Chromatin conformation capture in the clinic: 4C-seq/HiC distinguishes pathogenic from neutral duplications at the GPR101 locus.
4C
Chromosome microarray
Enhancer
GPR101
HiC
Neo-TAD
Pituitary tumor
Prenatal diagnosis
Topologically associating domains
X-linked acrogigantism
Journal
Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844
Informations de publication
Date de publication:
13 Sep 2024
13 Sep 2024
Historique:
received:
16
05
2024
accepted:
23
08
2024
medline:
14
9
2024
pubmed:
14
9
2024
entrez:
13
9
2024
Statut:
epublish
Résumé
X-linked acrogigantism (X-LAG; MIM: 300942) is a severe form of pituitary gigantism caused by chromosome Xq26.3 duplications involving GPR101. X-LAG-associated duplications disrupt the integrity of the topologically associating domain (TAD) containing GPR101 and lead to the formation of a neo-TAD that drives pituitary GPR101 misexpression and gigantism. As X-LAG is fully penetrant and heritable, duplications involving GPR101 identified on prenatal screening studies, like amniocentesis, can pose an interpretation challenge for medical geneticists and raise important concerns for patients and families. Therefore, providing robust information on the functional genomic impact of such duplications has important research and clinical value with respect to gene regulation and triplosensitivity traits. We employed 4C/HiC-seq as a clinical tool to determine the functional impact of incidentally discovered GPR101 duplications on TAD integrity in three families. After defining duplications and breakpoints around GPR101 by clinical-grade and high-density aCGH, we constructed 4C/HiC chromatin contact maps for our study population and compared them with normal and active (X-LAG) controls. We showed that duplications involving GPR101 that preserved the centromeric invariant TAD boundary did not generate a pathogenic neo-TAD and that ectopic enhancers were not adopted. This allowed us to discount presumptive/suspected X-LAG diagnoses and GPR101 misexpression, obviating the need for intensive clinical follow-up. This study highlights the importance of TAD boundaries and chromatin interactions in determining the functional impact of copy number variants and provides proof-of-concept for using 4C/HiC-seq as a clinical tool to acquire crucial information for genetic counseling and to support clinical decision-making in cases of suspected TADopathies.
Sections du résumé
BACKGROUND
BACKGROUND
X-linked acrogigantism (X-LAG; MIM: 300942) is a severe form of pituitary gigantism caused by chromosome Xq26.3 duplications involving GPR101. X-LAG-associated duplications disrupt the integrity of the topologically associating domain (TAD) containing GPR101 and lead to the formation of a neo-TAD that drives pituitary GPR101 misexpression and gigantism. As X-LAG is fully penetrant and heritable, duplications involving GPR101 identified on prenatal screening studies, like amniocentesis, can pose an interpretation challenge for medical geneticists and raise important concerns for patients and families. Therefore, providing robust information on the functional genomic impact of such duplications has important research and clinical value with respect to gene regulation and triplosensitivity traits.
METHODS
METHODS
We employed 4C/HiC-seq as a clinical tool to determine the functional impact of incidentally discovered GPR101 duplications on TAD integrity in three families. After defining duplications and breakpoints around GPR101 by clinical-grade and high-density aCGH, we constructed 4C/HiC chromatin contact maps for our study population and compared them with normal and active (X-LAG) controls.
RESULTS
RESULTS
We showed that duplications involving GPR101 that preserved the centromeric invariant TAD boundary did not generate a pathogenic neo-TAD and that ectopic enhancers were not adopted. This allowed us to discount presumptive/suspected X-LAG diagnoses and GPR101 misexpression, obviating the need for intensive clinical follow-up.
CONCLUSIONS
CONCLUSIONS
This study highlights the importance of TAD boundaries and chromatin interactions in determining the functional impact of copy number variants and provides proof-of-concept for using 4C/HiC-seq as a clinical tool to acquire crucial information for genetic counseling and to support clinical decision-making in cases of suspected TADopathies.
Identifiants
pubmed: 39272130
doi: 10.1186/s13073-024-01378-5
pii: 10.1186/s13073-024-01378-5
doi:
Substances chimiques
Receptors, G-Protein-Coupled
0
Chromatin
0
GPR101 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
112Subventions
Organisme : Fondazione Telethon
ID : GGP20130
Organisme : Centre Hospitalier Universitaire de Liège
ID : 2018/20
Organisme : Eunice Kennedy Shriver National Institute of Child Health and Human Development
ID : Z1A HD008920
Organisme : National Institute of Health (NINDS)
ID : R35NS105078
Organisme : Ministero della Salute
ID : Ricerca Corrente"
Organisme : Ministero della Salute
ID : T3-AN-14 "LifeMap"
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca
ID : PRIN PNRR 2022
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca
ID : PRIN 2022
Organisme : 'la Caixa' Foundation
ID : 100010434
Organisme : 'la Caixa' Foundation
ID : fellowship code LCF/BQ/PR22/11920006
Informations de copyright
© 2024. The Author(s).
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