Miller-Dieker syndrome (MDS) is a multiple malformation syndrome characterized 
by classical lissencephaly and a characteristic facies. It is associated with 
visible or submicroscopic deletions within chromosome band 17p13.3. 
Lissencephaly without facial dysmorphism has also been observed and is referred 
to as isolated lissencephaly sequence (ILS). Apparently partial and 
non-overlapping deletions of the 5' or 3' end of a candidate gene LIS1 in one 
ILS and one MDS patient had suggested that MDS was a single gene disorder, and 
that LIS1 spans in excess of 400 kb. However, the originally presumed 5' end of 
LIS1 was found to belong to the 14-33 epsilon gene residing more distally on 
17p13.3. We have now isolated the correct 5' end of LIS1, constructed a 
approximately 500 kb genomic contig encompassing LIS1, and estimated its gene to 
be approximately 80 kg. Fluorescence in situ hybridization analysis of an ILS 
patient with a de novo balanced translocation, as well as analysis of several 
other key MDS and ILS deletion patients, localizes the lissencephaly critical 
region within the LIS1 gene. Therefore, LIS1 remains the strongest candidate 
gene for the lissencephaly phenotype in ILS and MDS. Our analyses also suggest 
that additional genes distal to LIS1 may be responsible for the facial 
dysmorphology and other abnormalities seen in MDS but not in ILS patients, 
supporting our original concept MDS as a contiguous gene deletion syndrome.