ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This elegant study analysed a phenotype-driven screen for developmental lethal mouse genes to identify candidate genes that drive hypothalamo-pituitary phenotypes.

The authors used a publicly-available phenotype-driven screen, performed by the mouse models phenotyping facility at the DMDD Wellcome Sanger Institute, to identify key genes important in pituitary development. High-Resolution Episcopic Microscopy (HREM) from 209 knockout lines was used to identify abnormal HP-axis phenotypes and 51 candidate genes. These candidate genes were used to screen for congenital hypopituitarism (CH) genes in a large cohort of patients. 137 patients with CH and associated syndromes, previously sequenced by NGS were then analysed using a candidate gene approach from the 51 murine transgenic candidate genes. The authors identify a valuable list of new CH-candidate-causing genes and pituitary developmental-related genes.

The authors report CH-causative variants in two patients with CH in two new genes: MORC2 and SETD5. MORC2 has been previously associated with Charcot-Marie-Tooth (CMT2Z) and a developmental syndrome associated with impaired growth, craniofacial dysmorphism and axonal neuropathy (DIGFAN syndrome). SETD5  is located on chromosome 3 and has been implicated in the 3p25 deletion syndrome characterised for severe developmental, growth restriction and delay and CNS abnormalities.

A crucial finding of this research is the identification of specific gene mutations that cause hypopituitarism. The authors use reverse genetics, starting from a murine HP-axis driven phenotypes to identify human CH-causing genes. Importantly, this study unravels important candidate genes for HP-axis development whose function is yet unknown providing a valuable resource of novel genes to study pituitary organogenesis. The study uncovered previously unrecognized genetic mutations that affect pituitary formation, and these findings were later verified in human patients with similar hormonal deficiencies. Beautifully, this article highlights a pivotal connection between mouse genetic alterations driving pituitary phenotypes and its application to identify candidate genes involved in CH and associated syndromes. Moreover, the study also brings attention to the potential for genetic heterogeneity in hypopituitarism cases. Identifying multiple gene mutations contributing to pituitary defects highlights the complexity of CH disease and the importance of comprehensive genetic analyses for accurate diagnosis and treatment planning.