Most children who go to the clinic with brain disorders have symptoms combining autism, cerebral palsy and epilepsy, suggesting underlying and shared mechanisms of brain dysfunction in these conditions. Such disorders affect 4-6% of the population with life-long disease, and account for about 10% of health care expenditures in the US. Genetic studies have pointed to frequent low-penetrant or low-frequency genetic alterations, but there is no clear way to use this information to make gene-specific diagnosis, to predict short- or long-term prognosis or to develop disease-specific therapy. We propose to recruit about 500 patients with these disorders mostly from our Children’s Hospital, through a dedicated on-site collaborative approach. Extracting from existing medical records, taking advantage of years of experience in recruitment and stem cell generation, and already existing or planned whole exome or genome sequencing on most patients, we propose a safe, anonymous database linked to meaningful biological, medical, radiographic and genetic data. Because team members will be at the hospital, we can adjust future disease-specific recruitment goals depending upon scientific priorities, and re-contact patients if necessary. The clinical data, coupled with the proposed hiPSC lines, represents a platform for cell-based disease investigation and therapeutic discovery, with benefits to the children of California.
This project can benefit Californians both in financial and non-financial terms. NeuroDevelopmental Disabilities (NDDs) affect 4-6% of Californians, create a huge disease burden estimated to account for 10% of California health care costs, and have no definitive treatments. Because we cannot study brain tissue directly, it is extraordinarily difficult to arrive at a specific diagnosis for affected children, so doctors are left ordering costly and low-yield tests, which limit prognostic information, counseling, prevention strategies, quality of life, and impede initiation of potentially beneficial therapies. Easily obtainable skin cells from Californians will be the basis of this project, so the study results will have maximal relevance to our own population. By combining “disease in a dish” platforms with cutting edge genomics, we can improve diagnosis and treatments for Californians and their families suffering from neurodevelopmental disorders.
Additionally, this project, more than others, will help Californians financially because: 1] The ongoing evaluations of this group of patients utilizes medical diagnostics and genetic sequencing tools developed and manufactured in California, increasing our state revenues. 2] The strategy to develop “disease in a dish” projects centered on Neurodevelopmental Disabilities supports opportunities for ongoing efforts of California-based pharmaceutical and life sciences companies to leverage these discoveries for future therapies.
Childhood Neurodevelopmental Disabilities (NDDs) affect approximately 12% of children in the US, and account for >5% of total healthcare costs. The ability to use induced pluripotent stem cells (iPSCs) to incorporate characteristics of patient cells into models that predict patient disease characteristics and clinical outcomes can have a major impact on care for the children with these conditions. We have proposed to ascertain pediatric patient samples which represent a range of NDDs including Autism Spectrum Disorders (ASD), Intellectual Disability (ID), Cerebral Palsy (CP) and Epilepsy for iPSC banking. These disorders were chosen because they have high heritability rates but remain genetically complex, and therefore, will greatly benefit from further in-depth study using iPSCs
To date we have enrolled 128 patients (72 affected patients, 56 healthy control patients) representing a range of racial and ethnic backgrounds (39% White, 2% Black, 2% Asian, 57% Arabic/Middle Eastern) and both genders (52% Male, 48% Female). The patients in the affected patient group carry a primary diagnosis of one of the NDD disease categories (19% Autism Spectrum Disorder, 44% Epilepsy, 28% Intellectual Disability, 9% Cerebral Palsy). Approximately half of the patients are comorbid for one or more of the other disorders. The control patients consist of healthy family members of the affected patient group. Since family members share many common DNA features this will help us better identify and hone in on disease causing variants more effectively.
iPSC lines have not yet been returned from these patients so there are no research results to report at this time. We are continuing with our recruitment efforts to reach our goal of 450 affected patients and 100 healthy controls.