Miller-Dieker syndrome (MDS), a disorder manifesting the severe brain 
malformation lissencephaly ("smooth brain"), is caused, in the majority of 
cases, by a chromosomal microdeletion of the distal short arm of chromosome 17. 
Using human chromosome 17-specific DNA probes, we have begun a molecular 
dissection of the critical region for MDS. To localize cloned DNA sequences to 
the MDS critical region, a human-rodent somatic cell hybrid panel was 
constructed which includes hybrids containing the abnormal chromosome 17 from 
three MDS patients with deletions of various sizes. Three genes (myosin heavy 
chain 2, tumor antigen p53, and RNA polymerase II) previously mapped to 17p were 
excluded from the MDS deletion region and therefore are unlikely to play a role 
in its pathogenesis. In contrast, three highly polymorphic anonymous probes, 
YNZ22.1 (D17S5), YNH37.3 (D17S28), and 144-D6 (D17S34), were deleted in each of 
four patients with visible deletions, including one with a ring chromosome 17 
that is deleted for a portion of the single telomeric prometaphase subband 
p13.3. In two MDS patients with normal chromosomes, a combination of somatic 
cell hybrid, RFLP, and densitometric studies demonstrated deletion for YNZ22.1 
and YNH37.3 in the paternally derived 17's of both patients, one of whom is also 
deleted for 144-D6. The results indicate that MDS can be caused by 
submicroscopic deletion and raises the possibility that all MDS patients will 
prove to have deletions at a molecular level. The two probes lie within a 
critical region of less than 3,000 kb and constitute potential starting points 
in the isolation of genes implicated in the severe brain maldevelopment in MDS.