Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort.

Autor: Hendricks LAJ; Department of Human Genetics, Radboudumc Expert Center for PHTS, Radboud university medical center, Nijmegen, the Netherlands; Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, the Netherlands., Hoogerbrugge N; Department of Human Genetics, Radboudumc Expert Center for PHTS, Radboud university medical center, Nijmegen, the Netherlands; Radboud university medical center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands., Venselaar H; Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, the Netherlands., Aretz S; Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany; Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany., Spier I; Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany; Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany., Legius E; Department of Human Genetics, University of Leuven, Leuven, Belgium., Brems H; Department of Human Genetics, University of Leuven, Leuven, Belgium., de Putter R; Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium., Claes KBM; Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium., Evans DG; Manchester Centre for Genomic Medicine, St Mary's Hospital, Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK., Woodward ER; Manchester Centre for Genomic Medicine, St Mary's Hospital, Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK., Genuardi M; Department of Laboratory and Infectious Diseases, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Medical Genetics Section, Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy., Brugnoletti F; Department of Laboratory and Infectious Diseases, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy., van Ierland Y; Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands; ENCORE Expertise Center, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, the Netherlands., Dijke K; Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands., Tham E; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden., Tesi B; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden., Schuurs-Hoeijmakers JHM; Department of Human Genetics, Radboudumc Expert Center for PHTS, Radboud university medical center, Nijmegen, the Netherlands., Branchaud M; Department of Genetics, Normandy Center for Genomic and Personalized Medicine, Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France., Salvador H; Department of Oncology, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain., Jahn A; Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Hereditary Cancer Syndrome Center Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany., Schnaiter S; Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria., Anastasiadou VC; Karaiskakio Foundation, Nicosia Cyprus and Archbishop Makarios III Children's Hospital, Cyprus., Brunet J; Hereditary Cancer Program, Catalan Institute of Oncology, ONCOBELL-IDIBELL-IDIBGI-IGTP, CIBERONC, Barcelona, 08908, Spain., Oliveira C; Instituto de Investigação e Inovação em Saúde & Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; Department of Pathology, University of Porto, Porto, Portugal., Roht L; Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia., Blatnik A; Department of Clinical Cancer Genetics, Institute of Oncology Ljubljana, Ljubljana, Slovenia., Irmejs A; Institute of Oncology, Riga Stradins University, Riga, Latvia; Breast Unit, Pauls Stradins Clinical University Hospital, Riga, Latvia., Mensenkamp AR; Department of Human Genetics, Radboudumc Expert Center for PHTS, Radboud university medical center, Nijmegen, the Netherlands; Radboud university medical center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands., Vos JR; Department of Human Genetics, Radboudumc Expert Center for PHTS, Radboud university medical center, Nijmegen, the Netherlands; Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, the Netherlands. Electronic address: janet.vos@radboudumc.nl.
Jazyk: angličtina
Zdroj: European journal of medical genetics [Eur J Med Genet] 2022 Dec; Vol. 65 (12), pp. 104632. Date of Electronic Publication: 2022 Oct 18.
DOI: 10.1016/j.ejmg.2022.104632
Abstrakt: Background: Pathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and genotype-phenotype associations could help diagnostics and potentially lead to personalized care. Therefore, we assessed the PHTS genotype and phenotype spectrum in a large cohort study.
Methods: Information was collected of 510 index patients with pathogenic or likely pathogenic (LP/P) PTEN variants (n = 467) or variants of uncertain significance. Genotype-phenotype associations were assessed using logistic regression analyses adjusted for sex and age.
Results: At time of genetic testing, the majority of children (n = 229) had macrocephaly (81%) or developmental delay (DD, 61%), and about half of the adults (n = 238) had cancer (51%), macrocephaly (61%), or cutaneous pathology (49%). Across PTEN, 268 LP/P variants were identified, with exon 5 as hotspot. Missense variants (n = 161) were mainly located in the phosphatase domain (PD, 90%) and truncating variants (n = 306) across all domains. A trend towards 2 times more often truncating variants was observed in adults (OR = 2.3, 95%CI = 1.5-3.4) and patients with cutaneous pathology (OR = 1.6, 95%CI = 1.1-2.5) or benign thyroid pathology (OR = 2.0, 95%CI = 1.1-3.5), with trends up to 2-4 times more variants in PD. Whereas patients with DD (OR = 0.5, 95%CI = 0.3-0.9) or macrocephaly (OR = 0.6, 95%CI = 0.4-0.9) had about 2 times less often truncating variants compared to missense variants. In DD patients these missense variants were often located in domain C2.
Conclusion: The PHTS phenotypic diversity may partly be explained by the PTEN variant coding effect and the combination of coding effect and domain. PHTS patients with early-onset disease often had missense variants, and those with later-onset disease often truncating variants.
Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare.
(Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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