RESUMO
It is well known that modifiers play a role in ameliorating or exacerbating disease phenotypes in patients and carriers of recessively inherited disorders such as sickle cell disease and thalassemia. Here, we give an overview of the literature concerning a recently described association in carriers of SUPT5H Loss-of-Function variants with a beta-thalassemia-like phenotype including the characteristic elevated levels of HbA2. That SUPT5H acts as modifier in beta-thalassemia carriers became evident from three reported cases in whom combined heterozygosity of SUPT5H and HBB gene variants was observed to resemble a mild beta-thalassemia intermedia phenotype. The different SUPT5H variants and hematologic parameters reported are collected and reviewed to provide insight into the possible effects on hematologic expression, as well as potential disease mechanisms in carriers and patients.
Assuntos
Proteínas Nucleares , Fatores de Elongação da Transcrição , Talassemia beta , Humanos , Talassemia beta/genética , Heterozigoto , Mutação com Perda de Função , Fenótipo , Proteínas Nucleares/genética , Fatores de Elongação da Transcrição/genéticaAssuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Proteínas Nucleares/genética , Fatores de Elongação da Transcrição/genética , Talassemia beta/diagnóstico , Talassemia beta/genética , Biomarcadores , Feminino , Estudos de Associação Genética/métodos , Humanos , MasculinoRESUMO
Hemoglobinopathies are the most common monogenic disorders in the world with an ever increasing global disease burden each year. As most hemoglobinopathies show recessive inheritance carriers are usually clinically silent. Programmes for preconception and antenatal carrier screening, with the option of prenatal diagnosis are considered beneficial in many endemic countries. With the development of genetic tools such as Array analysis and Next Generation Sequencing in addition to state of the art screening at the hematologic, biochemic and genetic level, have contributed to the discovery of an increasing number of rare rearrangements and novel factors influencing the disease severity over the recent years. This review summarizes the basic requirements for adequate carrier screening analysis, the importance of genotype-phenotype correlation and how this may lead to the unrevealing exceptional interactions causing a clinically more severe phenotype in otherwise asymptomatic carriers. A special group of patients are ß-thalassemia carriers presenting with features of ß-thalassemia intermedia of various clinical severity. The disease mechanisms may involve duplicated α-globin genes, mosaic partial Uniparental Isodisomy of chromosome 11p15.4 where the HBB gene is located or haplo-insufficiency of a non-linked gene SUPT5H on chromosome 19q, first described in two Dutch families with ß-thalassemia trait without variants in the HBB gene.