Next-generation sequencing for the diagnosis of hereditary pheochromocytoma and paraganglioma syndromes.

PURPOSE OF REVIEW: About 40% of the neuroendocrine tumors pheochromocytomas and paragangliomas (PPGLs) are caused by an inherited mutation. Diagnostic genetic screening is recommended for patients and their families. However, the number of susceptibility genes involved is high and continues to grow, making conventional sequencing costly and burdensome. Next-generation sequencing (NGS) enables accurate, thorough, and cost-effective identification of inherited mutations. Here we review recent successes, limitations, and the future of NGS for diagnosis of pheochromocytoma and paraganglioma syndromes.

RECENT FINDINGS: NGS-based screen of genetic disorders in the clinical setting shows improved diagnostic rates over conventional tests. Both broad, whole-exome sequencing, and targeted NGS approaches have been tested for screening of PPGLs, with accurate mutation detection, higher speed, and reduced costs compared with current assays. Flexibility to expand the targeted gene set is immediate in whole-exome sequencing, and adjustable in targeted NGS, but both methods have limitations.

SUMMARY: The high degree of genetic heterogeneity and heritability of PPGLs make NGS an ideal medium for their diagnostic screening. However, improved detection of large genomic defects and underrepresented gene areas are needed before NGS can fully realize its potential as the premier option for routine genetic testing of these syndromes.