A Novel UPF1 Variant Associated With a Rare UPF1-Related Neurodevelopmental Disorder

Nonsense-mediated mRNA decay (NMD) plays a crucial role in degrading aberrant transcripts with premature termination codons, with the Up-frameshift (UPF) protein family—UPF1, UPF2, and UPF3A/UPF3B—being vital components of this machinery. While several variants in genes encoding UPF2 and UPF3A/3B have been associated with neurodevelopmental disorders, only three germline UPF1 variants have been reported to date. Here, we report a male patient with a de novo missense variant, p.(Ala526Thr), in a highly conserved helicase motif of UPF1. The patient presented with moderate intellectual disability (ID), atypical autism, attention deficit hyperactivity disorder (ADHD), and behavioral disturbances. The common features observed among the four patients with UPF1 variants are moderate to severe ID and developmental delays in motor and verbal skills. A comparison across the disorders related to the UPF genes suggests that neurodevelopmental delay, including ID and impaired verbal skills, is a common feature, and these disorders may collectively be referred to as UPF-related neurodevelopmental disorders (NDDs). ADHD, autism, seizures, hypotonia, and non-specific dysmorphic features are also reported in some patients, suggesting that these disorders can be classified as non-specific intellectual disability syndromes. However, further studies are necessary to elucidate genotype–phenotype correlations and the molecular mechanisms underlying these rare disorders, particularly those related to UPF1.