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

• Published in: Endocrinology and metabolism (Seoul) Vol. 35; no. 4; pp. 909 - 917
• Main Authors: Seo, Soo Hyun, Kim, Jung Hee, Kim, Man Jin, Cho, Sung Im, Kim, Su Jin, Kang, Hyein, Shin, Chan Soo, Park, Sung Sup, Lee, Kyu Eun, Seong, Moon-Woo
• Format: Journal Article
• Language: English
• Published: Korea (South) Korean Endocrine Society 01.12.2020; 대한내분비학회
• Subjects: germ-line mutation; molecular diagnostic techniques; Original; paraganglioma; pheochromocytoma; whole exome sequencing; 내과학; Paraganglioma; Germ-line mutation; Pheochromocytoma; Whole exome sequencing; Molecular diagnostic techniques
• ISSN: 2093-596X; 2093-5978
• DOI: 10.3803/ENM.2020.756

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. 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. 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. 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.