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. 2022 Dec;65(12):104632.
doi: 10.1016/j.ejmg.2022.104632. Epub 2022 Oct 18.

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

Linda A J Hendricks  1 , Nicoline Hoogerbrugge  2 , Hanka Venselaar  3 , Stefan Aretz  4 , Isabel Spier  4 , Eric Legius  5 , Hilde Brems  5 , Robin de Putter  6 , Kathleen B M Claes  6 , D Gareth Evans  7 , Emma R Woodward  7 , Maurizio Genuardi  8 , Fulvia Brugnoletti  9 , Yvette van Ierland  10 , Kim Dijke  11 , Emma Tham  12 , Bianca Tesi  12 , Janneke H M Schuurs-Hoeijmakers  13 , Maud Branchaud  14 , Hector Salvador  15 , Arne Jahn  16 , Simon Schnaiter  17 , Violetta Christophidou Anastasiadou  18 , Joan Brunet  19 , Carla Oliveira  20 , Laura Roht  21 , Ana Blatnik  22 , Arvids Irmejs  23 ; PTEN Study Group; Arjen R Mensenkamp  2 , Janet R Vos  32
Collaborators, Affiliations
Free article

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

Linda A J Hendricks et al. Eur J Med Genet. 2022 Dec.
Free article

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.

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Conflict of interest statement

Declaration of competing interest The authors have no conflict of interest to declare.

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