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José Ferrão1, Marisa Silva1, Lúcia Gonçalves1, Susana Gomes1, Pedro Loureiro1, Andreia Coelho1, Armandina Miranda2, Filomena Seuanes2, Ana Batalha Reis3, Francisca Pina4, Raquel Maia5, Paula Kjöllerström5, Estela Monteiro6,7, João F. Lacerda6,8 , João Lavinha1,9, João Gonçalves1,10, Paula Faustino1,11

1. Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge (INSA)
2. Departamento de Promoção da Saúde e Prevenção de Doenças não Transmissíveis, INSA
3. Serviço de Patologia Clínica, Hospital São Francisco Xavier, Centro Hospitalar de Lisboa Ocidental
4. Serviço de Hemato-Oncologia, Hospital do Espírito Santo de Évora
5. Unidade de Hematologia, Hospital D. Estefânia, Centro Hospitalar de Lisboa Central
6. Faculdade de Medicina, Universidade de Lisboa
7. Serviço de Gastroenterologia, Hospital de Santa Maria, Centro Hospitalar de Lisboa Norte (CHLN)
8. Serviço de Hematologia, Hospital de Santa Maria, CHLN
9. BioISI, Faculdade de Ciências, Universidade de Lisboa
10. ToxOmics, Faculdade de Ciências Médicas, Universidade Nova de Lisboa
11. ISAMB, Faculdade de Medicina, Universidade de Lisboa

- Artigo científico publicado na revista Annals of Hematology - Ann Hematol - DOI 10.1007/s00277-017-3090-y – Setembro de 2017

Abstract: Inherited deletions of α-globin genes and/or their upstream regulatory elements (MCSs) give rise to α-thalassemia, an autosomal recessive microcytic hypochromic anemia. In this study, multiplex ligation-dependent probe amplification performed with commercial and synthetic engineered probes, Gap-PCR, and DNA sequencing were used to characterize lesions in the sub-telomeric region of the short arm of chromosome 16, possibly explaining the α-thalassemia/HbH disease phenotype in ten patients.We have found six diferente deletions, in heterozygosity, ranging from approximately 3.3 to 323 kb, two of them not previously described. The deletions fall into two categories: one includes deletions which totally remove the α-globin gene cluster, whereas the other includes deletions removing only the distal regulatory elements and keeping the α-globin genes structurally intact. An indel was observed in one patient involving the loss of the MCS-R2 and the insertion of 39 bp originated from a complex rearrangement spanning the deletion breakpoints. Finally, in another case, no α-globin gene cluster deletion was found and the patient revealed to be a very unusual case of acquired α-thalassemiamyelodysplastic syndrome. This study further illustrates the diversity of genomic lesions and underlying molecular mechanisms leading to α-thalassemia.

Keywords: Alpha-thalassemia, Acquired HbH, ATMDS, Novel deletions, MLPA