Cargando…
Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic
PURPOSE: Congenital hypopituitarism usually occurs sporadically. In most patients, the etiology remains unknown. METHODS: We studied 13 children with sporadic congenital hypopituitarism. Children with non-endocrine, non-familial idiopathic short stature (NFSS) (n = 19) served as a control group. Exo...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386283/ https://www.ncbi.nlm.nih.gov/pubmed/34456972 http://dx.doi.org/10.3389/fgene.2021.697549 |
_version_ | 1783742230703374336 |
---|---|
author | Jee, Youn Hee Gangat, Mariam Yeliosof, Olga Temnycky, Adrian G. Vanapruks, Selena Whalen, Philip Gourgari, Evgenia Bleach, Cortney Yu, Christine H. Marshall, Ian Yanovski, Jack A. Link, Kathleen Ten, Svetlana Baron, Jeffrey Radovick, Sally |
author_facet | Jee, Youn Hee Gangat, Mariam Yeliosof, Olga Temnycky, Adrian G. Vanapruks, Selena Whalen, Philip Gourgari, Evgenia Bleach, Cortney Yu, Christine H. Marshall, Ian Yanovski, Jack A. Link, Kathleen Ten, Svetlana Baron, Jeffrey Radovick, Sally |
author_sort | Jee, Youn Hee |
collection | PubMed |
description | PURPOSE: Congenital hypopituitarism usually occurs sporadically. In most patients, the etiology remains unknown. METHODS: We studied 13 children with sporadic congenital hypopituitarism. Children with non-endocrine, non-familial idiopathic short stature (NFSS) (n = 19) served as a control group. Exome sequencing was performed in probands and both unaffected parents. A burden testing approach was used to compare the number of candidate variants in the two groups. RESULTS: First, we assessed the frequency of rare, predicted-pathogenic variants in 42 genes previously reported to be associated with pituitary gland development. The average number of variants per individual was greater in probands with congenital hypopituitarism than those with NFSS (1.1 vs. 0.21, mean variants/proband, P = 0.03). The number of probands with at least 1 variant in a pituitary-associated gene was greater in congenital hypopituitarism than in NFSS (62% vs. 21%, P = 0.03). Second, we assessed the frequency of rare, predicted-pathogenic variants in the exome (to capture undiscovered causes) that were inherited in a fashion that could explain the sporadic occurrence of the proband’s condition with a monogenic etiology (de novo mutation, autosomal recessive, or X-linked recessive) with complete penetrance. There were fewer monogenic candidates in the probands with congenital hypopituitarism than those with NFSS (1.3 vs. 2.5 candidate variants/proband, P = 0.024). We did not find any candidate variants (0 of 13 probands) in genes previously reported to explain the phenotype in congenital hypopituitarism, unlike NFSS (8 of 19 probands, P = 0.01). CONCLUSION: Our findings provide evidence that the etiology of sporadic congenital hypopituitarism has a major genetic component but may be infrequently monogenic with full penetrance, suggesting a more complex etiology. |
format | Online Article Text |
id | pubmed-8386283 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-83862832021-08-26 Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic Jee, Youn Hee Gangat, Mariam Yeliosof, Olga Temnycky, Adrian G. Vanapruks, Selena Whalen, Philip Gourgari, Evgenia Bleach, Cortney Yu, Christine H. Marshall, Ian Yanovski, Jack A. Link, Kathleen Ten, Svetlana Baron, Jeffrey Radovick, Sally Front Genet Genetics PURPOSE: Congenital hypopituitarism usually occurs sporadically. In most patients, the etiology remains unknown. METHODS: We studied 13 children with sporadic congenital hypopituitarism. Children with non-endocrine, non-familial idiopathic short stature (NFSS) (n = 19) served as a control group. Exome sequencing was performed in probands and both unaffected parents. A burden testing approach was used to compare the number of candidate variants in the two groups. RESULTS: First, we assessed the frequency of rare, predicted-pathogenic variants in 42 genes previously reported to be associated with pituitary gland development. The average number of variants per individual was greater in probands with congenital hypopituitarism than those with NFSS (1.1 vs. 0.21, mean variants/proband, P = 0.03). The number of probands with at least 1 variant in a pituitary-associated gene was greater in congenital hypopituitarism than in NFSS (62% vs. 21%, P = 0.03). Second, we assessed the frequency of rare, predicted-pathogenic variants in the exome (to capture undiscovered causes) that were inherited in a fashion that could explain the sporadic occurrence of the proband’s condition with a monogenic etiology (de novo mutation, autosomal recessive, or X-linked recessive) with complete penetrance. There were fewer monogenic candidates in the probands with congenital hypopituitarism than those with NFSS (1.3 vs. 2.5 candidate variants/proband, P = 0.024). We did not find any candidate variants (0 of 13 probands) in genes previously reported to explain the phenotype in congenital hypopituitarism, unlike NFSS (8 of 19 probands, P = 0.01). CONCLUSION: Our findings provide evidence that the etiology of sporadic congenital hypopituitarism has a major genetic component but may be infrequently monogenic with full penetrance, suggesting a more complex etiology. Frontiers Media S.A. 2021-08-11 /pmc/articles/PMC8386283/ /pubmed/34456972 http://dx.doi.org/10.3389/fgene.2021.697549 Text en Copyright © 2021 Jee, Gangat, Yeliosof, Temnycky, Vanapruks, Whalen, Gourgari, Bleach, Yu, Marshall, Yanovski, Link, Ten, Baron and Radovick. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Genetics Jee, Youn Hee Gangat, Mariam Yeliosof, Olga Temnycky, Adrian G. Vanapruks, Selena Whalen, Philip Gourgari, Evgenia Bleach, Cortney Yu, Christine H. Marshall, Ian Yanovski, Jack A. Link, Kathleen Ten, Svetlana Baron, Jeffrey Radovick, Sally Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic |
title | Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic |
title_full | Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic |
title_fullStr | Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic |
title_full_unstemmed | Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic |
title_short | Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic |
title_sort | evidence that the etiology of congenital hypopituitarism has a major genetic component but is infrequently monogenic |
topic | Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386283/ https://www.ncbi.nlm.nih.gov/pubmed/34456972 http://dx.doi.org/10.3389/fgene.2021.697549 |
work_keys_str_mv | AT jeeyounhee evidencethattheetiologyofcongenitalhypopituitarismhasamajorgeneticcomponentbutisinfrequentlymonogenic AT gangatmariam evidencethattheetiologyofcongenitalhypopituitarismhasamajorgeneticcomponentbutisinfrequentlymonogenic AT yeliosofolga evidencethattheetiologyofcongenitalhypopituitarismhasamajorgeneticcomponentbutisinfrequentlymonogenic AT temnyckyadriang evidencethattheetiologyofcongenitalhypopituitarismhasamajorgeneticcomponentbutisinfrequentlymonogenic AT vanapruksselena evidencethattheetiologyofcongenitalhypopituitarismhasamajorgeneticcomponentbutisinfrequentlymonogenic AT whalenphilip evidencethattheetiologyofcongenitalhypopituitarismhasamajorgeneticcomponentbutisinfrequentlymonogenic AT gourgarievgenia evidencethattheetiologyofcongenitalhypopituitarismhasamajorgeneticcomponentbutisinfrequentlymonogenic AT bleachcortney evidencethattheetiologyofcongenitalhypopituitarismhasamajorgeneticcomponentbutisinfrequentlymonogenic AT yuchristineh evidencethattheetiologyofcongenitalhypopituitarismhasamajorgeneticcomponentbutisinfrequentlymonogenic AT marshallian evidencethattheetiologyofcongenitalhypopituitarismhasamajorgeneticcomponentbutisinfrequentlymonogenic AT yanovskijacka evidencethattheetiologyofcongenitalhypopituitarismhasamajorgeneticcomponentbutisinfrequentlymonogenic AT linkkathleen evidencethattheetiologyofcongenitalhypopituitarismhasamajorgeneticcomponentbutisinfrequentlymonogenic AT tensvetlana evidencethattheetiologyofcongenitalhypopituitarismhasamajorgeneticcomponentbutisinfrequentlymonogenic AT baronjeffrey evidencethattheetiologyofcongenitalhypopituitarismhasamajorgeneticcomponentbutisinfrequentlymonogenic AT radovicksally evidencethattheetiologyofcongenitalhypopituitarismhasamajorgeneticcomponentbutisinfrequentlymonogenic |