In Case Report “The tale of two genes: from next-generation sequencing to phenotype” 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 – Bohring-Opitz Syndrome. In addition, a maternally inherited and likely pathogenic variant in the MC4R associated with monogenic obesity.
Dual genetic diagnosis is rare and results in unique clinical phenotypes which makes it difficult to make a diagnosis based on the phenotype of the patient.
When two genetic conditions are present with contradicting clinical features, it can be particularly challenging for making a treatment and management plan. Obesity is not a usual feature of Bohring-Opitz Syndrome (BOS) and has only been reported in one case previously. The patient has significant increased BMI between age 3 and 5 ½ which was not explained by medications or endocrinoligical problems. In contrast, the patient had all the classic features of BOS, but the MC4R variant likely caused abnormal accumulation of body fat, thereby rescuing the patient from failure to thrive at age 15.
The exact impact of the MC4R variant on the ASXL1 variant and his prognosis is unclear, but it may be the reason for his non-classical phenotype, i.e. obesity in teen years. The case reported herein signifies how the presence of a second genetic diagnosis, can modify the classic presentation of a well-described syndrome, and why the possibility of a genetic dual diagnosis should be considered in cases with unusual phenotypical features. This case highlights the utility of next-generation sequencing in patients with unique, unrecognizable phenotypes for several domains of precision medicine including (1) diagnosis; (2) prognosis and outcome; (3) management and therapy.
Source: Mersedeh Rohanizadegan, Aishwarya Siddharth, Kyle Retterer, et al. The tale of two genes-from next generation sequencing to phenotype Cold Spring Harb Mol Case Stud published online January 22, 2020. Access the most recent version at doi:10.1101/mcs.a004846