An Asymptomatic Case With MEN1 Slipping Through Genetic Screening by SNV-dependent Allelic Dropout

Context: Genetic testing is useful not only for the diagnosis of the MEN1 proband but also for determining the putative asymptomatic variant carriers to improve the prognosis or to avoid unnecessary medical intervention. However, we must be aware of the putative pitfalls of polymerase chain reaction (PCR)-based genetic testing in specific conditions that lead to medical mismanagement. Objective: To warn of the putative pitfalls of PCR-based genetic testing, we report an overlooked case of MEN1 due to PCR allelic dropout. Methods: A 69-year-old man was clinically diagnosed with MEN1, and genetic testing revealed that he had a pathogenic variant in the MEN1 gene. His 36-year-old son was completely asymptomatic. As the son was 50% at risk of MEN1, he was willing to undergo genetic testing himself after genetic counseling. Results: Genetic testing was carried out in 2 independent laboratories. Although laboratory A showed that he carried a pathogenic variant, laboratory B showed that he had the wild-type genotype of MEN1. The discrepancy in these results was due to PCR allelic dropout by singlenucleotide variations of the MEN1 gene in the 5' region. The surveillance revealed that he had asymptomatic primary hyperparathyroidism and a neuroendocrine tumor of the pancreas. Conclusion: PCR-dependent genetic analysis may be susceptible to PCR allelic dropout in an SNV-specific manner. We must be careful when genetically testing individuals of relatives with clinical MEN1 disease.

Automated summary

Genetic testing is crucial for diagnosing MEN1 disease and identifying potential asymptomatic carriers among relatives. However, PCR-based genetic testing may be prone to allelic dropout, leading to discrepancies in diagnosis results.