Alpha-thalassaemia is inherited as an autosomal recessive disorder characterised by a microcytic hypochromic anaemia, and a clinical phenotype varying from almost asymptomatic to a lethal haemolytic anaemia.

α-Thalassemia is an inherited, autosomal recessive, disorder characterized by a microcytic hypochromic anemia. It is one of the most common monogenic gene disorders in the world population. The clinical severity varies from almost asymptomatic, to mild microcytic hypochromic, and to a lethal hemolytic condition, called Hb Bart's Hydrops Foetalis Syndrome. The molecular basis are usually deletions and less frequently, point mutations affecting the expression of one or more of the duplicated α-genes. The clinical variation and increase in disease severity is directly related to the decreased expression of one, two, three or four copies of the α-globin genes. Deletions and point mutations in the α-globin genes and their regulatory elements have been studied extensively in carriers and patients and these studies have given insight into the α-globin genes are regulated. By looking at naturally occurring deletions and point mutations, our knowledge of globin-gene regulation and expression will continue to increase and will lead to new targets of therapy.

Background: Approximately 80% of the α- and 10% of the β-thalassaemias are caused by genomic deletions involving the α- and β-globin gene clusters on chromosomes 16p13.3 and 11p15.5, respectively. Gap-PCR, Southern blot analysis, and fluorescent in situ hybridisation are commonly used to identify these deletions; however, many deletions go undetected using conventional techniques. Methods: Patient samples for which no abnormalities had been found using conventional DNA techniques were analysed by a three colour multiplex ligation-dependent probe amplification assay. Two sets of 35 and 50 probes, covering a region of 700 kb of the α- and 500 kb of the β-globin gene cluster, respectively, were designed to detect rearrangements in the α- and β-globin gene clusters. Results: In 19 out of 38 patient samples, we found 11 different α-thalassaemia deletions, six of which were not previously described. Two novel deletions leaving the α-globin gene cluster intact were found to cause a complete downregulation of the downstream α-genes. Similarly, 31 out of 51 patient samples were found to carry 10 different deletions involving the β-globin gene cluster, three of which were not previously described. One involves the deletion of the locus control region leaving the β-globin gene cluster intact. Conclusions: These deletions, which are not easily detected by conventional techniques, may have clinical implications during pregnancy ranging from mild to life threatening microcytic haemolytic anaemia in neonates. The approach as described here is a rapid and sensitive method for high resolution analysis of the globin gene clusters and for any region of the genome.

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 β‐thalassemia carriers presenting with features of β‐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 β‐thalassemia trait without variants in the HBB gene.

We describe the molecular spectrum of α‐thalassemia mutations in a population sample of newborns in the South‐Iranian province of Hormozgan. Out of 660 randomly collected blood samples 218 (33%) had visibly elevated Hb Bart's. DNA was extracted from 78 samples out of this selection (n = 156), of which 114 alleles were found to carry an α‐thalassemia defect. Besides the common −α^3.7 (79.1%), −α^4.2 (1.7%), and α^‐5nt α alleles (4.3%), three novel nondeletional α‐thalassemia mutations were found; the α₂ cd19 (‐G) frameshift mutation (12.2%), the α₁ IVS1‐148(A→G) (0.9%) affecting the splice acceptor site consensus sequence and the cd14 (TGG→TAG) (0.9%), which creates a premature stop codon in the first exon of the α₁‐gene. A fourth mutation in the α₁‐gene, the IVS1‐38 (C→T) (0.9%) of undetermined effect, was found in an individual heterozygous for the α₂ cd19(‐G) mutation. Am. J. Hematol. 74:99–103, 2003. © 2003 Wiley‐Liss, Ins.

Accurate and consistent interpretation of sequence variants is integral to the delivery of safe and reliable diagnostic genetic services. To standardize the interpretation process, in 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published a joint guideline based on a set of shared standards for the classification of variants in Mendelian diseases. The generality of these standards and their subjective interpretation between laboratories has prompted efforts to reduce discordance of variant classifications, with focus on the expert specification of the ACMG/AMP guidelines for individual genes or diseases. Herein, we describe our experience as a ClinGen Variant Curation Expert Panel (VCEP) to adapt the ACMG/AMP criteria for the classification of variants in three globin genes (HBB, HBA2, HBA1) related to recessively inherited hemoglobinopathies, including five evidence categories, as use cases demonstrating the process of specification and the underlying rationale.