Deletions of 17p13.3, including the LIS1 gene, result in the brain malformation lissencephaly, which is characterized by reduced gyration and cortical thickening; however, the phenotype can vary from isolated lissencephaly sequence (ILS) to Miller-Dieker syndrome (MDS). At the clinical level, these two phenotypes can be differentiated by the presence of significant dysmorphic facial features and a more severe grade of lissencephaly in MDS. Previous work has suggested that children with MDS have a larger deletion than those with ILS, but the precise boundaries of the MDS critical region and causative genes other than LIS1 have never been fully determined. We have completed a physical and transcriptional map of the 17p13.3 region from LIS1 to the telomere. Using fluorescence in situ hybridization, we have mapped the deletion size in 19 children with ILS, 11 children with MDS, and 4 children with 17p13.3 deletions not involving LIS1. We show that the critical region that differentiates ILS from MDS at the molecular level can be reduced to 400 kb. Using somatic cell hybrids from selected patients, we have identified eight genes that are consistently deleted in patients classified as having MDS. In addition, deletion of the genes CRK and 14-3-3ε delineates patients with the most severe lissencephaly grade. On the basis of recent functional data and the creation of a mouse model suggesting a role for 14-3-3ε in cortical development, we suggest that deletion of one or both of these genes in combination with deletion of LIS1 may contribute to the more severe form of lissencephaly seen only in patients with MDS.
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We would like to thank the patients, their families, and their physicians who referred them for study. We gratefully acknowledge the help of Dr. Akira Tanigami, Patti Mills, Albert Leung, Anthony Bodin, Dr. Andrew Wong, and Dr. J. L. Ceballos. This work was supported in part by grants from the National Institutes of Health (PO1 NS39404, to W.B.D. and D.H.L., and 1 RO1 HD36715-03, to D.H.L.), the Lissencephaly Network, and the March of Dimes (6-FY00-404, to D.H.L. and C.L.M.). C.C. is supported by an INSERM Fellowship and the David and Janice Katz Fellowship in Human Genetics.