A novel compound heterozygous mutation of UFC1 in a patient with neurodevelopmental disorder.

Background: Neurodevelopmental disorders (NDDs) encompass a diverse group of disorders characterized by impaired cognition, behavior, and motor skills. Genetic factor is the leading cause in about 35% of NDDs patients. Mutations of UFC1, an E2 enzyme participating in the post-translational modification of proteins through attachment of ubiquitin-like proteins, were recently reported to be associated with NDDs. However, the UFC1 associated NDDs are rare and the data are scarce, thus making it difficult to identify this disease.

Objective: This study reported a novel compound heterozygous mutation of UFC1 in a Chinese patient with NDD.

Methods: Detailed clinical data were recorded. Whole exome sequencing (WES) was performed to determine the genetic cause of the patient. The candidate mutation was verified using Sanger sequencing.

Results: WES analysis identified a novel compound heterozygous mutation of UFC1 (c.19 C > T, p.Arg7* and c.164G > A, p.Arg55Gln). The nonsense mutation c.19 C > T (p.Arg7*) led to a premature truncation of UFC1 and nonsense-mediated RNA decay. Arg55 is highly conserved among orthologues. Molecular modeling predicted that mutation c.164G > A (p.Arg55Gln) may influence the correct folding of UFC1. These two mutations were evaluated as likely pathogenic based on the ACMG guideline. Moreover, neurodevelopmental delay, microcephaly, and epilepsy were confirmed as major phenotypes of UFC1 mutation.

Conclusion: This study expands the mutational spectrum of NDDs. We reported the nonsense mutation of UFC1 for the first time. We also confirmed the major phenotypes that may guide clinical identification of UFC1 mutation. Ubiquitination mechanism is highlighted in NDDs pathogenesis.