Malformations of the brainstem and cerebellum are collectively a relatively common (at least 0.24 per 1000 births) cause of developmental disabilities in humans that have been understudied compared to other types of brain malformations. The best known and most common of these is Dandy-Walker malformation (DWM), but this is often confused with isolated cerebellar vermis hypoplasia (CVH) and the molar tooth malformation (MTM) seen in Joubert syndrome and related disorders. Here we propose a comprehensive approach to syndrome delineation and gene identification for these 3 overlapping malformations. We approach them together as most clinicians have difficulty distinguishing between them, and our experience to date suggests that mild variants of DWM and MTM may be very difficult or impossible to distinguish from isolated CVH. Our preliminary studies have resulted in significant progress in our understanding of these disorders, and include useful clinical delineation combined with identification of at least 4 potentially important causative genes and physical mapping of several more. Specifically, we have found the first causative genes for CVH (OPHN1), DWM (ZIC1 and ZIC4) and MTM (AHI1 and NPHP1), and mapped additional causative genes for DWM to chromosome 6p25 and for MTM to chromosomes 7 and 13. We have already ascertained sufficient subjects for to allow identification of the 6p25 DWM gene, and to map additional hindbrain malformation genes. Our experience with genotype-phenotype analysis will allow progress to be quickly translated to clinical usefulness. Overall, we believe that intensive studies of these malformations and their causative genes are very timely, and will advance knowledge regarding brain development in general, and contribute to the diagnosis and medical care of the individuals and families affected by these disorders.
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