ESPE Abstracts (2022) 95 P1-347

1Department of Pediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences, Poznan, Poland; 2Service of Endocrinology, Diabetology & Metabolism, Lausanne University Hospital, Lausanne, Switzerland; 3Department of Endocrinology, Hospital S João; Department of Biomedicine, Faculty of Medicine of the University of Porto; IPATIMUP - I3S, Porto, Portugal; 4University Medical Centre Ljubljana, University Children's Hospital, Ljubljana, Slovenia; 5Brigham and Women's Hospital Center for Infertility and Reproductive Surgery, Boston, USA; 6Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, USA

Background: Congenital hypogonadotropic hypogonadism (CHH) is caused by impaired function of GnRH neurons, which clinically manifests by incomplete or absent puberty and infertility. The phenotype may be broader with other developmental anomalies such as anosmia, which is known as Kallmann syndrome. To date, there are more than 40 genes in which mutations underlie CHH. Cornelia de Lange Syndrome (CdLS) is characterized by facial dysmorphia, psychomotor delay, growth impairment and upper limb malformations. A subset of CdLS patients present cryptorchidism, micropenis, delayed puberty, and hyposmia/anosmia. Heterozygous mutations in 7 genes (SMC3, NIPBl, SMC1A, RAD21, HDAC8, BRD4 and ANKRD11) involved in the cohesion complex underlie CdLS. Given the clinical overlap between CHH and CdLS patients, we hypothesised that they may share the genetic background.

Methods: Whole exome sequencing (WES) was performed in CdLS patients with signs of CHH (n=4) as well as CHH patients in search of pathogenic variants in known CdLS genes. In vitro assays were performed on identified mutants. GnRH3:GFP zebrafish model was used to explore the role of SMC3 and NIPBL in GnRH neuron development.

Results: WES identified rare sequencing variants (RSV) in NIPBL (P.P2761Cfs*4, p.R2298C) and a de novo missense RSV in SMC3 (P.C549Y) in 3 patients exhibiting signs of CHH and CdLS. None of these variants were seen in the control population in gnomAD. NIPBL p.R2298C has been reported in CdLS patients and is considered to be pathogenic. NIPBL p.P2761Cfs*4 may escape nonsense-mediated decay and thus lead to a truncated NIBPL protein lacking 39 amino acids on the N-terminal region. SMC3 p.C549Y is located in the hinge domain of SMC3 and enhances the hinge binding to SMC1 in vitro. Further we identified two protein truncating variants in NIPBL (P.E2656*, p.E2696Sfs*6) and a RSV in SMC3 (P.R199K) in three CHH patients without diagnosis of CdLS. Both Nipbl and Smc3 are highly expressed along the GnRH migratory path from the nose to the hypothalamus. Knock down of Smc3 and Nipbl in GnRH-GFP zebrafish led to reduced GnRH neuron numbers, indicating their implication in GnRH neuron biology.

Conclusions: Pathogenic variants in cohesion genes (NIPBL and SMC3) underlie CHH with or without CdLS and implicate cohesion complex in GnRH neuron biology. Transcriptomic and DNA accessibility (ATAC-seq) studies in zebrafish and fibroblasts from the SMC3-mutated patient are underway to further explore the common mechanism of these two rare developmental diseases.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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