High Resolution FMR1 Genetic and Epigenetic Molecular Assessments in a Well Characterized Cohort of Full Mutation and Premutation Fragile X Patients

Principal Investigator: Dejan Budimirovic

The fragile X gene, FMR1, is critical for brain development and has many markers. Syndromic autism spectrum disorder (ASD) is common in males with an FMR1 full mutation (FM, >200 CGG). Yet males with the premutation (PM, 55-200 CGG) may also represent a significant form of FMR1 relevant to ASD. In light of the enormous progress in fragile X targeted therapeutics, further studies are needed to understand the full value of FMR1 as a diagnostic and therapeutic marker for ASD. In this study, we will examinee a cohort of FM and PM patients for high resolution FMR1 molecular testing using a panel of next generation PCR assays developed by Asuragen. Retrospective data will be collected from medical records of the clinical cohort (n= 60, predominantly males) which consists of patients from the Kennedy Krieger Institute’s Fragile X Clinic who have consented to be a part of the current study, as well as non-patients who have had previous neuropsychology testing completed. If the patient has not had testing done at the Kennedy Krieger Institute in the past, but has records available, data consisting of reports of previous testing will be collected from the patient with his or her informed consent. All patients will have had previous FMR1 genetic testing. Standardized measures include assessed skills (i.e., cognitive, adaptive, language) and autistic behavior (i.e., ADOS). DSM-based ASD diagnoses will have been complemented with ADOS in most cases. Parent rating scales (i.e., ABC, CBCL, BASC) will have been completed in most cases. Established FMR1 gene features (CGG repeat sizing, size mosaicism, X-activation, and methylation status) and emerging markers (AGG interruptions) will be interrogated using highly sensitive and quantitative assays to evaluate associations between genotype/phenotype in fragile X patients with a range of genetic, cognitive, and behavioral characteristics. We plan to use these data for presentations at conferences, publication(s), and possible grant applications.