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Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohortHendricks, Linda A. J. ...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.Source: European journal of medical genetics. - ISSN 1769-7212 (Vol. 65, no. 12, 2022, str. 104632-1-104632-13)Type of material - article, component part ; adult, seriousPublish date - 2022Language - englishCOBISS.SI-ID - 144795395
Author
Hendricks, Linda A. J. |
Hoogerbrugge, Nicoline |
Venselaar, Hanka |
Aretz, Stefan |
Spier, Isabel |
Legius, Eric |
Brems, Hilde |
Dijke, Kim |
Tham, Emma |
Blatnik, Ana, 9.8.1980-
Topics
genetika |
genetske študije |
humana genetika |
onkologija |
genetics |
genetic association studies |
human genetics |
oncology
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Hendricks, Linda A. J. | |
Hoogerbrugge, Nicoline | |
Venselaar, Hanka | |
Aretz, Stefan | |
Spier, Isabel | |
Legius, Eric | |
Brems, Hilde | |
Dijke, Kim | |
Tham, Emma | |
Blatnik, Ana, 9.8.1980- | 32428 |
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