Authors :
Presenting Author: Sonal Mahida, MGC, CGC – Boston Children's Hospital
Dustin Baldridge, MD, PhD – University of Washington, St. Loius; Maya Chopra, MBBS, FRACP – Boston Children's Hospital; Aditi Gupta, PhD – University of Washington, St. Loius; Christina Gurnett, MD – University of Washington, St. Loius; Inez Oh, PhD – University of Washington, St. Loius; Phillip Payne, PhD, FACMI – University of Washington, St. Loius
Rationale:
Recent advances in clinical genomic sequencing have resulted in a rapid increase in the identification of rare variants in genes implicated in intellectual and developmental disabilities (IDD) and developmental and epileptic encephalopathies (DEE). The identification of these variants has major implications for the discovery and improvement of targeted clinical treatment. However, many of these variants are of unknown clinical significance and their role in epilepsy and brain development has not been established. The pace of discovery in interpreting variation in DEE-related genes would be markedly accelerated by co-registering information on clinically-identified genetic variants with standardized neurobehavioral phenotypes and electronic health record data (EHR).
Methods:
The Brain Gene Registry (BGR) aims to address this roadblock in translational science in patients with IDD/DEE by co-registering clinical genetic and phenotypic data from 13 Intellectual and Developmental Disabilities Research Center (IDDRC) sites. Subject eligibility is determined by the presence of a pathogenic, likely pathogenic, or uncertain variant in a gene implicated in neurodevelopment on clinical genetic testing. Genes of interest are selected based on curation status, phenotype, presence on clinical genetic testing panels, and by nomination by investigators, with regular updates to the list. Each enrolled participant completes telehealth assessments (cognitive, neurologic, dysmorphology, and guided interaction) and questionnaires that comprise the Rapid Neurophenotypic Assessment protocol (RNAP). The RNAP screens for differences in motor and sensory function, as well as psychiatric disorders such as ADHD and autism.
Results:
The Brain Gene Registry now contains genetic and phenotypic data on over 330 participants with ongoing recruitment. We have performed deep phenotyping on 58% (n=192) of participants and have complete electronic health records for 38% (n=138). At least 30% (n=42) of those on whom records are available have a diagnosis of epilepsy, ranging from self-limited familial neonatal-infantile epilepsy (SelFNIE), to developmental and epileptic encephalopathy (DEE). Among these participants, variants in 33 distinct genes are represented and ACMG variant classifications include variant of uncertain significance (46%), likely pathogenic (17%), and pathogenic (37%). A handful of genes within this cohort are currently known primarily as complex autism susceptibility genes, with one or fewer cases of epilepsy reported in the literature.
Conclusions:
Data from the BGR is accelerating gene curation for ID/autism, including more than 15 genes recently evaluated by our dedicated BGR ID/autism ClinGen Gene Curation Expert panel. Curation of epilepsy related genes with BGR data will further enhance collaborative translational science by enabling effective and efficient interpretation of clinical genomic information in patients with DEE.
Funding: NIH, NCATS