Reassessing the role of the p.(Arg304Gln) missense AIP variant in pituitary tumorigenesis.

IF 5.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Paul Benjamin Loughrey, Nadira B Mothojakan, Donato Iacovazzo, Ankit Arni, Elena D Aflorei, Giorgio Arnaldi, Anne Barlier, Albert Beckers, Mariana F Bizzi, Philippe Chanson, Jakob Dal, Adrian F Daly, Mary N Dang, Alessia David, Matheus de Oliveira Andrade, Tobias Else, Marianne S Elston, Amy Evans, Francesco Ferrau, Simona Fica, Daniel Flanagan, Monica R Gadelha, Ashley B Grossman, Sonal Kapur, Bernard Khoo, Ajith V Kumar, Chandan Kumar-Sinha, Ronald M Lechan, Mark Ludman, Louise A Metherell, Dragana Miljic, Vishnou Mourougavelou, Madalina Musat, Gianluca Occhi, Martina Owens, Ionela Pascanu, Sergio V B Pinheiro, Serban Radian, Antonio Ribeiro-Oliveira, Christof Schöfl, Kashyap A Patel, Laura C Hernández-Ramírez, Márta Korbonits
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引用次数: 0

Abstract

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: 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 with 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 < .001). R304Q cohort was older at disease onset and diagnosis than the AIPmut cohort (median [quartiles] onset: 25 y [16-35] vs 16 y [14-23], P < .001; median [quartiles] diagnosis: 36 y [24-44] vs 21 y [15-29], P < .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.

重新评估p.(Arg304Gln)错义AIP变异在垂体肿瘤发生中的作用。
目的:AIP的杂合子生殖系功能丧失变异与年轻发病的生长激素和/或泌乳素分泌垂体肿瘤有关。然而,c.911G . >;p.(Arg304Gln) (R304Q) AIP变体一直存在争议。最近来自公共外显子组/基因组数据库的数据表明,这种变异并不罕见。这项工作的目的是基于临床、基因组和功能分析数据重新评估R304Q的致病性。设计、材料和方法:数据收集已发表的R304Q垂体神经内分泌肿瘤病例,以及国际家族性孤立性垂体腺瘤联盟R304Q病例(n=38, R304Q队列)。评估临床特征、人群队列频率、计算分析、预测模型、杂合缺失的存在以及体外/体内功能研究,并与致病性/可能致病性AIP变异患者(AIPmut队列,n=184)的数据进行比较。结果:38例R304Q患者中,61%(23/38)存在生长激素过量,而AIPmut队列中这一比例为80%(147/184)。结论:有证据表明R304Q对垂体神经内分泌肿瘤无致病性。我们建议将这种变异分类为可能是良性的,并且不建议对家庭成员进行症状前基因检测或对已确定的未受影响的R304Q变异个体进行随访。
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来源期刊
European Journal of Endocrinology
European Journal of Endocrinology 医学-内分泌学与代谢
CiteScore
9.80
自引率
3.40%
发文量
354
审稿时长
1 months
期刊介绍: European Journal of Endocrinology is the official journal of the European Society of Endocrinology. Its predecessor journal is Acta Endocrinologica. The journal publishes high-quality original clinical and translational research papers and reviews in paediatric and adult endocrinology, as well as clinical practice guidelines, position statements and debates. Case reports will only be considered if they represent exceptional insights or advances in clinical endocrinology. Topics covered include, but are not limited to, Adrenal and Steroid, Bone and Mineral Metabolism, Hormones and Cancer, Pituitary and Hypothalamus, Thyroid and Reproduction. In the field of Diabetes, Obesity and Metabolism we welcome manuscripts addressing endocrine mechanisms of disease and its complications, management of obesity/diabetes in the context of other endocrine conditions, or aspects of complex disease management. Reports may encompass natural history studies, mechanistic studies, or clinical trials. Equal consideration is given to all manuscripts in English from any country.
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