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Project One: Humans

Project I: Identification of genes that when mutated cause structural brain defects in humans

Human structural birth defects are present in 4-5% of live births in the US, contributing to half of all pediatric hospitalizations. Importantly, the rates are double in most of the Middle East, Central Asia and North Africa where consanguinity rates approaching 60% are the norm. Of these, Structural Brain Disorders (SBDs) are probably the single biggest component to the long-term medical complications, greatly increased morbidity and mortality.

Our data demonstrate tremendous locus and genetic heterogeneity among patients with SBDs from these geographic regions, presenting both a challenge as well as an opportunity. The challenge is to derive strategies to molecularly classify patients with these diseases. The opportunity is that these populations offer the chance to identify a much fuller picture of the genes contributing to SBDs in humans. Comprehensive discovery of mutations contributing to SBDs holds great promise for advancing understanding of determinants of brain development and function, and its consequences including epilepsy, developmental delay, and motor deficits.

The search for SBD genes has been hampered by the lack of well-characterized pedigrees to perform gene discovery. The ability to generate whole exome sequence (WES) from such patients only increases the need for multiplex consanguineous pedigrees for these strategies, because the validation of potentially deleterious sequence variants (PDSV) requires segregation analysis.

Dr. Gleeson has collected probably the world's largest cohort of such pedigrees with SBDs over the past 10 years, which will continue in years 1-5 of the project. From these, we will perform WES on 30 probands per year in Core A, and sequence analysis in Core B.

Segregation analysis in the initial family and subsequent screening in patient cohorts, both from the Gleeson Lab, as well as local clinics and the massive California Birth Defects Monitoring Service, will help will validate the gene's involvement in the disease.

Finally, genes identified from Project 2 and 3 will be screened in the cohort using similar high-throughput re-sequencing strategies. In Project 2 and 3, animal models will be created and utilized to identify underlying cellular pathophysiology, with a focus on altered cell polarity.

Joseph Gleeson, M.D.
Professor of Neurosciences and Pediatrics
UC San Diego
Gleeson Lab Website

For Physicians

The most direct way to help your patient with a structural brain disorder arrive at a genetic diagnosis is to enroll the patient into our approved study protocol.  You can find specific information about how to enroll your patient at our laboratory website, including all consent forms, instructions for phlebotomy and shipping samples to the Gleeson lab, all at no cost to the patient.

Gleeson Lab

This project seeks to engage physicians around the country and around the world caring for patients with structural brain disorders.  If you are caring for a patient with such a condition, we urge you to review information on individual conditions available from publicly funded enterprises including:

NINDS Disorders website: Information on specific neurological diseases

GeneReviews: Comprehensive information on genetic conditions

Online Mendelian Inheritance of Man (OMIM): Detailed information on specific Mendelian diseases

PUBMED: Searchable database of the whole medical literature

A number of collaborative agreements have been established to support this project.  Project 1 has obtained agreements from several local and state-wide institutions in support of this project.

  1. Rady Children's Hospital has agreed to provide bioinformatics support to identify patients with structural brain disorders appropriate for study, in both retrospective and prospective fashions, as well as support for enrolling patients into our study and for phlebotomy.
  2. Kaiser Permanente Southern California has agreed to provide bioinformatics support to identify patients with structural brain disorders from their entire patient population of over 3 million individuals.
  3. The California Birth Defects Monitoring Program (CBDMP), which maintains neonatal Gutherie blood spots on all newborns in the state since 1986, has agreed to search their entire database of medical records (updated with all birth defects noted by 1 year of age), consisting of 10-15 million individuals, and provide blood spots for our study.

For Parents

As a parent of a child with a structural brain disorder, you have the power and the right to seek the best in care, diagnosis, and treatment.  Many parents turn to relevant parent support groups, which can be identified once a specific diagnosis is made by your child's physician. 

For our study, we receive many inquiries from parents, and we directly enroll patients into our study, usually with their physician's involvement.  Parents can contact us directly at, call our study coordinator at 858-246-0547 or go to the Gleeson Lab, to obtain necessary information on sending copies of brain MRIs, photos of your child, questionnaires, and instructions on shipping biological samples for study.


You are not alone

If you are the parent of a child with a structural brain disorder, you are not alone.  There are many support groups for individual disorders, so the first step is to identify the support group appropriate for your child, and connect with the parent coordinator.  This can serve several useful functions, as the coordinators typically have many years of experience, not just with their own child, but also helping other parents navigate through the complex web of seeking the best specialist to evaluate your child, arranging special services, determining the best course of action and any medication.

Patient Advocacy Groups in the United States

Genetic Alliance
Provides information and assistance to increase the capacity of genetic advocacy organizations through networking and education and assists individuals with genetic conditions.

National Organization for Rare Disorders (NORD)
A federation of voluntary health organizations helping people with rare diseases; includes a database of patient support and health-related organizations.

The Global Genes Project
The Global Genes Project will create greater public awareness for rare disease while connecting, educating, and empowering the millions of families and caregivers affected through an online community and collaborative portal.