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Orientador(es)
Resumo(s)
Hemoglobinopathies encompass all genetic diseases of hemoglobin (Hb), the iron-containing oxygen-transport protein present in red blood cells. They occur due to mutations in globin genes or in their regulatory regions, and are classified as Hb variants and thalassemias. The aim of this work was to identify the molecular lesions in the origin of complex cases of hemoglobinopathies and understand the underlying pathophysiological mechanisms.
We investigated 15 clinical cases suspected of having one or more hemoglobinopathy, presenting with atypical hematological phenotypes. The study included the search for alterations in beta- and alpha-globin gene clusters by PCR, Gap-PCR, Sanger sequencing, and Multiplex Ligation-dependent Probe Amplification. In silico analyses were performed using Polyphen-2, SIFT, and varSeak.
Two beta-thalassemia carriers with abnormally low HbA2 level were found to have double heterozygosity for a mutation in HBB gene (c.92+1G>A, c.92+6T>C) and a delta-chain Hb variant (Hb A2-Yialousa). Another case was justified by a novel large deletion, which removes the entire beta-globin gene cluster as well as the olfactory receptor genes, OR52A1 and OR51V1. Changes in HbA2 values were also justified by a deletion that eliminates the HBD (Corfu deletion) or by the presence of the HbA2´variant. Atypically high levels of fetal Hb were explained by alterations in promoters of HBG genes (HBG1:c.-248C>G, HBG1:c.-228T>C, HBG2:c.-211C>T) or by deletions that remove both HBD and HBB (HPFH-1, HPFH-2). An even more complex case was originated by triple heterozygosity involving the Southeast Asian alpha-thalassemia deletion, the alpha-chain variant Hb Westmead, and the beta-chain variant HbE. As far as we know, this is the first case in which the three alterations were found in the same individual.
Individuals presenting abnormal phenotypes due to more than one hemoglobinopathy may be misdiagnosed if not correctly studied. Unravelling the genetic basis of complex clinical cases allows a better referral to genetic counselling, improves the understanding of the pathophysiology of the disease and its modifying factors, and may reveal new therapeutic targets.
Descrição
Abstract publicado em: Medicine 104(4): p e39478, January 24, 2025; P53. DOI: 10.1097/MD.0000000000039478
Palavras-chave
Hb A2-Yialousa HPFH Alfa-talassémia Alpha-thalassemia Doenças Genéticas Hemoglobinopatias Beta-talassémia Doenças Raras Genética Humana Modificadores genéticos Hemoglobina Variantes de hemoglobina Beta-thalassaemia