Abstract
The molecular defects underlying haemoglobinopathies are both deletions and point mutations in the alpha- or beta-globin genes or gene-clusters. To detect point mutations causing alpha- or beta-thalassaemia, direct sequencing is the method of choice to detect the widest spectrum of molecular defects. The most established approach in DNA diagnostics to screen for the most common deletion defects causing alpha-thalassaemia or beta-thalassaemia is gap- PCR, Multiplex Ligation-dependent Probe Amplification (MLPA) and Sanger Sequencing technology to detect breakpoint sequences of previously uncharacterized deletions/duplications. We demonstrate the recent advances in the determination of duplications and deletions causing alpha- or beta-thalassemia, using Next Generation Sequencing, array Comparative Genome Hybridization and Target Locus Amplification. We present three cases in which the use of advanced technologies allow the diagnosis of unexpected disease genotypes.
Highlights
We demonly strate the recent advances in the determination of duplications and deletions causing alpha- or beta-thalassemia, using Generation n Sequencing, array Comparative Genome Hybridization and Target o Locus Amplification
We present three cases in which the use of advanced technoloe gies allow the diagnosis of unexpected disease genotypes. l us Introduction ia The thalassaemias are a diverse group of disorders of haemoglobin synthesis, all of which result from a reduced output of the rc alpha- or beta-globin chains of the adult haemoglobin
This enables the detection of single nucleotide variants, deletion/duplication/inversion breakpoint sequences and local haplotyping of neighbouring stretches of DNA, which have been cross-linked, digested and ligated to form anchor-containing DNA circles amplified by inverse PCR
Summary
We demonly strate the recent advances in the determination of duplications and deletions causing alpha- or beta-thalassemia, using Generation n Sequencing, array Comparative Genome Hybridization and Target o Locus Amplification. Recent advances in technology, -c such as array Comparative Genome Hybridization (aCGH), Target Locus Amplification (TLA) and Generation n Sequencing (NGS), may help to determine deletion/duplication o breakpoints to the sequence level, and provide more insight in N rare disease mechanisms.
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