Twins with psychiatric features and a nonsense HRAS variant affecting transcript processing

Abstract

Background

Heterozygous germline variants in HRAS can lead to RASopathies, a group of disorders caused by gain-of-function variants in several components and modulators of the Ras-MAPK pathway. Recently, different missense variants, indels and a frameshift variant, have been associated with attenuated or distinctive phenotypes, suggesting a wider clinical spectrum.

Case presentation

We report a pair of twins with shared distinctive features, including mild intellectual disability, anxiety, psychosis, dysmorphism, short stature, early hair loss, vitamin D deficiency, osteopenia and hematuria, harboring a novel de novo nonsense variant in HRAS. Targeted RNA-sequencing demonstrates that this variant affects splicing.

Conclusion

Our report provides evidence that variants affecting transcript processing in HRAS may lead to an attenuated phenotype associated with neuropsychiatric features. Further studies are needed to fully understand the mechanism and phenotypic variability.