Abstract

A patient with microcephaly, microphthalmia, ectrodactyly, and prognathism (MMEP) and mental retardation was previously reported to carry a de novo reciprocal t(6;13)(q21;q12) translocation. In an attempt to identify the presumed causative gene, we mapped the translocation breakpoints using fluorescence in situ hybridisation (FISH). Two overlapping genomic clones crossed the breakpoint on the der(6) chromosome, locating the breakpoint region between D6S1594 and D6S1250. Southern blot analysis allowed us to determine that the sorting nexin 3 gene (SNX3) was disrupted. Using Inverse PCR, we were able to amplify and sequence the der(6) breakpoint region, which exhibited homology to a BAC clone that contained marker D13S250. This clone allowed us to amplify and sequence the der(13) breakpoint region and to determine that no additional rearrangement was present at either breakpoint, nor was another gene disrupted on chromosome 13. Therefore, the translocation was balanced and SNX3 is probably the candidate gene for MMEP in the patient. However, mutation screening by dHPLC and Southern blot analysis of another sporadic case with MMEP failed to detect any point mutations or deletions in the SNX3 coding sequence. Considering the possibility of positional effect, another candidate gene in the vicinity of the der(6) chromosome breakpoint may be responsible for MMEP in the original patient or, just as likely, the MMEP phenotype in the two patients results from genetic heterogeneity.