Identification of genomic loci contributing to agenesis of the corpus callosum.

Agenesis of the corpus callosum (ACC) is a common brain malformation of variable clinical expression that is seen in many syndromes of various etiologies. Although ACC is predominantly genetic, few genes have as yet been identified. We have constructed and analyzed a comprehensive map of ACC loci across the human genome using data generated from 374 patients with ACC and structural chromosome rearrangements, most having heterozygous loss or gain of genomic sequence and a few carrying apparently balanced rearrangements hypothesized to disrupt key functional genes. This cohort includes more than 100 previously unpublished patients. The subjects were ascertained from several large research databases as well as the published literature over the last 35 years. We identified 12 genomic loci that are consistently associated with ACC, and at least 30 other recurrent loci that may also contain genes that cause or contribute to ACC. Our data also support the hypothesis that many ACC loci confer susceptibility to other brain malformations as well as ACC, such as cerebellar hypoplasia, microcephaly, and polymicrogyria. The database presented here provides a valuable resource for diagnosis and management of individuals with ACC and individuals with chromosome rearrangements in whom ACC should be suspected, and of course for identifying ACC causal and contributory genes. Well-defined diagnostic criteria, improved scanning techniques, and increased recognition of associated abnormalities will further facilitate gene mapping and allow definition of distinct syndromes within this heterogeneous group of patients.