What Do We Know About ReNU Syndrome?

RNU4-2 / ReNU Syndrome is a neurodevelopmental disorder caused by mutations in the RNU4-2 gene.

Variants in the RNU4-2 gene, a non-coding gene responsible for producing U4 snRNA, have been identified as a significant cause of previously undiagnosed neurodevelopmental disorders. These mutations, particularly the insertion of a T between positions 64 and 65 of the gene, disrupt the RNA splicing process, causing errors in how RNA is processed and leading to improper protein synthesis. This exciting discovery highlights the importance of whole-genome sequencing, as traditional exome sequencing often overlooks non-coding genes like RNU4-2.

The name "ReNU" was given by families and researchers to symbolize the “renewed hope” for a better future for those affected. This diagnosis opens avenues for future research and potential treatments for those affected, and aids in the understanding that there wasn’t anything parents did prior to or during pregnancy to cause the disorder.

ReNU Syndrome is currently characterized by hypotonia, global developmental delay, severely impaired intellectual development with poor or absent speech, delayed walking or inability to walk, feeding difficulties with poor overall growth, seizures (in most), dysmorphic facial features, and brain anomalies, including ventriculomegaly, thin corpus callosum, and white matter loss (Greene et al., 2024; Schot et al., 2024; Chen et al., 2024).

This figure is taken, with permission, from Chen et al (http://creativecommons.org/licenses/by/4.0/)

Examples of Some Traits in Individuals with ReNU Syndrome

  • Reduced white matter volume, non-specific abnormalities of the white matter, hypoplasia of corpus callosum (connection between cerebral hemispheres thinner than normal, or missing parts), ventriculomegaly (enlarged ventricles), delayed myelination

  • When a child takes longer to reach certain development milestones than other children their age

  • Significant limitations in intellectual functioning and adaptive behavior, for example difficulty learning or understanding instructions, remembering things, solving problems, and applying new information

  • Some research participants were found to experience infantile spasms, focal seizures and generalized tonic-clonic seizures, febrile seizures, or status epilepticus

  • Optic nerve hypoplasia, cortical vision impairment (aka CVI, the brain cannot process visual information despite the eyes being functional), strabismus (misalignment of the eyes), nystagmus (involuntary, rhythmic, and repetitive eye movements)

  • Myopathic face with deep set eyes (some widely spaced, some narrowly spaced), epicanthus (skin fold extending from upper to lower eyelid, partially covering the inner corner of the eye), wide nasal bridge, anteverted nares (upturned nose), large cupped ears (some posteriorly rotated), full cheeks, a distinctive mouth with full lips with downturned corners, high arched palate, and a large or protruding tongue

  • Low muscle tone or muscle weakness

  • Delayed walking, inability to walk, or mobility impairment

  • Growth problems have been identified, such as microcephaly (head size smaller than expected at birth), short stature, and endocrine issues such as hypothyroidism or growth hormone deficiency

  • Feeding difficulties and excessive drooling, constipation, gastro-esophageal reflux disease, G-tube (gastronomy tube)

  • Communication difficulties such as difficulty acquiring language (but may develop alternative communication skills)

  • Bone issues, such as low bone density, hip dysplasia, and/or recurrent fractures

Anecdotally, many people affected by ReNU Syndrome also exhibit a happy demeanor, may use alternative means of communication, are affectionate, and tend to enjoy swings, clapping, routines, playing with water, drinking water, humming, and music.

Ashley, age 8, playing in the water

Ashley, age 8

It is common to participate in therapies for skills development to enhance the quality of life, and to have multidisciplinary care by numerous specialists in relevant fields. Not everyone with ReNU syndrome has the same set of symptoms; this is not a comprehensive list.

What makes RNU4-2 a unique discovery?

RNU4-2 wasn't discovered until 2024 because the majority of genetic studies previously focused on protein-coding genes, as non-coding genes like RNU4-2 were not thought to have the same effects. Until recently, clinical genetic tests also almost exclusively focused on protein-coding genes. It was only with the advent of comprehensive "whole-genome sequencing” (WGS) and research projects, like the 100,000 Genomes Project - an initiative to sequence and study the role our genes play in health and disease - that enabled researchers to analyze variations in non-coding regions, revealing the link between mutations in RNU4-2 and neurodevelopmental disorders. We hope for a future where WGS becomes more accessible.