P227: Variant interpretation and reporting approaches in the GUARDIAN study of genomic newborn screening

Results: Re-analysis of BMP4's gene disease relationship verified that syndromic patients with developmental defects but lacking ocular anomalies are within the same disease mechanism.Additionally, isolated developmental phenotypes, such as pituitary deficiencies, orofacial clefts and dental anomalies, kidney dysplasias, and genital abnormalities, are each seen regularly throughout the clinical literature and accompanied by robust functional and model studies.Reevaluation using the comprehensive and abundant evidence published in the literature, dramatically expanded our understanding of the BMP4 disease spectrum as well as the number of clinically actionable variants.Addition of the previously insufficient phenotypic patients that met the new and expanded BMP4 disease spectrum tripled the number of published probands.Additional segregation data was also included, furthering our understanding of intrafamilial phenotypic consistency and variability.Previously, 82% of the variants identified in patients were frameshift and nonsense variants.However, due to the disease phenotype expansion, there are at least 9 additional missense variants implicated in this disease.Conclusion: Performing variant curation at a gene wide scale creates a unique opportunity to identify accumulating evidence towards novel gene disease patterns that are not visible when curating a single variant or single phenotype at a time.This process exposed a new population of BMP4 patients with various development anomalies not previously associated with the disease spectrum.This feedback loop between variant and gene curation ultimately increases the number of actionable variants and patients who receive a diagnosis.