LISSENCEPHALY - A HUMAN BRAIN MALFORMATION ASSOCIATED WITH DELETION OF THE LIS1 GENE LOCATED AT CHROMOSOME-17P13

Objective.-We review the clinical phenotype, pathological changes, and results of cytogenetic and molecular genetic studies in 90 probands w ith lissencephaly (smooth brain) with emphasis on patients with the cl assical form (type I). We also describe the recent discovery of the li ssencephaly gene (LIS1), deletions of which have been implicated as th e cause of this disorder in many patients. Data Sources.-We have perfo rmed clinical, cytogenetic, and molecular genetic studies of 25 proban ds with Miller-Dieker syndrome and 65 probands with isolated lissencep haly sequence (ILS). We have further subdivided patients with ILS into those with classical lissencephaly and those with lissencephaly varia nts. Study Selection.-We consider primarily our own published and unpu blished data, but include references to studies of other series of pat ients with lissencephaly. Data Synthesis.-Visible cytogenetic deletion s of 17p13.3 were detected in 14 of 25 Miller-Dieker syndrome probands , and either visible cytogenetic or submicroscopic deletions in 23 (92 %) of 25. Submicroscopic deletions were detected in eight of 45 patien ts with all types of ILS. If only ILS patients with the classical form are considered, we detected deletions in eight (38%) of 21. Conclusio ns.-Deletions of the lissencephaly critical region in chromosome 17p13 .3, including LIS1, appear to be the most frequent cause of classical lissencephaly. Molecular cytogenetic studies, particularly fluorescenc e in situ hybridization, should be performed in all such patients. LIS 1 shows homology to genes involved in signal transduction, which may b e its function in development of the telencephalon. Other genetic caus es of classical lissencephaly and genetic and nongenetic causes of oth er types of lissencephaly exist and are under study.