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

in European journal of endocrinology by 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

TLDR

  • The study found that the R304Q variant in the AIP gene is not pathogenic for pituitary neuroendocrine tumour, and it is recommended to classify the variant as likely benign. Pre-symptomatic genetic testing and follow-up of unaffected individuals are not recommended.

Abstract

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. 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). 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. 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.

Overview

  • The study reassessed the pathogenicity of the c.911G>A; p.(Arg304Gln) (R304Q) AIP variant, previously associated with young-onset growth hormone and/or prolactin-secreting pituitary tumours.
  • The authors collected clinical, genomic, and functional data from 38 R304Q pituitary neuroendocrine tumour cases (R304Q cohort) and 184 pathogenic/likely pathogenic AIP variant patients (AIPmut cohort).
  • The main objective was to determine whether R304Q is pathogenic for pituitary neuroendocrine tumour and to provide recommendations for variant classification and genetic testing.

Comparative Analysis & Findings

  • In the R304Q cohort, 61% of patients had growth hormone excess, which is lower than the 80% observed in the AIPmut cohort (p<0.001).
  • The R304Q cohort was older at disease onset and diagnosis than the AIPmut cohort (median onset: 25y vs 16y, p<0.001; median diagnosis: 36y vs 21y, p<0.001).
  • In silico predictions and experimental data were conflicting, with no loss-of-heterozygosity detected in four R304Q pituitary neuroendocrine tumour samples.

Implications and Future Directions

  • The study suggests that R304Q is not pathogenic for pituitary neuroendocrine tumour, and it is recommended to classify the variant as likely benign.
  • The authors do not recommend pre-symptomatic genetic testing of family members or follow-up of already identified unaffected individuals with the R304Q variant.
  • Further studies are needed to elucidate the mechanisms underlying heterozygous germline loss-of-function variants in AIP and to develop effective predictive models for pituitary tumour risk.
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