Consistent chromosome abnormalities identify novel polymicrogyria loci in 1p36.3, 2p16.1-p23.1, 4q21.21-q22.1, 6q26-q27, and 21q2.

Polymicrogyria is a malformation of cortical development characterized by loss of the normal gyral pattern, which is replaced by many small and infolded gyri separated by shallow, partly fused sulci, and loss of middle cortical layers. The pathogenesis is unknown, yet emerging data supports the existence of several loci in the human genome. We report on the clinical and brain imaging features, and results of cytogenetic and molecular genetic studies in 29 patients with polymicrogyria associated with structural chromosome rearrangements. Our data map new polymicrogyria loci in chromosomes 1p36.3, 2p16.1-p23, 4q21.21-q22.1, 6q26-q27, and 21q21.3-q22.1, and possible loci in 1q44 and 18p as well. Most and possibly all of these loci demonstrate incomplete penetrance and variable expressivity. We anticipate that these data will serve as the basis for ongoing efforts to identify the causal genes located in these regions.

Clinical and molecular basis of classical lissencephaly: Mutations in the LIS1 gene (PAFAH1B1).

Classical lissencephaly (LIS) and subcortical band heterotopia (SBH) are related cortical malformations secondary to abnormal migration of neurons during early brain development. Approximately 60% of patients with classical LIS, and one patient with atypical SBH have been found to have deletions or mutations of the LIS1 gene, located on 17p13.3. This gene encodes the LIS1 or PAFAH1B1 protein with a coiled-coil domain at the N-terminus and seven WD40 repeats at the C-terminus. It is highly conserved between species and has been shown to interact with multiple proteins involved with cytoskeletal dynamics, playing a role in both cellular division and motility, as well as the regulation of brain levels of platelet activating factor. Here we report 65 large deletions of the LIS1 gene detected by FISH and 41 intragenic mutations, including four not previously reported, the majority of which have been found as a consequence of the investigation of 220 children with LIS or SBH by our group. All intragenic mutations are de novo, and there have been no familial recurrences. Eight-eight percent (36/41) of the mutations result in a truncated or internally deleted protein-with missense mutations found in only 12% (5/41) thus far. Mutations occurred throughout the gene except for exon 7, with clustering of three of the five missense mutations in exon 6. Only five intragenic mutations were recurrent. In general, the most severe LIS phenotype was seen in patients with large deletions of 17p13.3, with milder phenotypes seen with intragenic mutations. Of these, the mildest phenotypes were seen in patients with missense mutations.