Update on Aicardi Syndrome Research at Baylor

Published on: July 11th, 2016, by Carrie Paup

The progress report below summarizes what we have pursued over the last year.

Progress report:

  1. High-throughput next-generation sequencing approaches:


Over the last six months, we have been very fortunate that we were able to submit samples for sequencing to the NIH-funded Baylor-Hopkins Centers for Mendelian Genomics (BHCMG) program [http://bhcmg.org/]. The CMG is a cooperative, international research effort funded by the NIH, where researchers can submit DNA samples from their research subjects for whole exome sequencing at no cost to the individual labs. We have reached an agreement with one of the three CMG sequencing centers situated here at the Baylor College of Medicine, to submit more than 40 available samples in our lab from girls with Aicardi Syndrome for whole exome sequencing by one of the best teams in the country. By participating in this, we will finally be able to obtain genomic-level data on a large number of samples at once, a feat that has yet to be accomplished. Our hope is that this large-scale dataset will give us a better chance at discovering the genetic changes that underlie Aicardi Syndrome.

  1. Validation of previous reported finding that Aicardi syndrome in some cases may be caused by mutations in TEAD1 or OCEL1:


Recently, another group has reported their results from high-throughput sequencing on 10 Aicardi syndrome samples. They identified a mutation in a gene TEAD1 and a potential mutation in another gene OCEL1. They concluded from this, that these genes may play a role in Aicardi syndrome and that Aicardi syndrome may therefore be a more heterogeneous disorder than previously thought. Considering the importance of this information and these conclusions for the progress of research in the field, we felt that it was important to validate this finding in other samples from girls with Aicardi syndrome. We therefore performed and completed a study in which we sequenced TEAD1 and OCEL1 coding regions using DNA from 38 clinically well-characterized girls with Aicardi syndrome. A manuscript summarizing the results from this study has been submitted to an open-access journal and we are awaiting the peer-review process. Furthermore, an abstract describing our findings has been submitted to the American Society of Human Genetics annual meeting and is currently under review.



Although we will focus most of our attention next year on the work in collaboration with the Center for Mendelian Genomics, I am also providing brief updates on other aspects of the project that I presented in last year’s progress report.

  1. Bioinformatic approach to systematically identify candidate genes:


We are not currently actively continuing our collaborative work in this area with a former collaborator Dr. Tabach, however we are still using systematically annotated lists of characteristics observed in girls with Aicardi syndrome together with gene information from regularly mining the Online Mendelian Inheritance in Man (OMIM) database (with help from bioinformatician Dr. Ying-Wooi Wan) and other newer resources such as GeneMatcher (from the Centers for Mendelian Genomics) and the ExAc database (from the Broad Institute), to compare any of our data to comprehensive catalogs of human genes and their role in genetic disorders. The lists of interesting genes we obtained in this manner are compiled into one master list that ultimately will assist in prioritization of genetic variants from our high-throughput sequencing projects.

  1. Search for difficult to find small genomic rearrangements:


Inversions occur when DNA breaks and the pieces between two breakpoints are flipped around during the process of fixing the breaks by DNA repair mechanisms in the cell; these are still considered a possible mechanism for Aicardi syndrome. However, screening the DNA for these changes proves to be very difficult. We previously reported our collaboration with Dr. Pawel Stankiewicz in this area. We experimentally tested the top 93 potential inversion events from our list, however upon evaluation we did not detect any of these inversion events in the samples from girls with Aicardi syndrome. While Dr. Stankiewicz is still actively pursuing the development of better methods to search for inversion events on the X chromosome, we are pausing intense collaboration with his team until these methods are more optimized.

Instead, we are hopeful that the renewed sequencing efforts with the CMG outlined above and the new analysis methods developed by their team of bioinformatics experts will allow us to identify at least a subset of possible inversions that disrupt coding sequences by searching for sequences that may span inversion breakpoints.

  1. Improving database and tissue resource for Aicardi syndrome:

As we also reported also last year, we are continuing to collect samples and clinical information from newly identified girls with Aicardi syndrome and I am contacted regularly by such families. This activity is time-consuming as it requires careful collection and storage of data and follow-up with families. I remain very keen in continuing to work with the Foundation to widen this effort, improve the content of this resource, and enhance its accessibility to other researchers.

Along those lines, I am happy to report this year, that as part of our sequencing collaboration with the CMG, we have now systematically catalogued all our phenotypic (clinical characteristics) information in a clinical-database developed by CMG, called PhenoDb [https://mendeliangenomics.org/]. The benefit of this effort is that it employs standardized terms from the Human Phenotype Ontology (HPO) resource for data collection, which allows for easy comparison across different centers, groups and collaborators. We are happy to share information on which HPO terms we have used with other groups working on Aicardi syndrome research.

  1. Other experiments

In addition to these major efforts, we also performed some smaller experiments including mutation analysis of previously unexplored regions of a previously partially tested gene (ARX) and an interesting new candidate gene (DDX3X).

We have also performed RNASeq (a large-scale study of all expressed or active genes) in six samples from Aicardi syndrome individuals (including 4 cell lines and 2 brain tissue samples). Analysis of these is ongoing, but unfortunately, so far the results have not yielded immediately useful information that would help us get closer to the genetic cause. These results will however remain useful to support future analysis of sequencing data. For example, if we find a gene that may be important, we can then go look at how it is working (expressed) in the RNASeq data.


All these ongoing and newly planned experiments continue to rely heavily on the work of Dr. Bibiana Wong, a very talented postdoctoral researcher in my laboratory, who continues to enthusiastically lead and coordinate all those efforts with strong dedication to this research. She continues to make a real difference to the project and is gaining important expertise on all aspects.