OVERLAPPING SUBMICROSCOPIC DELETIONS IN XQ28 IN 2 UNRELATED BOYS WITHDEVELOPMENTAL DISORDERS - IDENTIFICATION OF A GENE NEAR FRAXE

Two unrelated boys are described with delay in development and submicr oscopic deletions in Xq28, near FRAXE. Molecular diagnosis to exclude the fragile X (FRAXA) syndrome used the direct probe pfxa3, together w ith a control probe pS8 (DXS296), against PstI restriction digests of DNA. Deletions were detected initially by the control probe pS8, which is an anonymous fragment subcloned from YAC 539, within 1 Mb distal t o FRAXA. Further molecular analyses determined that the maximum size o f the deletion is <100 kb in one boy (MK) and is wholly overlapped by the deletion of up to similar to 200 kb in the other (CB). These delet ions lie between the sequences detected by the probe VK21C (DXS296) an d a dinucleotide repeat VK18AC (DXS295). The patient MK had only speec h delay with otherwise normal development, while patient CB had global developmental delay that included speech delay. Detection of overlapp ing deletions in these two cases led to speculation that coding sequen ces of a gene(s) important in language development may be affected. Hy bridization of the pS8 and VK21A probes to zoo-blots revealed cross-sp ecies homology. This conservation during evolution suggested that this region contains sequences with functional significance in normal deve lopment. The VK21A probe detected a 9.5-kb transcript in placenta and brain and a smaller, 2.5-kb, transcript in other tissues analyzed.