P264: The eXtraordinarY Baby Study: Natural history of infants identified with XXYY in the prenatal period

Introduction:The HNRNP-Related Neurodevelopmental Disorders (HNRNP-RNDDs) are a group of NDDs caused by damaging variants in the heterogeneous nuclear ribonucleoprotein (HNRNP) gene family.To date, eight HNRNP-RNDDs have been described and multiple candidate HNRNP-RNDDs are being investigated.By approaching these disorders as a group of related disorders, we hope to uncover shared aspects that may lead to shared therapeutics.Methods: Here we are utilizing direct interactions with patient families through the HNRNP Family Foundation and a novel platform, Geneial, to integrate three natural history studies in order to compare phenotypes within and across the HNRNP genes.To date, over 100 individuals representing HNRNPH2-RNDD, HNRNPK-RNDD (Au-Kline syndrome), HNRNPQ/SYNCRIP-RNDD, HNRNPU-RNDD, and HNRNPUL2-RNDD are included in this joint natural history study.Results: High level phenotyping has shown that the HNRNP-RNDDs are more alike to each other than compared to other NDDs, and this study will allow for deeper phenotyping to identify similarities and differences.Shared features include borderline to severe developmental delay/intellectual disability, speech delays and challenges, hypotonia, behavioral differences such as autism spectrum disorder, and epilepsy.Each disorder has characteristic features, such as skeletal anomalies in Au-Kline syndrome and HNRNPR-RNDD. Conclusion:The natural history of the HNRNP-RNDDs is still unclear, as is the range of clinical features.Incorporation of the previously established studies and novel individuals allows for inclusion of the rarer, "orphan" HNRNP genes that have evidence for pathogenicity but lack both clinical and research attention.This international endeavor aids in understanding of these disorders and serves as a model for investigation of other related diseases.