Genetic linkage studies of X-linked hypophosphataemic rickets in a Saudi Arabian family.

Abstract

OBJECTIVE, PATIENTS AND DESIGN: X-linked hypophosphataemic rickets (HYP) is the most common inherited form of rickets and the gene causing this disorder has been localized to Xp22.3-p21.3 by linkage studies of affected families of Northern European origin. In addition, the locus order Xpter-(DXS207-DXS43,DXS197)-HYP-DXS41-X cen has been established and the flanking markers are useful for the presymptomatic diagnosis of HYP. However, a recent study indicates locus heterogeneity and this may hinder the use of the flanking markers for presymptomatic diagnosis in additional families and in particular those from different populations. We have therefore investigated one Saudi-Arabian family (13 affected and six unaffected members) with hypophosphataemic rickets for linkage to these and other X-linked markers. A total of 17 cloned human X chromosome sequences identifying restriction fragment length polymorphisms were used to localize the mutant gene causing this disorder in the Saudi Arabian family. Nine (four from Xp and five from Xq) of the 17 X-linked DNA probes proved informative and linkage was established between HYP and the DSX41 locus, peak LOD score = 4.22 (recombination fraction, theta = 0.00). A positive peak LOD score of 2.32 (theta = 0.05) was also obtained between HYP and the DXS207 locus. Thus, the HYP gene in this Saudi Arabian family is linked to two of the four flanking markers which demonstrated linkage in families of Northern European origin. We conclude that the X-linked hypophosphataemic rickets gene in a Saudi Arabian family is located in the Xp22.3-p21.3, a region where this gene has previously been mapped by linkage studies of families of Northern European origin. Our studies have not demonstrated locus heterogeneity, so the flanking markers for HYP previously established in the families of Northern-European origin will be useful in the genetic counselling and presymptomatic diagnosis of this disorder in the Saudi Arabian family.