Unravelling the genetic basis of complex clinical cases of hemoglobinopathies

Silva, Eduarda; Pena, Rita; Miranda, Armandina; Costa, Alcina; Gaspar, Gisela; Lopes, Pedro; Faustino, Paula

Publicação

Unravelling the genetic basis of complex clinical cases of hemoglobinopathies

2023-11Documento de conferência

dc.contributor.author	Silva, Eduarda
dc.contributor.author	Pena, Rita
dc.contributor.author	Miranda, Armandina
dc.contributor.author	Costa, Alcina
dc.contributor.author	Gaspar, Gisela
dc.contributor.author	Lopes, Pedro
dc.contributor.author	Faustino, Paula
dc.date.accessioned	2026-02-03T16:09:23Z
dc.date.available	2026-02-03T16:09:23Z
dc.date.issued	2023-11
dc.description	Abstract publicado em: Medicine 104(4): p e39478, January 24, 2025; P53. DOI: 10.1097/MD.0000000000039478
dc.description.abstract	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.	pt_PT
dc.description.version	info:eu-repo/semantics/publishedVersion	pt_PT
dc.identifier.uri	http://hdl.handle.net/10400.18/10801
dc.language.iso	eng	pt_PT
dc.peerreviewed	yes	pt_PT
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject	Hb A2-Yialousa	pt_PT
dc.subject	HPFH	pt_PT
dc.subject	Alfa-talassémia	pt_PT
dc.subject	Alpha-thalassemia	pt_PT
dc.subject	Doenças Genéticas	pt_PT
dc.subject	Hemoglobinopatias	pt_PT
dc.subject	Beta-talassémia	pt_PT
dc.subject	Doenças Raras	pt_PT
dc.subject	Genética Humana	pt_PT
dc.subject	Modificadores genéticos	pt_PT
dc.subject	Hemoglobina	pt_PT
dc.subject	Variantes de hemoglobina	pt_PT
dc.subject	Beta-thalassaemia	pt_PT
dc.title	Unravelling the genetic basis of complex clinical cases of hemoglobinopathies	pt_PT
dc.type	conference object
dspace.entity.type	Publication
oaire.citation.conferenceDate	2025-11-23
oaire.citation.conferencePlace	Lisboa, Portugal
oaire.citation.title	27st Anual Meeting of the Portuguese Society of Human Genetics, 23-25 November 2023
oaire.version	http://purl.org/coar/version/c_970fb48d4fbd8a85
person.familyName	Faustino
person.givenName	Paula
person.identifier.ciencia-id	F01A-353A-433E
person.identifier.orcid	0000-0002-6269-4867
person.identifier.rid	M-3519-2014
person.identifier.scopus-author-id	8158641100
rcaap.rights	openAccess	pt_PT
rcaap.type	conferenceObject	pt_PT
relation.isAuthorOfPublication	94303e78-8b7d-4e24-811d-3af3b1a4e330
relation.isAuthorOfPublication.latestForDiscovery	94303e78-8b7d-4e24-811d-3af3b1a4e330