The SPCH1 region on human 7q31: Genomic characterization of the critical interval and localization of translocations associated with speech and language disorder

The KE family is a large three-generation pedigree in which half the member s are affected with a severe speech and language disorder that is transmitt ed as an autosomal dominant monogenic trait. In previously published work, we localized the gene responsible (SPCH1) to a 5.6-cM region of 7q31 betwee n D7S2459 and D7S643. In the present study, we have employed bioinformatic analyses to assemble a derailed BAC-/PAC-based sequence map of this interva l, containing 152 sequence tagged sites (STSs), 20 known genes, and >7.75 M b of completed genomic sequence. We screened the affected chromosome 7 from the KE family with 120 of these STSs (average spacing <100 kb), but we did not detect any evidence of a microdeletion. Novel polymorphic markers were generated from the sequence and were used to further localize critical rec ombination breakpoints in the KE family. This allowed refinement of the SPC H1 interval to a region between new markers 013A and 330B, containing simil ar to 6.1 Mb of completed sequence. In addition, we have studied two unrela ted patients with a similar speech and language disorder, who have de novo translocations involving 7q31. Fluorescence in situ hybridization analyses with BACs/PACs from the sequence map localized the t(5;7)(q22;q31.2) breakp oint in the first patient (CS) to a single clone within the newly refined S PCH1 interval. This clone contains the CAGH44 gene, which encodes a brain-e xpressed protein containing a large polyglutamine stretch. However, we foun d that the t(2;7)(p23;q31.3) breakpoint in the second patient (BRD) resides within a BAC clone mapping >3.7 Mb distal to this, outside the current SPC H1 critical interval. Finally, we investigated the CAGH44 gene in affected individuals of the KE family, but we found no mutations in the currently kn own coding sequence. These studies represent further steps toward the isola tion of the first gene to be implicated in the development of speech and la nguage.