Co-inheritance of HBB:c.-106G > C, a rare single nucleotide variation at position -56 relative to transcription initiation site, with other known mutations in the globin clusters.

Objectives: We performed molecular analysis to evaluate clinical implications of a rare nucleotide change, particularly when co-inherited with other known mutations in the globin clusters, in order to conduct an appropriate genetic counselling.

Methods: Complete blood cell counts and high-performance liquid chromatography were the routine first level analysis for patients referred to our Hospital Center in Palermo to undergo the screening test for haemoglobinopathies. Sequencing analysis was the selected method for the phenotypic characterization, especially in case of new or very rare mutations in globin genes.

Results: We report data of a rare single nucleotide variation at position -56 relative to transcription initiation site (NM_000518.4(HBB):c.-106G > C), identified in ten patients of Italian origin during the screening programme of the 'Sicilian population'. It was found in simple heterozygosity (n = 8), in association with beta haemoglobin variant Hb S (n = 1) and in heterozygosity with beta-thalassaemic allele IVS-I-1 G->A [(HBB):c.92 + 1G > A] and ααα rearrangement (n = 1).

Discussion: Heterozygous subjects for this substitution showed normal haematological and electrophoretic features. Heterozygotes for this mutation and other defect in globin genes showed the classical phenotype of a healthy carrier, therefore it can be considered a benign variant that does not alter the production and function of haemoglobin.

Conclusion: This is another example of rare or new nucleotide variations whose identification and characterization is crucial in order to carry out appropriate genetic counselling to a potential risk couple.