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Endocrine Abstracts (2020) 70 AEP788 | DOI: 10.1530/endoabs.70.AEP788

1Lausanne University Hospital, Service of Endocrinology, Diabetology & Metabolism, Lausanne, Switzerland; 2Hospital S João, Department of Endocrinology, Porto, Portugal; 3University Medical Centre Ljubljana, Ljubljana, Slovenia; 4Brigham and Women’s Hospital, Center for Infertility and Reproductive Surgery, Boston, United States; 5Massachusetts General Hospital, Center for Genomic Medicine, Boston, United States

Background: Congenital hypogonadotropic hypogonadism (CHH), a clinically and genetic heterogenous sydrome, is caused by > 40 known loci whose mutations share the ability to cause defects in the ontogeny of the GnRH neuron network leading to absent/incomplete puberty and infertility. Cornelia de Lange Syndrome (CdLS) is similarly heterogenous disorder (distinctive facies, psychomotor delay, growth retardation and upper limb malformation) caused by mutations in 7 different genes in the cohension complex with a subset who share CHH phenotypes including cryptorchidism, micropenis, and/or delayed puberty, suggesting hypogonadism, although formal endocrine evaluation is lacking.

Methods: Given thephenotypic overlap between these syndromes, exome sequencing was performed in probands with clinical features of both CHH and CdLS or CHH alone, focusing specifically on pathogenic variants in known 7 CdLS genes (SMC3, NIPBL, SMC1A, RAD21, HDAC8, BRD4 and ANKRD11). In vitro assays were performed on identified mutants and GnRH3:GFP zebrafish were used to explore the pathogenic role of SMC3 and NIPBL in GnRH neuron development.

Results: Exome sequencing revealed 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 CHH and CdLS, all of which were absent in gnomAD controls.NIPBLp.R2298C has previously been reported in CdLS patients and is considered to be pathogenic. NIPBLp.P2761Cfs*4may escape nonsense-mediated decay, thus leading to a truncated NIBPL protein that lacksits 39 N-terminal amino acids. SMC3 C549 residue is located in the hinge domain of SMC3, and C549Y enhances the hinge binding to SMC1 in vitro. We also identified two novel protein truncating variants in NIPBL (p.E2656*& p.E2696Sfs*6) in different CHH patients without a CdLS diagnosis. Both Nipbl and Smc3 are highly expressed along the migratory path of GnRH neurons from the nasal placode to the hypothalamus. Knock down of Smc3 and Nipbl in GnRH3:GFP zebrafish reduced GnRH neuron numbers, indicating their implication in GnRH neuron biology.

Conclusion: Novel pathogenic variants in cohesion genes (NIPBL and SMC3) underly CHH with or without CdLS implicating the 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 70

22nd European Congress of Endocrinology

05 Sep 2020 - 09 Sep 2020

European Society of Endocrinology 

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