SAT-022 A targeted hypopituitarism gene panel in patients with variable congenital hypopituitarism identifies variants in known and novel candidate genes with evidence of oligogenicity.

Abstract Disclosure: L.C. Gregory: None. M.T. Dattani: None. Background: Congenital hypopituitarism (CH) is a highly variable disorder involving deficiencies in one or more of 7 pituitary hormones, and is often associated with accompanying features in the eye, midline brain, and face. Normal development of the hypothalamo-pituitary (HP) region of the brain is dependent on a complex network of numerous transcription factors and signalling molecules. Methods: We designed a targeted gene panel including 135 genes, incorporating known CH-related genes, novel genes identified through our next generation sequencing data, and genes implicated in murine HP development that have not been previously investigated in humans. We ran 144 samples on this gene panel, from a large CH patient cohort (n=>1900) within our hospital and other national/international centres, using stringent variant filtering criteria. Patients run in this first batch had variable phenotypes including a broad spectrum of CH, including isolated growth hormone deficiency (GHD), combined pituitary hormone deficiency (CPHD), hypogonadotropic hypogonadism (HH), and septo-optic dysplasia (SOD). Results: revealed a total of 226 variants in 108/144 patients; including known pathogenic variants and variants of unknown significance, incorporating 218 different variants. There were a total of 84/218 novel variants across all genes screened, and 16/84 of these occurred in novel CH candidate genes. One of the genes in which we more frequently identify variants is GLI2, which can be polymorphic and variably penetrant. Phenotypes vary with polydactyly, isolated hypopituitarism, and severe SOD, with one patient having a homozygous novel frameshift, GLI2 p.Ser690fsTer5, which is extremely rare. Other novel variants that were identified in known genes were PNPLA6, LHX4, CHD7, TCF7L1 and POLR3A. Conclusion: There were 15 cases that had variants identified in known CH-related genes that have previously been functionally tested, and therefore may be considered as genetically ‘solved’. Data suggest an oligogenic basis in many cases, with multiple gene variants involved in the pathogenicity of the disease. Novel variants are being considered for functional characterization. These data have provided a molecular diagnosis for many of these patients, which will lead to improved genetic counselling and long-term care for these patients and their families. Presentation: Saturday, July 12, 2025