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

Linda A. J. Hendricks, Nicoline Hoogerbrugge, Hanka Venselaar, Stefan Aretz, Isabel Spier, Eric Legius, Hilde Brems, Robin de Putter (UGent) , Kathleen Claes (UGent) , Gareth Evans, et al.
(2022) EUROPEAN JOURNAL OF MEDICAL GENETICS. 65(12).
Author
Organization
Abstract
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.
Keywords
COWDEN-DISEASE, MUTATIONS, CANCER, SPECTRUM, AUTISM, RISKS, Genetic variation, Genetic association studies, Human genetics, Medical, oncology, Phenotype

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MLA
Hendricks, Linda A. J., et al. “Genotype-Phenotype Associations in a Large PTEN Hamartoma Tumor Syndrome (PHTS) Patient Cohort.” EUROPEAN JOURNAL OF MEDICAL GENETICS, vol. 65, no. 12, Elsevier, 2022, doi:10.1016/j.ejmg.2022.104632.
APA
Hendricks, L. A. J., Hoogerbrugge, N., Venselaar, H., Aretz, S., Spier, I., Legius, E., … PTEN Study Grp, [missing]. (2022). Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort. EUROPEAN JOURNAL OF MEDICAL GENETICS, 65(12). https://doi.org/10.1016/j.ejmg.2022.104632
Chicago author-date
Hendricks, Linda A. J., Nicoline Hoogerbrugge, Hanka Venselaar, Stefan Aretz, Isabel Spier, Eric Legius, Hilde Brems, et al. 2022. “Genotype-Phenotype Associations in a Large PTEN Hamartoma Tumor Syndrome (PHTS) Patient Cohort.” EUROPEAN JOURNAL OF MEDICAL GENETICS 65 (12). https://doi.org/10.1016/j.ejmg.2022.104632.
Chicago author-date (all authors)
Hendricks, Linda A. J., Nicoline Hoogerbrugge, Hanka Venselaar, Stefan Aretz, Isabel Spier, Eric Legius, Hilde Brems, Robin de Putter, Kathleen Claes, Gareth Evans, Emma R. Woodward, Maurizio Genuardi, Fulvia Brugnoletti, Yvette van Ierland, Kim Dijke, Emma Tham, Bianca Tesi, Janneke H. M. Schuurs-Hoeijmakers, Maud Branchaud, Hector Salvador, Arne Jahn, Simon Schnaiter, Violetta Christophidou Anastasiadou, Joan Brunet, Carla Oliveira, Laura Roht, Ana Blatnik, Arvids Irmejs, Arjen R. Mensenkamp, Janet R. Vos, and [missing] PTEN Study Grp. 2022. “Genotype-Phenotype Associations in a Large PTEN Hamartoma Tumor Syndrome (PHTS) Patient Cohort.” EUROPEAN JOURNAL OF MEDICAL GENETICS 65 (12). doi:10.1016/j.ejmg.2022.104632.
Vancouver
1.
Hendricks LAJ, Hoogerbrugge N, Venselaar H, Aretz S, Spier I, Legius E, et al. Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort. EUROPEAN JOURNAL OF MEDICAL GENETICS. 2022;65(12).
IEEE
[1]
L. A. J. Hendricks et al., “Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort,” EUROPEAN JOURNAL OF MEDICAL GENETICS, vol. 65, no. 12, 2022.
@article{01GST11V80Y1F0JGM8K2C7GP2N,
  abstract     = {{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.}},
  articleno    = {{104632}},
  author       = {{Hendricks, Linda A. J. and  Hoogerbrugge, Nicoline and  Venselaar, Hanka and  Aretz, Stefan and  Spier, Isabel and  Legius, Eric and  Brems, Hilde and de Putter, Robin and Claes, Kathleen and  Evans, Gareth and  Woodward, Emma R. and  Genuardi, Maurizio and  Brugnoletti, Fulvia and  van Ierland, Yvette and  Dijke, Kim and  Tham, Emma and  Tesi, Bianca and  Schuurs-Hoeijmakers, Janneke H. M. and  Branchaud, Maud and  Salvador, Hector and  Jahn, Arne and  Schnaiter, Simon and  Anastasiadou, Violetta Christophidou and  Brunet, Joan and  Oliveira, Carla and  Roht, Laura and  Blatnik, Ana and  Irmejs, Arvids and  Mensenkamp, Arjen R. and  Vos, Janet R. and  PTEN Study Grp, [missing]}},
  issn         = {{1769-7212}},
  journal      = {{EUROPEAN JOURNAL OF MEDICAL GENETICS}},
  keywords     = {{COWDEN-DISEASE,MUTATIONS,CANCER,SPECTRUM,AUTISM,RISKS,Genetic variation,Genetic association studies,Human genetics,Medical,oncology,Phenotype}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{13}},
  publisher    = {{Elsevier}},
  title        = {{Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort}},
  url          = {{http://doi.org/10.1016/j.ejmg.2022.104632}},
  volume       = {{65}},
  year         = {{2022}},
}
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