Fluorescence in situ hybridization analysis with LIS1 specific probes reveals a high deletion mutation rate in isolated lissencephaly sequence

Purpose: Recent revision of the lissencephaly critical region on chromosome 17p13.3 and confirmation of LIS1 as the causative gene for classical lissencephaly has allowed the development and application of fluorescence in situ hybridization (FISH) probes corresponding directly to this gene. Method: We have analyzed patients with isolated lissencephaly sequence (ILS) by FISH with probes at D17S379, an anonymous locus distal to LIS1, and with LIS1 specific probes. Results: In 110 patients with ILS, a deletion at D17S379 was detected in 23.6%. Of those patients without a deletion, 32 were available for further study with LIS1 probes. Deletions were found in eight additional individuals. Conclusion: The overall deletion mutation rate detectable by FISH with LIS1 probes is ≈40%. This rate is significantly higher than the deletion rate observed at D17S379. This indicates that FISH studies using probes specific to LIS1 should be undertaken as the initial diagnostic assay for the evaluation of patients with ILS, and the high frequency of deletions raises the possibility of "hotspots" for chromosome breakage in this region.