Chromatin conformation capture in the clinic: 4C-seq/HiC distinguishes pathogenic from neutral duplications at the GPR101 locus.

Autor: Daly AF; Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Liège, Belgium., Dunnington LA; Department of Pediatrics, Division of Medical Genetics, McGovern Medical School, University of Texas Health Science Center (UTHealth Houston), Houston, TX, USA.; Memorial Hermann-Texas Medical Center, University of Texas Health Science Center at Houston, Houston, TX, USA., Rodriguez-Buritica DF; Department of Pediatrics, Division of Medical Genetics, McGovern Medical School, University of Texas Health Science Center (UTHealth Houston), Houston, TX, USA.; Memorial Hermann-Texas Medical Center, University of Texas Health Science Center at Houston, Houston, TX, USA., Spiegel E; Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY, 10032, USA., Brancati F; Department of Life, Health and Environmental Sciences, University of L'Aquila, Via Spennati N.1, L'Aquila, 67010, Italy.; Human Functional Genetics Laboratory, IRCCS San Raffaele Roma, Rome, Italy., Mantovani G; Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy., Rawal VM; Austin Diagnostic Clinic, 2400 Cedar Bend Dr, Austin, TX, 78758, USA., Faucz FR; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, MD, USA., Hijazi H; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Caberg JH; Department of Human Genetics, Centre Hospitalier Universitaire de Liège, University of Liège, Liège, Belgium., Nardone AM; Medical Genetics Laboratory, Policlinico Tor Vergata Hospital, Viale Oxford 81, Rome, 00133, Italy., Bengala M; Medical Genetics Laboratory, Policlinico Tor Vergata Hospital, Viale Oxford 81, Rome, 00133, Italy., Fortugno P; Human Functional Genetics Laboratory, IRCCS San Raffaele Roma, Rome, Italy.; Università Telematica San Raffaele, Rome, Italy., Del Sindaco G; Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy., Ragonese M; Department of Human Pathology of Adulthood and Childhood DETEV, Endocrinology Unit, University of Messina, 98125, Messina, Italy., Gould H; Austin Maternal Fetal Medicine, 12200 Renfert Way Ste G3, Austin, TX, 78758, USA., Cannavò S; Department of Human Pathology of Adulthood and Childhood DETEV, Endocrinology Unit, University of Messina, 98125, Messina, Italy., Pétrossians P; Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Liège, Belgium., Lania A; Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, Milan, 20072, Italy.; IRCCS Humanitas Research Hospital, Milan, Italy., Lupski JR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Hospital, Houston, TX, USA., Beckers A; Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Liège, Belgium., Stratakis CA; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, MD, USA.; Human Genetics and Precision Medicine, Institute of Molecular Biology and Biotechnology (IMBB), Foundation for Research and Technology Hellas, Heraklion, Greece.; ASTREA Health, Athens, Greece., Levy B; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA., Trivellin G; Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, Milan, 20072, Italy. giampaolo.trivellin@hunimed.eu.; IRCCS Humanitas Research Hospital, Milan, Italy. giampaolo.trivellin@hunimed.eu., Franke M; Andalusian Center for Developmental Biology (CABD), Junta de Andalucia - Universidad Pablo de Olavide (UPO) - Consejo Superior de Investigaciones Cientificas (CSIC), Seville, Spain. mfra2@upo.es.
Jazyk: angličtina
Zdroj: Genome medicine [Genome Med] 2024 Sep 13; Vol. 16 (1), pp. 112. Date of Electronic Publication: 2024 Sep 13.
DOI: 10.1186/s13073-024-01378-5
Abstrakt: 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: 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: 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: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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