are related to extensive (gEM), intermediate (gIM) and poor (gPM) metabolizers. Likewise, the inter-ethnic variability was intimately associated with different drug metabolism. Therefore, the aim of the present study was predict the metabolizer phenotypes in different Peruvian ethnic groups from lowland (<2,500 m) and highland (>2,500 m). METHODS: TaqMan genotyping assays were performed in a group of 174 healthy unrelated Peruvian individuals. RESULTS: In this study, the allelic comparison between the three eco-regions showed that the CYP2C9*1 was the most common in Andean (96.32%); the *2 was the most frequent in Coast (7.45%, p<0.05). Regarding the *3 was the most common in Amazonian (6.25%, p<0.05). In a corroborative manner, the gEM was the most common in Andean (94.74%), the gIM in Coast (17.02%) and gPM in Amazonian (6.25%) populations. CONCLUSIONS: Our study provides a valuable source of information about to metabolizer phenotype drugs in different Peruvian ethnic groups. In this way, it could be established suitable genetic-dosage medicaments for various common diseases in these heterogenetic populations.

Genomic Variability of Phytophthora palmivora Isolates from Different Oil Palm Cultivation Regions in Colombia.

Palm oil is the most consumed vegetable oil globally, and Colombia is the largest palm oil producer in South America and fourth worldwide. However, oil palm plantations in Colombia are affected by bud rot disease caused by the oomycete Phytophthora palmivora, leading to significant economic losses. Infection processes by plant pathogens involve the secretion of effector molecules, which alter the functioning or structure of host cells. Current long-read sequencing technologies provide the information needed to produce high-quality genome assemblies, enabling a comprehensive annotation of effectors. Here, we describe the development of genomic resources for P. palmivora, including a high-quality genome assembly based on long and short-read sequencing data, intraspecies variability for 12 isolates from different oil palm cultivation regions in Colombia, and a catalog of over 1,000 candidate effector proteins. A total of 45,416 genes were annotated from the new genome assembled in 2,322 contigs adding to 165.5 Mbp, which represents an improvement of two times more gene models, 33 times better contiguity, and 11 times less fragmentation compared with currently available genomic resources for the species. Analysis of nucleotide evolution in paralogs suggests a recent whole-genome duplication event. Genetic differences were identified among isolates showing variable virulence levels. We expect that these novel genomic resources contribute to the characterization of the species and the understanding of the interaction of P. palmivora with oil palm and could be further exploited as tools for the development of effective strategies for disease control.

Allelic Variants of ARMC5 in Patients With Adrenal Incidentalomas and in Patients With Cushing's Syndrome Associated With Bilateral Adrenal Nodules.

Objective: Germline ARMC5 mutations are considered to be the main genetic cause of primary macronodular adrenal hyperplasia (PMAH). PMAH is associated with high variability of cortisol secretion caused from subclinical hypercortisolism to overt Cushing's syndrome (CS), in general due to bilateral adrenal nodules and rarely could also be due to non-synchronic unilateral adrenal nodules. The frequency of adrenal incidentalomas (AI) associated with PMAH is unknown. This study evaluated germline allelic variants of ARMC5 in patients with bilateral and unilateral AI and in patients with overt CS associated with bilateral adrenal nodules. Methods: We performed a retrospective multicenter study involving 123 patients with AI (64 bilateral; 59 unilateral). We also analyzed 20 patients with ACTH pituitary independent overt CS associated with bilateral adrenal nodules. All patients underwent germline genotyping analysis of ARMC5; abdominal CT and were classified as normal, possible or autonomous cortisol secretion, according to the low doses of dexamethasone suppression test. Results: We identified only one pathogenic allelic variant among the patients with bilateral AI. We did not identify any pathogenic allelic variants of ARMC5 in patients with unilateral AI. Thirteen out of 20 patients (65%) with overt CS and bilateral adrenal nodules were carriers of pathogenic germline ARMC5 allelic variants, all previously described. The germline ARMC5 mutation was observed in only one patient with bilateral AI; it was associated with autonomous cortisol secretion and showed to be a familial form. Conclusion: The rarity of germline ARMC5 mutations in AI points to other molecular mechanisms involved in this common adrenal disorder and should be investigated. In contrast, patients with overt Cushing's syndrome and bilateral adrenal nodules had the presence of ARMC5 mutations that were with high prevalence and similar to the literature. Therefore, we recommend the genetic analysis of ARMC5 for patients with established Cushing's syndrome and bilateral adrenal nodules rather than patients with unilateral AI.

ID CORE XT as a tool for molecular red blood cell typing.

Introduction: Classic methods to determine human red blood cell (RBC) antigens are based on serologic testing, however there are some limitations. Based on these, several molecular techniques have been developed to bypass these restrictions and to detect the most important allelic variants, the last of great value for the approach in the personalized medicine, especially for patients in chronic transfusion regime. Areas covered: In this article, we provide an updated review of the ID CORE XT (Progenika Biopharma-Grifols, Bizkaia, Spain) that is one of the commercial DNA-based techniques available to genotyping of RBC antigens. Expert opinion: It is a platform based on Luminex technology with an automated workflow after DNA extraction and its robustness has been shown through validation studies. This technology provides a useful tool to increase the inventory of antigen-negative RBC units, through a mass-scale donor genotyping for RBC antigens and prevent immunization of patients who require chronic transfusion by providing compatible RBC units based on matching by DNA testing.

Prenatal exposure to particulate matter and ozone: Bulky DNA adducts, plasma isoprostanes, allele risk variants, and neonate susceptibility in the Mexico City Metropolitan Area.

Mexico City's Metropolitan Area (MCMA) includes Mexico City and 60 municipalities of the neighbor states. Inhabitants are exposed to emissions from over five million vehicles and stationary sources of air pollutants such as particulate matter (PM) and ozone. MCMA PM contains elemental carbon and organic carbon (OC). OCs include polycyclic aromatic hydrocarbons (PAHs), many of which induce mutagenic and carcinogenic DNA adducts. Gestational exposure to air pollution has been associated with increased risk of intrauterine growth restriction, preterm birth or low birth weight risk, and PAH-DNA adducts. These effects also depend on the presence of risk alleles. We investigated the presence of bulky PAH-DNA adducts, plasma 8-iso-PGF2α (8-iso-prostaglandin F2α ) and risk allele variants in neonates cord blood and their non-smoking mothers' leucocytes from families that were living in a highly polluted area during 2014-2015. The presence of adducts was significantly associated with both PM2.5 and PM10 levels, mainly during the last trimester of gestation in both neonates and mothers, while the last month of pregnancy was significant for the association between ozone levels and maternal plasma 8-iso-PGF2α . Fetal CYP1B1*3 risk allele was associated with increased adduct levels in neonates while the presence of the maternal allele significantly reduced the levels of fetal adducts. Maternal NQO1*2 was associated with lower maternal levels of adducts. Our findings suggest the need to reduce actual PM limits in MCMA. We did not observe a clear association between PM and/or adduct levels and neonate weight, length, body mass index, Apgar or Capurro score. Environ. Mol. Mutagen. 60:428-442, 2019. © 2019 Wiley Periodicals, Inc.

Polymorphisms in IMPDH2, UGT2B7, and CES2 genes influence the risk of graft rejection in kidney transplant recipients taking mycophenolate mofetil.

The immunosuppressant mycophenolic acid (MPA), derived from the prodrug mycophenolate mofetil (MMF), is a drug used widely by kidney transplant recipients. This drug selectively inhibits inosine monophosphate dehydrogenase that controls the proliferation of lymphocytes, aiding in the prevention of rejection of the transplanted organ. Polymorphisms in key genes involved in MMF metabolism may alter the function of the enzymes encoded by them and contribute to interindividual variability in the response to the drug and its efficacy. The aim of this study was to investigate the association of nine polymorphic variants of eight genes involved in MMF pharmacokinetics, with rejection and adverse effects exhibited by kidney transplant recipients who use this drug. Our sample comprised 145 kidney transplant recipients undergoing post-transplant treatment whose immunosuppressive therapy consisted of MMF and corticosteroid combined or not with a calcineurin inhibitor or mTOR inhibitor. The average age of the patients was 46.9 ±â€¯12.5 years, and they underwent transplantation 7 ±â€¯5.71 years ago. The combination of the T/C and C/C genotypes of the polymorphism rs11706052 (IMPDH2) was associated with a 4.2-fold protection, and the combination of the genotypes A/G and G/G of the polymorphism rs7438135 (UGT2B7) showed a 2.4-fold protection, against rejection. The association of T/C and C/C genotypes in the SNP rs11706052 (IMPDH2) with the occurrence of rejection episodes considering only patients who received immunosuppressive drug MMF associated with cyclosporine or tacrolimus and corticoids, demonstrated association with a protection against rejection 15.6-fold. The T/T genotype of the polymorphism rs2241409 (CES2) was associated with a 7.2-fold increased risk of rejection. Therefore, these polymorphisms that showed a strong association with rejection episodes should be considered in future studies on new prognostic markers for rejection in patients treated with MMF.

Genetic polymorphism of tumor necrosis factor promoter region and susceptibility to develop Hodgkin lymphoma in a Mexican population.

Hodgkin lymphoma (HL) is a rare neoplasm of the lymphatic system, in which inflammation and allelic variants in cytokines have been proposed as etiological factors. Epstein-Barr virus infection is often associated as a risk factor in HL and since cytokines are involved in the humoral response to viral infection. Our aim was to study the association between single nucleotide polymorphisms (SNPs) located in the tumor necrosis factor (TNF) gene (- 376G> A, - 238G> A and 581G> A) in a sample of Mexican patients (56 cases) and their susceptibility to develop HL, comparing these SNPs among healthy individuals (127 controls). Frequencies for TNF - 238G> A and TNF 581G> A showed no significant differences between cases and controls. However, the proportion of cases with the GA genotype of - 376 SNP showed a significant difference as compared to controls, odds ratio = 4.41 (95% confidence interval: 1.21-16.6), p = 0.02. We found that in this group of patients from Mexico the SNP - 376G> A in TNF shows an association with higher risk for HL.

The effect of fetal androgen metabolism-related gene variants on external genitalia virilization in congenital adrenal hyperplasia.

The 21-hydroxylase deficiency (21OHD) is caused by CYP21A2 mutations resulting in severe or moderate enzymatic impairments. 21OHD females carrying similar genotypes present different degrees of external genitalia virilization, suggesting the influence of other genetic factors. Single nucleotide variants (SNVs) in the CYP3A7 gene and in its transcription factors, related to fetal 19-carbon steroid metabolism, could modulate the genital phenotype. To evaluate the influence of the 21OHD genotypes and the CYP3A7, PXR and CAR SNVs on the genital phenotype in 21OHD females. Prader scores were evaluated in 183 patients. The CYP3A7, PXR and CAR SNVs were screened and the 21OHD genotypes were classified according to their severity: severe and moderate groups. Patients with severe genotype showed higher degree of genital virilization (Prader median III, IQR III-IV) than those with moderate genotype (III, IQR II-III) (p < 0.001). However, a great overlap was observed between genotype groups. Among all the SNVs tested, only the CAR rs2307424 variant correlated with Prader scores (r(2) = 0.253; p = 0.023). The CYP21A2 genotypes influence the severity of genital virilization in 21OHD females. We also suggest that the CAR variant, which results in a poor metabolizer phenotype, could account for a higher degree of external genitalia virilization.

Phenotypic variation of erythrocyte linker histone H1.c in a pheasant (Phasianus colchicus L.) population.

Our goal was to characterize a phenotypic variation of the pheasant erythrocyte linker histone subtype H1.c. By using two-dimensional polyacrylamide gel electrophoresis three histone H1.c phenotypes were identified. The differently migrating allelic variants H1.c1 and H1.c2 formed either two homozygous phenotypes, c1 and c2, or a single heterozygous phenotype, c1c2. In the pheasant population screened, birds with phenotype c2 were the most common (frequency 0.761) while individuals with phenotype c1 were rare (frequency 0.043).

Phenotypic variation of erythrocyte linker histone H1. c in a pheasant (Phasianus colchicus L.) population

Our goal was to characterize a phenotypic variation of the pheasant erythrocyte linker histone subtype H1.c. By using two-dimensional polyacrylamide gel electrophoresis three histone H1.c phenotypes were identified. The differently migrating allelic variants H1.c1 and H1.c2 formed either two homozygous phenotypes, c1 and c2, or a single heterozygous phenotype, c1c2. In the pheasant population screened, birds with phenotype c2 were the most common (frequency 0.761) while individuals with phenotype c1 were rare (frequency 0.043).