ESPE Abstracts

Background: Correct hypothalamo-pituitary (HP) formation is dependent on a complex network of numerous transcription factors and signalling molecules. Congenital hypopituitarism (CH) is a highly variable disorder involving deficiencies in one or more of the 7 pituitary hormones, and is often associated with syndromic features, spanning visual, midline brain, and facial abnormalities.

Methods: We used a targeted gene panel including 135 genes: a) known CH-related genes, b) novel genes identified through previous NGS data, and c) genes implicated in murine HP development not previously investigated in humans. We ran 144 samples from a large CH patient cohort (n = >1900) from our hospital and other national/international centres on this targeted gene panel, using stringent variant filtering criteria. Patient phenotypes included growth hormone deficiency (GHD), hypogonadotropic hypogonadism (HH), combined pituitary hormone deficiency (CPHD) 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. Examples of our overall findings are presented in this table:

There were 15 cases involving variants in known CH-related genes that do not require further functional investigation and may be considered as genetically ‘solved’. Data suggest an oligogenic basis in many of these cases, with the involvement of multiple genes in the pathogenicity of the disease. Novel variants are currently undergoing 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 patients and their families.