Development of a haemoglobinopathy genetic diagnostic service for the North West of England

Haemoglobinopathies represent the commonest single gene defects in the world and are found at highest frequency in those countries where malaria is prevalent. It is now recognised that due to the effect of migration they are not confined to specific geographical locations but occur at high frequency in local populations throughout many parts of the world. Although the haemoglobinopathies are highly heterogeneous at the molecular level with more than 1000 mutant alleles described (Hb Variant database), within each ethnic population group common subsets of mutations are found, consisting of a high frequency of several common mutations with a smaller number of rare mutations. As part of the existing national Antenatal and Newborn Screening Programme, and in order to achieve a high mutation detection rate in the heterogeneous population of the North West of England (NW), and Greater Manchester in particular, a comprehensive suite of genetic diagnostic methodologies were developed to detect the wide spectrum of mutational defects associated with the Haemoglobinopathy disorders. Between July 2008 and December 2011 a total of 328 referrals from the NW were genotyped at Manchester Royal Infirmary. The total number of haemoglobinopathy diagnoses comprised of: 34% (n=113) alpha thalassaemia, 33% (n=109) beta thalassaemia, 17% (n=55) were compound heterozygous for an alpha and beta thalassaemia mutation and/or variants and 3% (n=10) of patients had a mutation resulting in HPFH or δβ thalassaemia. In the remaining 13% (n=41) of referrals either no causative mutation was detected or the genotype detected was not enough on its own to account for the patients‟ phenotype. A broad spectrum of mutations were detected within our referral population by DNA sequencing, resulting in a wide range of genetic interactions between different alpha and beta thalassaemia associated alleles, reflecting the complex molecular heterogeneity of these disorders. This indicates that a comprehensive mutational screening approach, using multiplex Gap-PCR, DNA sequencing and MLPA is appropriate to detect the mutation spectrum found within the heterogeneous populations of the North-West of England, or in any other ethnically diverse populations