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Whole Exome Sequencing Identifies Novel Genetic Alterations in Patients with Pheochromocytoma/Paraganglioma

Endocrinology and Metabolism 2020년 35권 4호 p.909 ~ 917
서수현, 김정희, 김만진, 조성임, 김수진, 강혜인, 신찬수, 박성섭, 이규은, 성문우,
소속 상세정보
서수현 ( Seo Soo-Hyun ) - Seoul National University Bundang Hospital Department of Laboratory Medicine
김정희 ( Kim Jung-Hee ) - Seoul National University College of Medicine Seoul National University Hospital Department of Internal Medicine
김만진 ( Kim Man-Jin ) - Seoul National University College of Medicine Seoul National University Hospital Department of Laboratory Medicine
조성임 ( Cho Sung-Im ) - Seoul National University College of Medicine Seoul National University Hospital Department of Laboratory Medicine
김수진 ( Kim Su-Jin ) - Seoul National University College of Medicine Seoul National University Hospital Department of Surgery
강혜인 ( Kang Hye-In ) - Seoul National University College of Medicine Seoul National University Hospital Department of Surgery
신찬수 ( Shin Chan-Soo ) - Seoul National University College of Medicine Seoul National University Hospital Department of Internal Medicine
박성섭 ( Park Sung-Sup ) - Seoul National University College of Medicine Seoul National University Hospital Department of Laboratory Medicine
이규은 ( Lee Kyu-Eun ) - Seoul National University College of Medicine Seoul National University Hospital Department of Surgery
성문우 ( Seong Moon-Woo ) - Seoul National University College of Medicine Seoul National University Hospital Department of Laboratory Medicine

Abstract


Background: Pheochromocytoma and paragangliomas (PPGL) are known as tumors with the highest level of heritability, approximately 30% of all cases. Clinical practice guidelines of PPGL recommend genetic testing for germline variants in all patients. In this study, we used whole exome sequencing to identify novel causative variants associated with PPGL to improve the detection of rare genetic variants in our cohort.

Methods: Thirty-six tested negative for pathogenic variants in previous Sanger sequencing or targeted gene panel testing for PPGL underwent whole exome sequencing. Whole exome sequencing was performed using DNA samples enriched using TruSeq Custom Enrichment Kit and sequenced with MiSeq (Illumina Inc.). Sequencing alignment and variant calling were performed using SAMtools.

Results: Among previously mutation undetected 36 patients, two likely pathogenic variants and 13 variants of uncertain significance (VUS) were detected in 32 pheochromocytoma-related genes. SDHA c.778G>A (p.Gly260Arg) was detected in a patient with head and neck paraganglioma, and KIF1B c.2787-2A>C in a patient with a bladder paraganglioma. Additionally, a likely pathogenic variant in BRCA2, VUS in TP53, and VUS in NFU1 were detected.

Conclusion: Exome sequencing further identified genetic alterations by 5.6% in previously mutation undetected patients in PPGL. Implementation of targeted gene sequencing consisted of extended genes of PPGL in routine clinical screening can support the level of comprehensive patient assessment.

키워드

Pheochromocytoma; Paraganglioma; Whole exome sequencing; Germ-line mutation; Molecular diagnostic techniques

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