Copy Number Variation and Clinical Outcomes in Patients With Germline PTEN Mutations

Lamis Yehia,Thomas W Frazier,Dennis Lal,Ying Ni,Charis Eng,Marilyn Seyfi,Lisa-Marie Niestroj,Roshan Padmanabhan

doi:10.1001/jamanetworkopen.2019.20415

Abstract

PTEN is among the most common autism spectrum disorder (ASD)-predisposition genes. Germline PTEN mutation carriers can develop malignant neoplasms and/or neurodevelopmental disorders such as ASD and developmental delay. Why a single gene contributes to disparate clinical outcomes, even in patients with identical PTEN mutations, remains unclear. To investigate the association of copy number variations (CNVs), altered numbers of copies of DNA sequences within the genome, with specific phenotypes in patients with germline PTEN mutations. This prospective cohort study examined genome-wide microarrays performed on blood-derived DNA to detect germline CNVs from September 1, 2005, through January 3, 2018. Multicenter accrual occurred from community and academic medical centers throughout North America, South America, Europe, Australia, and Asia. Participants included patients with PTEN hamartoma tumor syndrome (PHTS) (n = 481), molecularly defined as carrying germline pathogenic PTEN mutations. Data were analyzed from November 14, 2018, to August 1, 2019. Detection of CNVs from patient-derived germline DNA. Prevalence of pathogenic and/or likely pathogenic CNVs in patients with PHTS and association with ASD/developmental delay and/or cancer, ascertained through medical records and pathology reports. The study included 481 patients with PHTS (mean [SD] age, 33.2 [21.6] years; 268 female [55.7%]). The analytic series consisted of 309 patients with PHTS and genetically determined European ancestry. Patients were divided into 3 phenotypic groups, excluding family members within each group. These include 110 patients with ASD/developmental delay, 194 without ASD/developmental delay, and 121 with cancer (of whom 116 were in the no ASD/developmental delay group). Genome-wide evaluation of autosomal CNVs indicated an increased CNV burden, particularly duplications in genic regions, in patients with ASD/developmental delay compared with those without ASD/developmental delay (odds ratio [OR], 1.9; 95% CI, 1.1-3.4; P = .03) and those with cancer (OR, 2.5; 95% CI, 1.3-4.6; P = .003). Eleven of the 110 patients (10.0%) with ASD/developmental delay carried pathogenic and/or likely pathogenic CNVs associated with neurodevelopmental disorders, compared with 5 of 194 (2.6%) without ASD/developmental delay (OR, 4.2; 95% CI, 1.4-13.7; P = .008) and 2 of 121 (1.7%) with cancer (OR, 6.6; 95% CI, 1.6-44.5; P = .007). Evidence of an association between pathogenic and/or likely pathogenic CNVs and PHTS with ASD/developmental delay was further supported in a validation series of 69 patients with PHTS of genetically determined non-European ancestry. These findings suggest that copy number variations are associated with the ASD/developmental delay clinical phenotype in PHTS, providing proof of principle for similarly heterogeneous disorders lacking outcome-specific associations.

Highlights

The triumph of using genetics in precision medicine is the ability to stratify individuals at very high risk of disease and thereby enact specific gene-informed medical management.[1,2] In the case of heritable disease, genetics allow testing of family members to determine with 100% accuracy whether they are at risk of disease
Eleven of the 110 patients (10.0%) with autism spectrum disorder (ASD)/developmental delay carried pathogenic and/or likely pathogenic Copy number variation (CNV) associated with neurodevelopmental disorders, compared with 5 of 194 (2.6%) without ASD/developmental delay (OR, 4.2; 95% CI, 1.4-13.7; P = .008) and 2 of 121 (1.7%) with cancer (OR, 6.6; 95% CI, 1.6-44.5; P = .007)
Pathogenic and/or likely pathogenic copy number variations were found in 2.6% of patients without autism spectrum disorder and/or developmental delay and 1.7% of patients with cancer. Meaning These findings suggest that copy number variations are associated with the autism spectrum disorder and/or developmental delay phenotype in patients with germline PTEN mutations

Summary

Introduction

The triumph of using genetics in precision medicine is the ability to stratify individuals at very high risk of disease and thereby enact specific gene-informed medical management.[1,2] In the case of heritable disease, genetics allow testing of family members to determine with 100% accuracy whether they are at risk of disease. For any single individual carrying a mutation, we can estimate risk by probabilities but not with certainty. A germline mutation in gene X may give an 80% lifetime risk of disease Y, but for the single patient with that germline mutation, the risk of developing disease Y will be 100% or 0%. Searching for genomic modifiers of heritable disease risk at the individual level in humans has proven challenging.[1,3] This makes estimation of clinical outcomes difficult, especially for phenotypically variable disorders. Why a mutation in 1 particular gene predisposes to disparate clinical outcomes, including in patients with identical mutations, remains poorly understood

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