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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\u2013phenotype 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 \u03b2\u2010thalassemia carriers presenting with features of \u03b2\u2010thalassemia intermedia of various clinical severity. The disease mechanisms may involve duplicated \u03b1\u2010globin genes, mosaic partial Uniparental Isodisomy of chromosome 11p15.4 where the <jats:italic>HBB<\/jats:italic> gene is located or haplo\u2010insufficiency of a non\u2010linked gene <jats:italic>SUPT5H<\/jats:italic> on chromosome 19q, first described in two Dutch families with \u03b2\u2010thalassemia trait without variants in the <jats:italic>HBB<\/jats:italic> gene.<\/jats:p>","DOI":"10.1111\/ijlh.13885","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T16:35:41Z","timestamp":1662654941000},"page":"28-36","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":104,"title":["The hemoglobinopathies, molecular disease mechanisms and diagnostics"],"prefix":"10.1111","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5135-6491","authenticated-orcid":false,"given":"Cornelis L.","family":"Harteveld","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics\/LDGA Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahlem","family":"Achour","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics\/LDGA Leiden University Medical Center  Leiden The Netherlands"},{"name":"Department of congenital and hereditary diseases Charles Nicolle Hospital  Tunis Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra J. 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