Linkage analysis of a large pedigree with hereditary sideroblastic anaemia

A large pedigree showing a history of pyridoxine responsive X linked sideroblastic anaemia was screened with several polymorphic DNA markers from the X chromosome. Linkage analysis between each marker and disease status was performed, giving a maximum two point lod score of 3.64 at zero recombination with the microsatellite marker PGK1P1 at Xq11.2-12. Close linkage to PGK at Xq13.3, one of the candidate regions for X linked sideroblastic anaemia, was excluded. Linkage to DNA markers distal to PGK and at Xp21 was also excluded. Multipoint linkage analysis was performed with markers located between Xq11.2-21. The maximum map specific lod score obtained was 3.56 at PGK1P1 (Xq11.2-12). Linkage remained significant over the interval 20 cM proximal to PGK1P1 and 5 cM distal to PGK1P1, with definite exclusion around the PGK locus. The most likely location of the gene involved in sideroblastic anaemia in this pedigree is therefore within the pericentromeric region of the X chromosome. This region includes the erythroid 5-aminolaevulinate synthetase gene of the haem synthesis pathway, which is a candidate gene for X linked sideroblastic anaemia located at Xp11.21.