| Title: | Reassessing the role of the p.(Arg304Gln) missense AIP variant in pituitary tumorigenesis |
| Journal: | European Journal of Endocrinology |
| Published: | 12 Mar 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40070360/ |
| DOI: | https://doi.org/10.1093/ejendo/lvaf044 |
| URL: | https://orbi.uliege.be/handle/2268/329357 |
Publication 15609
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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.</p>
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).</p>
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.</p>
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.</p>
13 Keywords
- Adenoma
- Adult
- Carcinogenesis
- Cohort Studies
- Female
- Growth Hormone-Secreting Pituitary Adenoma
- Humans
- Intracellular Signaling Peptides and Proteins
- Male
- Middle Aged
- Mutation, Missense
- Pituitary Neoplasms
- Young Adult
43 Authors
- 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
1 Application
| Application ID | Title |
|---|---|
| 103356 | Understanding the role of rare and common genetic variation in human phenotypes |
Enabling scientific discoveries that improve human health