The tale of two genes: from next-generation sequencing to phenotype

Abstract

An 18-year-old man with a history of intellectual disability, cranio-facial dysmorphism, seizure disorder and obesity was identified to carry a de novo, pathogenic variant in the ASXL1 (c.4198G>T; p.E1400X) associated with the diagnosis of Bohring Opitz syndrome based on exome sequencing. In addition, he was identified to carry a maternally inherited and likely pathogenic variant in the MC4R (c.817C>T; p.Q273X) associated with monogenic obesity. Dual genetic diagnosis occurs in 4-6% of patients and results in unique clinical phenotypes that are a function of tissue-specific gene expression, involved pathways, clinical expressivity and penetrance. This case highlights the utility of next-generation sequencing in patients with an unusual combination of clinical presentations for several pillars of precision medicine including (1) diagnosis; (2) prognosis and outcome; (3) management and therapy and (4) utilization of resources.