Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort
Por:
Hendricks LAJ, Hoogerbrugge N, Venselaar H, Aretz S, Spier I, Legius E, Brems H, de Putter R, Claes KBM, Evans DG, Woodward ER, Genuardi M, Brugnoletti F, van Ierland Y, Dijke K, Tham E, Tesi B, Schuurs-Hoeijmakers JHM, Branchaud M, Salvador-Hernandez H, Jahn A, Schnaiter S, Anastasiadou VC, Brunet J, Oliveira C, Roht L, Blatnik A, Irmejs A, Mensenkamp AR and Vos JR
Publicada:
1 dic 2022
Ahead of Print:
18 oct 2022
Resumen:
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.
Filiaciones:
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-Hernandez 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
Duijkers F:
Department of Human Genetics, University of Amsterdam, the Netherlands
Giltay JC:
Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
van Hest LP:
Amsterdam UMC, Vrije Universiteit Amsterdam, Clinical Genetics, De Boelelaan, 1117, Amsterdam, Netherlands
Kleefstra T:
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
Leter EM:
Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands
Nielsen M:
Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
Nijmeijer SWR:
Department of Clinical Genetics, The Netherlands Cancer Institute, Amsterdam, the Netherlands
Olderode-Berends MJW:
Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands
Green Published, hybrid
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