ReNU syndrome is the most common known autosomal dominant neurodevelopmental disorder and is caused by variants in the noncoding gene RNU4-2.* ReNU syndrome is almost always caused by a de novo pathogenic variant.

Very rarely, individuals diagnosed with ReNU syndrome have the disorder as the result of an RNU4-2 pathogenic variant inherited from a mildly affected parent. De novo means that the genetic variant is present for the first time in one family member and is not inherited from either parent. It is caused by a tiny, spontaneous change in a specific gene, known as RNU4-2, that usually happens by chance. Because it is "autosomal dominant," it only takes one changed copy of the gene for the condition to occur, meaning it typically doesn't run in families.

Here are some examples of traits associated with 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.

    A head tilt has also been noted anecdotally from comparing images.

  • Low muscle tone or muscle weakness.

  • Delayed walking, inability to walk, or mobility impairment, purple hands and/or feet

  • 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)

    Sialorrhea / excessive drooling

  • Bone issues, such as low bone density, hip dysplasia, recurrent fractures, club foot, scoliosis

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, bubbles, humming, and music. Genetic and Rare Diseases Information Center has also published a more comprehensive list of symptoms.

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. *Whole genome sequencing (WGS), Sanger sequencing, or a dedicated panel that includes RNU4-2 is usually needed to diagnose RNU4-2, and whole exome sequencing (WES) alone will not identify it without a specific add-on! Click here to learn more about testing. Not everyone with ReNU syndrome has the same set of symptoms; this is not a comprehensive list. Further research is currently underway.

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.

ReNU syndrome clinical databases:

NIH GeneReviews® • GARD • Human Phenotype Ontology • OMIM #620851 • Orphanet ORPHA:686488 • NCBI MedGen C5935628 • ClinVar – RNU4-2 gene entries • ClinGen – HGNC:10193 • NORD Rare Disease Database • Monarch Initiative MONDO:0971172 • MalaCards • Disease-Ontology 0061190

ReNU syndrome related search terms:

ReNU syndrome • RNU4-2 • RNU4-2–related disorder • RNU4-2 pathogenic variant–associated syndrome • U4 snRNA–related neurodevelopmental disorder • RNU4-2-related autosomal dominant neurodevelopmental disorder • RNU4-2–associated multisystem disorder • NEDHAFA • Neurodevelopmental disorder with hypotonia, brain anomalies, distinctive facies, absent language • dark genome • junk DNA • monogenic neurodevelopmental disorder • autosomal dominant intellectual developmental disorder • RNUopathies

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*https://scitechdaily.com - “In May 2024, they identified mutations in a related gene, RNU4-2, as the cause of the most common autosomal dominant NDD, now known as ReNU syndrome.”