[en] OBJECTIVE: Heterozygous germline loss-of-function variants in AIP are associated with young-onset growth hormone and/or prolactin-secreting pituitary tumours. However, the pathogenic role of the c.911G>A; p.(Arg304Gln) (R304Q) AIP variant has been controversial. Recent data from public exome/genome databases show this variant is not infrequent. The objective of this work was to reassess the pathogenicity of R304Q based on clinical, genomic and functional assay data.
DESIGN, MATERIALS AND METHODS: Data were collected on published R304Q pituitary neuroendocrine tumour cases, and from International Familial Isolated Pituitary Adenoma Consortium R304Q cases (n=38, R304Q cohort). Clinical features, population cohort frequency, computational analyses, prediction models, presence of loss-of-heterozygosity and in vitro/in vivo functional studies were assessed and compared to data from pathogenic/likely pathogenic AIP variant patients (AIPmut cohort, n=184).
RESULTS: Of 38 R304Q patients, 61% (23/38) had growth hormone excess, in contrast to 80% of AIPmut cohort (147/184, p<0.001). R304Q cohort was older at disease onset and diagnosis than the AIPmut cohort (median (quartiles) onset: 25y (16-35) vs 16y (14-23), p<0.001; median (quartiles) diagnosis: 36y (24-44) vs 21y (15-29), p<0.001). R304Q is present in gnomADv2.1 (0.31%) and UK Biobank (0.16%), including three persons with homozygous R304Q. No loss-of-heterozygosity was detected in four R304Q pituitary neuroendocrine tumour samples. In silico predictions and experimental data were conflicting.
CONCLUSIONS: Evidence suggests that R304Q is not pathogenic for pituitary neuroendocrine tumour. We recommend changing this variant classification to likely benign, and do not recommend pre-symptomatic genetic testing of family members or follow up of already identified unaffected individuals with the R304Q variant.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Loughrey, Paul Benjamin ; Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, UK ; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
Mothojakan, Nadira B; Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, UK
Iacovazzo, Donato; Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, UK
Arni, Ankit; Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK
Aflorei, Elena D; Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, UK
Arnaldi, Giorgio; Section of Endocrinology, PROMISE, University of Palermo, Palermo, Italy ; Unità Operativa Complessa of Endocrine Diseases. A.O.U.P. Paolo Giaccone of Palermo, Italy
Barlier, Anne; Aix Marseille Univ APHM, INSERM, UMR1251 MMG, Laboratory of Molecular Biology GEnOPé, Biogénopôle, Hôpital de la Timone, Marseille, France
Beckers, Albert ; Université de Liège - ULiège > Département des sciences cliniques
Bizzi, Mariana F; Department of Internal Medicine, Federal University of Minas Gerais, Belo Horizonte/Minas Gerais, Brazil
Chanson, Philippe; Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse HYPO, Le Kremlin-Bicêtre, France
Dal, Jakob; Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
Daly, Adrian ; Université de Liège - ULiège > Département des sciences cliniques
Dang, Mary N; Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, UK
David, Alessia; Centre for Bioinformatics, Department of Life Sciences, Imperial College London, London, UK
de Oliveira Andrade, Matheus; Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, UK ; University of Brasilia, Faculty of Medicine, Brasilia, Brazil
Else, Tobias ; MEND/Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, US
Elston, Marianne S ; Waikato Clinical Campus, The University of Auckland, Hamilton, New Zealand
Evans, Amy; Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, UK
Ferrau, Francesco; Department of Human Pathology of Adulthood and Childhood 'G. Barresi', University of Messina, Messina, Italy
Fica, Simona; Endocrinology and Diabetes Department, Elias Hospital, University of Medicine and Pharmacy Carol Davila Bucharest, Bucharest, Romania
Flanagan, Daniel; Department of Endocrinology, University Hospitals Plymouth NHS Trust, Plymouth, UK
Gadelha, Monica R; Endocrinology Unit, Department of Internal Medicine, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
Grossman, Ashley B ; Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, UK
Kapur, Sonal ; Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, UK
Khoo, Bernard; Division of Medicine, University College London, Royal Free Campus, London, UK
Kumar, Ajith V; North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London, UK
Kumar-Sinha, Chandan ; Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, US
Lechan, Ronald M; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, USA
Ludman, Mark; Institute of Genetics, Meir Medical Center, Kfar Saba, Israel
Metherell, Louise A ; Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, UK
Miljic, Dragana; Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Center of Serbia, and Faculty of Medicine, University of Belgrade, Belgrade, Serbia
Mourougavelou, Vishnou; Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, UK
Musat, Madalina; National Institute of Endocrinology, University of Medicine and Pharmacy Carol Davila Bucharest, Bucharest, Romania
Occhi, Gianluca ; Department of Biology, University of Padua, Padua, Italy
Owens, Martina; Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK
Pascanu, Ionela; Department of Endocrinology, George Emil Palade University of Medicine Pharmacy Science and Technology of Targu Mures, Targu Mures, Romania
Pinheiro, Sergio V B; Department of Pediatrics, Federal University of Minas Gerais, Belo Horizonte/Minas Gerais, Brazil
Radian, Serban; Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, UK
Ribeiro-Oliveira, Antonio; Department of Internal Medicine, Federal University of Minas Gerais, Belo Horizonte/Minas Gerais, Brazil
Schöfl, Christof; Center of Endocrinology and Metabolism, Bamberg and Erlangen, Obstmarkt 1 96047 Bamberg, Germany
Patel, Kashyap A ; Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK
Hernández-Ramírez, Laura C; Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, UK ; Red de Apoyo a la Investigación, Coordinación de la Investigación Científica, Universidad Nacional Autónoma de México e Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, Mexico
Korbonits, Márta; Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, UK
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