Analyzing the role of ACE2, AR, MX1 and TMPRSS2 genetic markers for COVID-19 severity.

BACKGROUND: The use of molecular biomarkers for COVID-19 remains unconclusive. The application of a molecular biomarker in combination with clinical ones that could help classifying aggressive patients in first steps of the disease could help clinician and sanitary system a better management of the disease. Here we characterize the role of ACE2, AR, MX1, ERG, ETV5 and TMPRSS2 for trying a better classification of COVID-19 through knowledge of the disease mechanisms. METHODS: A total of 329 blood samples were genotyped in ACE2, MX1 and TMPRSS2. RNA analyses were also performed from 258 available samples using quantitative polymerase chain reaction for genes: ERG, ETV5, AR, MX1, ACE2, and TMPRSS2. Moreover, in silico analysis variant effect predictor, ClinVar, IPA, DAVID, GTEx, STRING and miRDB database was also performed. Clinical and demographic data were recruited from all participants following WHO classification criteria. RESULTS: We confirm the use of ferritin (p < 0.001), D-dimer (p < 0.010), CRP (p < 0.001) and LDH (p < 0.001) as markers for distinguishing mild and severe cohorts. Expression studies showed that MX1 and AR are significantly higher expressed in mild vs severe patients (p < 0.05). ACE2 and TMPRSS2 are involved in the same molecular process of membrane fusion (p = 4.4 × 10-3), acting as proteases (p = 0.047). CONCLUSIONS: In addition to the key role of TMPSRSS2, we reported for the first time that higher expression levels of AR are related with a decreased risk of severe COVID-19 disease in females. Moreover, functional analysis demonstrates that ACE2, MX1 and TMPRSS2 are relevant markers in this disease.

Improved genetic counseling in Alport syndrome by new variants of COL4A5 gene.

There are current requirements of using genetic databases for offering a better genetic assistance to patients of some syndromes, especially those with X-linked heredity patterns (like Alport Syndrome) for the high probability of having descendants affected by the disease. We describe the first reported case of COL4A5 gene missense c.1499 G>T mutation in a 16-year-old girl confirmed to be affected by Alport Syndrome after genetic counseling. Next Generation Sequencing procedures let discover this mutation and offer an accurate clinical treatment to this patient. Current scientific understanding of genetic syndromes suggests the high importance of updated databases and the inclusion of Variant of Unknown Significance related to clinical cases. All of this updating could enable patients to have a better opportunity of diagnosis and having genetic and clinical counseling. This event is even more important in women planning to start a family to have correct genetic counseling regarding the risk posed to offspring, and allowing the decision to undergo prenatal testing.

Genetic diagnosis of idiopathic hypogonadotrophic hypogonadism: a new point mutation in the KAL2 gene.

Kallmann Syndrome (KS) is a genetic disease of embryonic development which is characterized by the association of hypogonadotropic hypogonadism (HH) due to a deficit of the gonadotropin-releasing hormone (GnRH) and a hypo/anosmia (including a hypoplasia of the nasal sulcus and agenesis of the olfactory bulbs). Even though it is a genotypically and phenotypically heterogeneous clinical disease, there are some key genes related to KS (KAL1, FGFR1 (KAL2), GNRHR, KISSR1 (GPR54), GNRH1, NELF and PROK2). The aim of this study was to present a case report of a genetic diagnosis of KS linked to the presence of mutations in the FGFR1 (fibroblast growth factor receptor 1, also known as KAL2) gene. This diagnosis was made in a 44-year old female affected by a hypogonadism for which she had received intermittent treatment until she was 30 years old based on the patient's own decision. The molecular analysis of FGFR1 identified the mutation c. 246_247delAG (p.T82Xfs110) in heterozygosis on exon 3 of the KAL2 gene. This is the first report of this mutation related to idiopathic hypogonadotrophic hypogonadism (IHH).

Noninvasive fetal RhD status determination in early pregnancy.

INTRODUCTION: The aim of this study was to examine if noninvasive fetal RhD genotyping from maternal blood cell-free fetal DNA performed in the first trimester of pregnancy is accurate enough to propose its routine application to replace usual immunoprophylaxis. MATERIAL AND METHODS: We carried out a prospective study analyzing fetal RhD genotype in 149 nonimmunized RhD-negative women with single pregnancies between 8 and 13 weeks of gestation. Fetal RhD genotype was detected by quantitative PCR targeting exons 5 and 7. The results were compared with postnatal cord blood phenotype, and discrepancy rates were calculated. RESULTS: The concordance of fetal RhD genotypes in maternal plasma and newborn D phenotypes at delivery was 98.2%, including 1 false-positive and 1 false-negative result. The specificity and sensitivity of the assay were 97.5% (95% CI 87.1-99.9) and 98.6% (95% CI 92.7-99.9), respectively, and 6.5% of the results were inconclusive. The application of this test in early pregnancy would avoid unnecessary antenatal prophylaxis in about 27% (40/143) of nonsensitized RhD-negative women. DISCUSSION: Determination of the fetal RhD status from cell-free fetal DNA in maternal plasma in the first trimester of pregnancy is feasible and highly accurate, thus allowing consideration of replacing general routine immunoprophylaxis in the cases of mothers with Rh-negative fetuses.

Undescribed mutations in FBN1 gene in two family cases of Marfan syndrome.

Marfan syndrome (MFS) is a multisystem autosomal dominant heritable disorder and, although there are over 1700 mutations that have been identified in the fibrillin-1 (FBN1) gene associated with it, there are many variants that remain unknown. Here we report two family cases of MFS with two new undescribed variations (C914S and H2426C) in FBN1 gene. Both variations produce alterations in the structural conformation of the protein resulting in pathogenic events in these patients. Finally, this case report includes both pathogenic mutations that have also been clinically and genetically confirmed to result in MFS. This clinical, genetic, and in silico analysis of potentially harmful variations in unrelated MFS patients provides additional evidence for the suggested causative role of the mutations c.2740T > A (C914S), c.7276_7278delCAT (p.H2426C) in FBN1 gene in MFS. .