Complex Genotype-Phenotype correlations in Hemoglobinopathies

Background and Objectives: Hemoglobinopathies and Red Blood Cell membrane disorders display a wide range of genetic and phenotypic heterogeneity. This dissertation describes a cohort of patients presenting with a complex phenotype not consistent with the expected genotype-phenotype correlations. Data and methods: Six patients were selected in this retrospective examination, by analyzing digital and paper-based data of the cohort of patients followed-up at the Hemoglobinopathies Reference Center of the San Luigi Gonzaga University Hospital. Molecular analysis was performed on the β-globin, α-globin, HFE, TFR2, HGB1, HGB2 and UGDT genes. To define the complex cases level and identify subjects with double genetic diagnosis, NGS gene panel analysis, Whole Exome Sequencing and SNP-Array analysis have been used. Results and discussion: The recognition of a more severe phenotype than what would be predicted by the first line diagnostic assessment is the common trait in this group of patients. There are several degrees of interest where this phenomenon is demonstrated, including the superimposition of Hemochromatosis, Gilbert syndrome, combined Thalassemia and RBCs membrane disorders or presence of anomalies in genes which predispose for hematological malignancies. We provide suggestions for clinical scenarios worth of extended genetic analysis. Conclusion: A plethora of knowledge on genetic variables that may influence the phenotype of carriers and patients has been made possible by developments in molecular genetics. We describe six patients presenting a complex Hemoglobinopathy with a double genetic diagnosis, demonstrating the usefulness of a comprehensive molecular genetic approach for the precise diagnosis of the most complex clinical cases. Key words: Hemoglobinopathies, RBC membrane disorders, genotype, phenotype, heterogeneity, severity, next-generation techniques.