Expanding the Genotypic Spectrum for ReNU Syndrome: A Clinical Laboratory Experience

Background

• ReNU syndrome was first described in 2024. It is an autosomal dominant neurodevelopmental disorder (NDD) characterized by developmental delays (DD), intellectual disability (ID), seizures, hypotonia, and microcephaly. Other features include short stature, visual impairment, and gastrointestinal issues.
• Literature suggests ReNU syndrome is emerging as one of the most prevalent causes for NDDs, estimated to account for around 0.4 – 0.5% of NDDs.
• ReNU syndrome is caused by variants in the RNU4-2 gene. This is a non-coding gene that encodes the U4 small nuclear RNA (snRNA), an essential component of the spliceosome complex responsible for pre-mRNA splicing. Pathogenic variants such as the common insertion, n.64_65insT, along with others, have been shown to disrupt the U4-U6 duplex region of the spliceosome (Figure 1).
• Detection of these variants present a diagnostic challenge due to the lack of detection on traditional
  exome sequencing and gene panels.
• This study sought to evaluate the clinical and genetic findings of affected individuals in our clinical laboratory cohort and assess the utility of genome sequencing (GS) in identifying and classifying RNU4-2 variants