Universität zu Köln

Yehia, Lamis ORCID: 0000-0002-6389-3059, Seyfi, Marilyn, Niestroj, Lisa-Marie, Padmanabhan, Roshan, Ni, Ying, Frazier, Thomas W., Lal, Dennis and Eng, Charis (2020). Copy Number Variation and Clinical Outcomes in Patients With Germline PTEN Mutations. JAMA Netw. Open, 3 (1). CHICAGO: AMER MEDICAL ASSOC. ISSN 2574-3805

Full text not available from this repository.

Abstract

Question Are copy number variations associated with specific clinical outcomes in patients with germline PTEN mutations? Findings In this cohort study of 481 patients with germline PTEN mutations, pathogenic and/or likely pathogenic copy number variations associated with neurodevelopmental disorders were found in 10.0% of patients with autism spectrum disorder and/or developmental delay. 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. Importance 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. Objective 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. Design, Setting, and Participants 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. Exposures Detection of CNVs from patient-derived germline DNA. Main Outcomes and Measures 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. Results 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. Conclusions and Relevance 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. This cohort study assesses whether copy number variations are associated with specific phenotypes in patients with germline PTEN mutations.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Yehia, Lamis UNSPECIFIED orcid.org/0000-0002-6389-3059 UNSPECIFIED Seyfi, Marilyn UNSPECIFIED UNSPECIFIED UNSPECIFIED Niestroj, Lisa-Marie UNSPECIFIED UNSPECIFIED UNSPECIFIED Padmanabhan, Roshan UNSPECIFIED UNSPECIFIED UNSPECIFIED Ni, Ying UNSPECIFIED UNSPECIFIED UNSPECIFIED Frazier, Thomas W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lal, Dennis UNSPECIFIED UNSPECIFIED UNSPECIFIED Eng, Charis UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-347956
DOI:	10.1001/jamanetworkopen.2019.20415
Journal or Publication Title:	JAMA Netw. Open
Volume:	3
Number:	1
Date:	2020
Publisher:	AMER MEDICAL ASSOC
Place of Publication:	CHICAGO
ISSN:	2574-3805
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language AUTISM SPECTRUM DISORDERS; COWDEN-SYNDROME; DISEASE; INDIVIDUALS; GENETICS; PHENOTYPE; GENOME; RECOMMENDATIONS; VARIANTS; BREAST Multiple languages Medicine, General & Internal Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/34795