Abstract
Disclosure: F.A. Correa: None. A. Boizot: None. Z. Kolesinska: None. I. Habibi: None. J. Zhai: None. Y. Zouaghi: None. F. Phan-Hug: None. D. l'Allemands: None. M. Antoniou: None. D. Pignatelli: None. M. Lang-Muritano: None. M. Niedziela: None. G. Papadakis: None. A. Ameti: None. N. J. Niederlander: None. J. S. Acierno: None. G. Ternier: None. P. Giacobini: None. F. Santoni: None. A. Messina: None. N. Pitteloud: None. Background: Congenital hypopituitarism (CH) is a rare heterogeneous genetic disorder characterized by a deficiency of pituitary hormones. CH can be associated with extra pituitary phenotypes such as midline craniofacial malformations. To date, a minority of patients carry pathogenic variants in more than 30 genes, and more than 80% of cases remain unresolved. Objective: To identify de novo pathogenic variants in novel CH genes using whole-exome sequencing (WES) on trios (unaffected parents and affected child). Methods: We selected 7 trios with detailed phenotyping and performed WES. Next, we used VariantMaster, a bioinformatics tool (Santoni FA, 2014) to detect de novo pathogenic variants. Finally, we prioritized the variants based on the type of mutation, gene expression in the pituitary, and association with known human phenotypes. Results: The 7 probands exhibit various types/degrees of pituitary hormone deficiencies. On neuroimaging, all patients had small anterior pituitaries: 3 had abnormalities in pituitary stalk and 5 had ectopic posterior pituitary. Extra pituitary phenotypes included ataxia, epilepsy, scoliosis, signs of absent minipuberty (micropenis and cryptorchidism), midline craniofacial malformations, and Joubert syndrome in one patient. In terms of genetics, we identified a homozygous pathogenic variant in the know CH gene POU1F1 (p.Arg291Trp) in a proband from a consanguineous family. Among the 6 remaining trios, we identified 5 de novo rare variants (MAF < 0.0001), in 4 novel genes (MED13, RASIP1, ECPAS and WBP11) among 3 patients. After prioritization, we selected a loss-of-function variant in WBP11 (p.Leu223ArgfsTer6) in a CH patient presenting with septo-optic dysplasia (SOD) and attention-deficit hyperactivity disorder (ADHD). Pathogenic WBP11 variants have been reported in VACTERL syndrome. Notably, some individuals also have delayed puberty, midline craniofacial malformations and proportionate short stature resembling CH. WBP11 is a gene coding for a protein that is part of the major spliceosome complex. We show ubiquitous expression of WBP11 in human pituitary single cell analysis, and Wbp11(+/-) mice at 17.5 dpc are smaller than WT and 2/9 exhibit anophthalmia resembling our patient with septo-optic dysplasia. Conclusions and perspectives: We present WBP11, a gene involved in the spliceosome machinery, mutated in a patient with CH with SOD. We are currently (i) expanding our cohort of CH and screening individuals for WBP11 mutations; ii) performing transcriptomic analysis of the proband to assess splicing errors; and iii) studying the morphology of the hypothalamic-pituitary region of the mutant mouse using the iDISCO technique. These preliminary findings have identified a promising new genetic basis for congenital hypopituitarism in humans. Presentation: 6/3/2024