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: Genetic association studies; Genetic variation; Human genetics; Medical oncology; Phenotype.

Hendricks, L., Hoogerbrugge, N., Venselaar, H., Aretz, S., Spier, I., Legius, E., Brems, H., De Putter, R., Claes, K., Evans, D., Woodward, E., Genuardi, M., Brugnoletti, F., Van Ierland, Y., Dijke, K., Tham, E., Tesi, B., Schuurs-hoeijmakers, J., Branchaud, M., Salvador, H., Jahn, A., Schnaiter, S., Anastasiadou, V., Brunet, J., Oliveira, C., Roht, L., Blatnik, A., Irmejs, A., Mensenkamp, A., Vos, J., Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort, <<EUROPEAN JOURNAL OF MEDICAL GENETICS>>, 2022; 2022 (12): 104632-104632. [doi:10.1016/j.ejmg.2022.104632]

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

Genuardi, M;
2022

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: Genetic association studies; Genetic variation; Human genetics; Medical oncology; Phenotype.
Inglese
Hendricks, L., Hoogerbrugge, N., Venselaar, H., Aretz, S., Spier, I., Legius, E., Brems, H., De Putter, R., Claes, K., Evans, D., Woodward, E., Genuardi, M., Brugnoletti, F., Van Ierland, Y., Dijke, K., Tham, E., Tesi, B., Schuurs-hoeijmakers, J., Branchaud, M., Salvador, H., Jahn, A., Schnaiter, S., Anastasiadou, V., Brunet, J., Oliveira, C., Roht, L., Blatnik, A., Irmejs, A., Mensenkamp, A., Vos, J., Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort, <<EUROPEAN JOURNAL OF MEDICAL GENETICS>>, 2022; 2022 (12): 104632-104632. [doi:10.1016/j.ejmg.2022.104632]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/219749
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