Abstract
Disclosure: M.L. Brinkmeier: None. J.J. Martínez Mayer: None. B.S. Ellsworth: None. L.T. Raetzman: None. L. Cheung: None. M.I. Perez-Millan: None. S.A. Camper: None. S.W. Davis: None. Congenital hypopituitarism (CH) and its associated syndromes, septo-optic dysplasia and holoprosencephaly, are midline defects that cause significant morbidity for affected people. Variants in 44 genes are associated with CH, but most cases of CH are caused by unknown variants. Whole exome (WES) and whole genome sequencing (WGS) of CH patient DNA identifies variants in genes known to cause CH and variants of uncertain significance (VUS) in genes that are not currently associated with CH. The functional significance of VUS in CH candidate genes can be established using mouse models. Many of the human CH genes were first discovered in mice, and in most cases the mouse phenotype was an excellent predictor of the human phenotype. The International Mouse Phenotyping Consortium (IMPC) is an invaluable resource of phenotyping data generated by the international effort to determine function of all protein coding genes in the mouse genome through targeted disruption. Using the mouse phenotyping data generated by the Deciphering Mechanisms of Developmental Disorders (DMDD) project to characterize targeted alleles that cause embryonic lethality or subviability, we have identified 51 genes that cause embryonic pituitary malformations. The malformations range in severity and include absent adenohypophysis, absent neurohypophysis, hypoplasia, and hyperplasia. Using the GenePaint RNA in situ hybridization data for mouse embryos and single cell RNA sequencing (scRNAseq) data from e14.5 dissected pituitary glands, we confirmed expression for all candidate genes in the tissues that contribute to the developing pituitary gland. Using gene ontology (GO) terms associated with these 51 genes, we identified molecular pathways not previously associated with pituitary gland organogenesis, including cilia formation, amino acid metabolism, and epigenetic regulation. We present here the candidate gene list, scRNAseq expression data, GO term analysis, select images from GenePaint, and select images of the observed malformations. These genes associated with mouse pituitary malformations significantly expand the list of candidate genes for screening in WES and WGS in human cases of CH. Presentation: Thursday, June 15, 2023