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Identification of genetic variants and phenotypic characterization of a large cohort of patients with congenital hypopituitarism and related disorders

Gregory, Louise C; Cionna, Cecilia; Cerbone, Manuela; GOSgene; Dattani, Mehul T; (2023) Identification of genetic variants and phenotypic characterization of a large cohort of patients with congenital hypopituitarism and related disorders. Genetics in Medicine , 25 (9) , Article 100881. 10.1016/j.gim.2023.100881. Green open access

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Abstract

PURPOSE: Congenital hypopituitarism (CH) disorders are phenotypically variable. Variants in multiple genes are associated with these disorders, with variable penetrance and inheritance. METHODS: We screened a large cohort (N = 1765) of patients with or at risk of CH using Sanger sequencing, selected according to phenotype, and conducted next-generation sequencing (NGS) in 51 families within our cohort. We report the clinical, hormonal, and neuroradiological phenotypes of patients with variants in known genes associated with CH. RESULTS: We identified variants in 178 patients: GH1/GHRHR (51 patients of 414 screened), PROP1 (17 of 253), POU1F1 (15 of 139), SOX2 (13 of 59), GLI2 (7 of 106), LHX3/LHX4 (8 of 110), HESX1 (8 of 724), SOX3 (9 of 354), OTX2 (5 of 59), SHH (2 of 64), and TCF7L1, KAL1, FGFR1, and FGF8 (2 of 585, respectively). NGS identified 26 novel variants in 35 patients (from 24 families). Magnetic resonance imaging showed prevalent hypothalamo-pituitary abnormalities, present in all patients with PROP1, GLI2, SOX3, HESX1, OTX2, LHX3, and LHX4 variants. Normal hypothalamo-pituitary anatomy was reported in 24 of 121, predominantly those with GH1, GHRHR, POU1F1, and SOX2 variants. CONCLUSION: We identified variants in 10% (178 of 1765) of our CH cohort. NGS has revolutionized variant identification, and careful phenotypic patient characterization has improved our understanding of CH. We have constructed a flow chart to guide genetic analysis in these patients, which will evolve upon novel gene discoveries.

Type: Article
Title: Identification of genetic variants and phenotypic characterization of a large cohort of patients with congenital hypopituitarism and related disorders
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.gim.2023.100881
Publisher version: https://doi.org/10.1016/j.gim.2023.100881
Language: English
Additional information: © 2023 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Keywords: Congenital hypopituitarism, Endocrinology, Genetic analysis, Hypothalamo-pituitary development
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10173299
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