ESPE Abstracts (2023) 97 RFC13.4

1Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital, Lausanne, Switzerland. 2Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. 3Poznan University of Medical Sciences, Poznan, Poland. 4Service of Pediatric Endocrinology and Diabetology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland. 5Department of Endocrinology, Hospital S João, Department of Biomedicine, Faculty of Medicine of the University of Porto, Porto, Portugal. 6Division of Pediatric Endocrinology and Diabetology and Children’s Research Centre, University Children’s Hospital, Zurich, Switzerland. 7Department of Pediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences, Poznan, Poland. 8Department of Endocrinology, Children’s Hospital of Eastern Switzerland, St. Gallen, Switzerland

Background: Congenital Hypopituitarism (CH) is a rare heterogeneous genetic disorder characterized by the 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 thus more than 80% of cases remain unresolved.

Objective: To identify de novo pathogenic variants in novel CH genes in trios using whole-exome sequencing (WES).

Method: We selected 7 trios, performed a detailed phenotyping in the probands and parents, collected DNA and performed WES. Further analysis using VariantMaster, a bioinformatics tool (Santoni FA, 2014) was performed to detect de novo pathogenic variants.

Results: The hormonal deficiencies presented by the 7 probands were: GH (n=7), TSH (n=4), LH/FSH (n=6), ACTH (n=4) and Prolactin (n=1). Regarding the neuroimaging all patients had small anterior pituitaries, 3 had abnormalities in pituitary stalk and 5 had ectopic posterior pituitary. Extra pituitary phenotypes were present in 4 patients: ataxia, epilepsy and scoliosis in combination in one patients, micropenis and chryptorquidism in two patients, midline craniofacial malformations in two patients, and Joubert syndrome in one patient. In terms of genetics, we identified a homozygous pathogenic variant in 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 5 novel genes in 3 patients. Genes were further filtered based on the type of the mutation, top expression in the pituitary and association with known human disorders leaving 4 putative candidate genes: MED13 (p.asn1986Ser); RASIP1 (p.Leu347Phe); ECPAS (p.Lys597Ile) and WBP11 (p.Leu223ArgfsTer6). WBP11, a gene involved in the major spliceosome complex, has been already associated with a variable human phenotype. Patients reported have delayed puberty, midline craniofacial malformations and proportionate short stature resembling CH and septo-optic dysplasia.

Conclusion: We identified 4 potentially pathogenic variants in new candidate genes for congenital hypopituitarism, one of them involved in the spliceosome machinery. We are currently following up to evaluate these genes in a larger population of singleton CH patients and performing studies to confirm the pathogenicity of these variants.

Volume 97

61st Annual ESPE (ESPE 2023)

The Hague, Netherlands
21 Sep 2023 - 23 Sep 2023

European Society for Paediatric Endocrinology 

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