Phenotypic and genotypic features of a large kindred with a germline AIP variant

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review


  • Jakob Dal
  • Eigil H Nielsen, Aalborg Universitet
  • ,
  • Marianne Klose, Rigshospitalet
  • ,
  • Ulla Feldt-Rasmussen, Rigshospitalet
  • ,
  • Marianne Andersen, Odense University Hospital
  • ,
  • Søren Vang
  • Márta Korbonits, Queen Mary University of London
  • ,
  • Jens Otto L Jørgensen

CONTEXT: Acromegaly is usually a sporadic disease, but familial cases occur. Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with familial pituitary adenoma predisposition. However, the pathogenicity of some AIP variants remains unclear and additional unknown genes may be involved.

OBJECTIVE: To explore the phenotype and genotype of a large kindred carrying the p.R304Q AIP variant.

METHODS: The family comprised 52 family members at risk of carrying the p.R304Q AIP variant including a case with gigantism and one with acromegaly and several family members with acromegalic features. Nine family members (three trios) underwent exome sequencing to identify putative pathogenic variants.

RESULTS: We identified 31 p.R304Q carriers, and based on two cases with somatotropinomas, the disease penetrance was 6%. We observed physical signs of acromegaly in several family members, which were independent of AIP status. Serum insulin-like growth factor-I (IGF-I) levels in all family members were above the mean for age and sex (IGF-I SDS: +0.6 [CI95% +0.4-0.9], P < .01). Exome analysis identified two candidate genes: PDE11A, known to be associated with the development of adrenal tumours, and ALG14. Ten asymptomatic p.R304Q family members (age >50 years) were screened for the PDE11A and ALG14 variant; both variants were present in five of ten persons.

CONCLUSIONS: This large family adds new information on the p.R304Q AIP variant, and data suggest two new candidate genes could be associated with growth hormone excess.

TidsskriftClinical Endocrinology
Sider (fra-til)146-153
Antal sider8
StatusUdgivet - aug. 2020

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© 2020 John Wiley & Sons Ltd.

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