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

Jakob Dal, Eigil H Nielsen, Marianne Klose, Ulla Feldt-Rasmussen, Marianne Andersen, Søren Vang, Márta Korbonits, Jens Otto L Jørgensen

    3 Citationer (Scopus)

    Abstract

    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.

    OriginalsprogEngelsk
    TidsskriftClinical Endocrinology
    Vol/bind93
    Udgave nummer2
    Sider (fra-til)146-153
    Antal sider8
    ISSN0300-0664
    DOI
    StatusUdgivet - 2020

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