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

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Dal, Jakob ; Nielsen, Eigil H ; Klose, Marianne ; Feldt-Rasmussen, Ulla ; Andersen, Marianne ; Vang, Søren ; Korbonits, Márta ; Jørgensen, Jens Otto L. / Phenotypic and genotypic features of a large kindred with a germline AIP variant. In: Clinical Endocrinology. 2020 ; Vol. 93, No. 2. pp. 146-153.

Bibtex

@article{6bc12e4d2d844aa0811cd764d43a3b60,
title = "Phenotypic and genotypic features of a large kindred with a germline AIP variant",
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.",
keywords = "acromegaly, AIP gene variant, familial acromegaly, GH, gigantism, IGF-I, pituitary adenoma",
author = "Jakob Dal and Nielsen, {Eigil H} and Marianne Klose and Ulla Feldt-Rasmussen and Marianne Andersen and S{\o}ren Vang and M{\'a}rta Korbonits and J{\o}rgensen, {Jens Otto L}",
note = "{\textcopyright} 2020 John Wiley & Sons Ltd.",
year = "2020",
doi = "10.1111/cen.14207",
language = "English",
volume = "93",
pages = "146--153",
journal = "Clinical Endocrinology",
issn = "0300-0664",
publisher = "Wiley-Blackwell Publishing Ltd",
number = "2",

}

RIS

TY - JOUR

T1 - Phenotypic and genotypic features of a large kindred with a germline AIP variant

AU - Dal, Jakob

AU - Nielsen, Eigil H

AU - Klose, Marianne

AU - Feldt-Rasmussen, Ulla

AU - Andersen, Marianne

AU - Vang, Søren

AU - Korbonits, Márta

AU - Jørgensen, Jens Otto L

N1 - © 2020 John Wiley & Sons Ltd.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - acromegaly

KW - AIP gene variant

KW - familial acromegaly

KW - GH

KW - gigantism

KW - IGF-I

KW - pituitary adenoma

U2 - 10.1111/cen.14207

DO - 10.1111/cen.14207

M3 - Journal article

C2 - 32324286

VL - 93

SP - 146

EP - 153

JO - Clinical Endocrinology

JF - Clinical Endocrinology

SN - 0300-0664

IS - 2

ER -

ID: 59977616