SAT-023 Recessive truncations in CCDC149, a previously uncharacterized gene, are a novel cause of Congenital Hypopituitarism.

Abstract Disclosure: L.C. Gregory: None. S. Rath: None. H. Mandel: None. G. Elias-Assad: None. N.N. Samra: None. M.J. Parker: None. P. Dimitri: None. N.K. Hanchate: None. M.T. Dattani: None. Background: Congenital Hypopituitarism (CH) is a life-threatening developmental disorder ranging in severity, characterized by a variable combination of pituitary hormone deficiencies. These include GH deficiency (GHD) (most predominant), gonadotropin, ACTH, TSH, prolactin and vasopressin deficiencies respectively. To date, pathogenic variants have been identified in ∼10-15 % of patients, however the majority do not have a molecular diagnosis. Methods: Whole exome sequencing was performed in two unrelated kindreds including three patients with GHD, hypogonadotropic hypogonadism, and developmental delay/autism. Magnetic resonance imaging (MRI) was performed on the three patients to analyse their pituitary gland anatomy and visualize any structural brain defects. In situ hybridisation was conducted on embryonic human brain tissue sections at different Carnegie stages (CS) of development to generate a developmental expression profile of CCDC149. A null Ccdc149 mouse model was generated for phenotypic characterization. Results: Severe scoliosis was present in two out of the three patients, the two siblings from Pedigree 1 had a normal pituitary, with the third unrelated patient having a small anterior pituitary on MRI. Two novel homozygous CCDC149 frameshifts, c.832G>T p.G278* and c.665T>A, p.L222* respectively, were identified in the two unrelated kindreds with CH. Human embryonic expression of CCDC149 was specific to the developing hypothalamo-pituitary (HP) region at CS16, 19, 20 and 23. Preliminary murine data suggest that Ccdc149-knockout mice exhibit growth impairment and reduced fertility compared to their wildtype littermates. Conclusion: We report the first genetic variant in CCDC149, a novel gene associated with CH, scoliosis and learning difficulties/autism. CCDC149 variants have not been reported in any human disease previously. We present clinical and molecular data in two kindreds with CH, as well as gene expression in human embryonic brain and murine data, to confirm the association between CH and CCDC149 variations. Our study demonstrates that CCDC149 is a novel candidate gene for this disorder, and should be considered as a potential cause in patients with unsolved CH. Previous studies in C.elegans have identified expression of the CCDC149 orthologue in the basal bodies of ciliated neurons, suggesting that impaired cilia function may be an underlying mechanism in this complex disorder. Further functional investigations in patient fibroblasts in this context are currently underway. Presentation: Saturday, July 12, 2025