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

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Phenotypic and genotypic features of a large kindred with a germline AIP variant. / Dal, Jakob; Nielsen, Eigil H; Klose, Marianne; Feldt-Rasmussen, Ulla; Andersen, Marianne; Vang, Søren; Korbonits, Márta; Jørgensen, Jens Otto L.

In: Clinical Endocrinology, Vol. 93, No. 2, 08.2020, p. 146-153.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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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{615df70fc09e4643b1b82825ff73eff7,

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 = "AIP gene variant, COHORT, FREQUENT, GH, IGF-I, INTERACTING-PROTEIN GENE, MUTATIONS, PHOSPHODIESTERASE 11A PDE11A, PITUITARY-ADENOMA PREDISPOSITION, PREVALENCE, SEQUENCE VARIANTS, YOUNG-PATIENTS, acromegaly, familial acromegaly, gigantism, 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",

month = aug,

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

PY - 2020/8

Y1 - 2020/8

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 - AIP gene variant

KW - COHORT

KW - FREQUENT

KW - GH

KW - IGF-I

KW - INTERACTING-PROTEIN GENE

KW - MUTATIONS

KW - PHOSPHODIESTERASE 11A PDE11A

KW - PITUITARY-ADENOMA PREDISPOSITION

KW - PREVALENCE

KW - SEQUENCE VARIANTS

KW - YOUNG-PATIENTS

KW - acromegaly

KW - familial acromegaly

KW - gigantism

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 -