Identification and characterization of an Xq26-q27 duplication in a familywith spina bifida and panhypopituitarism suggests the involvement of two distinct genes

We investigated a family with a duplication, dup(X)q26-q27, that was presen t in two brothers, their mother, and their maternal grandmother. The brothe rs carrying the duplication displayed spina bifida and panhypopituitarism, whereas a third healthy brother inherited the normal X chromosome. Preferen tial inactivation of the X chromosome containing the duplication was eviden t in healthy carrier females. We determined the boundaries of the Xq26-q27 duplication. Via interphase FISH analysis we narrowed down each of the two breakpoint regions to similar to 300-kb intervals. The proximal breakpoint is located in Xq26.1 between DXS1114 and HPRT and is contained in YAC yWXD5 99, while the distal breakpoint is located in Xq27.3 between DXS369 and DXS 1200 and contained in YAC yWXD758, The duplication comprises about 13 Mb. E vidence from the literature points to a predisposing gene for spina bifida in Xq27. We hypothesize that the spina bifida in the two brothers may be du e to interruption of a critical gene in the Xq27 breakpoint region. Several candidate genes were mapped to the Xq27 critical region but none was shown to be disrupted by the duplication event. Recently, M. Lagerstrom-Fermer e t al (1997, Am. J. Hum. Genet. 60, 910-916) reported on a family with X-lin ked recessive panhypopituitarism associated with a duplication in Xq26; how ever, no details were reported on the extent of the duplication. Our study corroborates their hypothesis that X-linked recessive panhypopituitarism is likely to be caused by a gene encoding a dosage-sensitive protein involved in pituitary development. We place the putative gene between DXS1114 and D XS1200, corresponding to the interval defined by the duplication in the pre sent family. (C) 2000 Academic Press.