Clinical characteristics.

RNU4-2–related autosomal dominant neurodevelopmental disorder (ReNU syndrome) is characterized by moderate-to-severe developmental delay (DD) or intellectual disability (ID) and the following features presenting in infancy or childhood: microcephaly, generalized neonatal hypotonia, infant feeding difficulties, poor weight gain and linear growth, epilepsy, neurobehavioral/psychiatric manifestations (autism spectrum disorder, midline stereotypies, sleep disturbances, aggressive or self-injurious behaviors), and bone/skeletal involvement (club feet, hip dysplasia, joint hyperlaxity, osteopenia/osteoporosis or history of low-impact fractures).

Diagnosis/testing.

The diagnosis of ReNU syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in RNU4-2 identified by molecular genetic testing.

Management.

Supportive treatment: Multidisciplinary care by specialists in management of developmental delay / intellectual disability and neurobehavioral issues; seizures; feeding therapy and gastrointestinal issues; kidney anomalies; urinary tract anomalies; bone health; and sleep issues.

Surveillance: Regularly scheduled follow-up evaluations to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations.

Agents/circumstances to avoid: Consider avoiding or limiting any substance or medication that may affect bone health (e.g., steroids).

Genetic counseling.

ReNU syndrome is an autosomal dominant disorder that 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. In principle, an individual with a pathogenic RNU4-2 variant has a 50% chance of transmitting the RNU4-2 pathogenic variant to offspring (although it has been hypothesized that sperm with an RNU4-2 pathogenic variant are at a disadvantage and, consequently, that the risk to offspring of a male with such a variant may be lower [i.e., less than 50%]). Once the RNU4-2 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

ReNU syndrome should be considered in probands with the following clinical and brain MRI findings and family history.

Clinical findings

• Moderate-to-severe developmental delay (DD) or intellectual disability (ID)

AND

• The following features presenting in infancy or childhood:
  • Prenatal history of intrauterine growth restriction, decreased fetal movements, and/or breech presentation
  • Generalized neonatal hypotonia
  • Microcephaly (at birth or postnatal)
  • Poor linear growth and weight gain with height and weight below 10th centile
  • Infant feeding difficulties
  • Epilepsy. Seizures vary in type (febrile, generalized, focal, status epilepticus, drug resistant) and can also change over time.
  • Neurobehavioral/psychiatric manifestations. Autism spectrum disorder, midline stereotypies, sleep disturbances
  • Bone/skeletal involvement. Club feet, hip dysplasia, joint hyperlaxity, osteopenia/osteoporosis or history of low-impact fractures

Brain MRI findings

• Dysgenesis of the corpus callosum with a short and thin corpus callosum is often seen, sometimes with absent rostrum (see Figure 1 in Barbour et al [2024]).
• Ventriculomegaly. Enlarged ventricles are often observed (see Figure 1 in Schot et al [2024]).

Family history. Because ReNU syndrome is typically caused by a de novo heterozygous pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may suggest autosomal dominant inheritance (e.g., affected individuals in multiple generations).

Establishing the Diagnosis

The diagnosis of ReNU syndrome is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in RNU4-2 identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous RNU4-2 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include comprehensive genomic testing (genome sequencing) and gene-targeted testing (single-gene testing, multigene panel). Comprehensive genomic testing does not require that the clinician determine which gene(s) are likely involved (see Option 1), whereas gene-targeted testing does (see Option 2).

Clinical Description

RNU4-2–related autosomal dominant neurodevelopmental disorder (ReNU syndrome) is characterized by moderate-to-severe developmental delay (DD) or intellectual disability (ID) and the following features presenting in infancy or childhood: microcephaly, generalized neonatal hypotonia, infant feeding difficulties, poor weight gain and linear growth, epilepsy, neurobehavioral/psychiatric manifestations (autism spectrum disorder, midline stereotypies, sleep disturbances, aggressive or self-injurious behaviors), and bone/skeletal involvement (club feet, hip dysplasia, joint hyperlaxity, osteopenia/osteoporosis or history of low-impact fractures).

To date, more than 200 individuals have been identified with a pathogenic variant in RNU4-2 [Chen et al 2024, Greene et al 2024, Valenzuela et al 2024, Nava et al 2025]. (Note: There is substantial overlap in the study participants reported in Greene et al [2024] and those reported in Chen et al [2024]). The following description of the clinical features associated with ReNU syndrome is based on these reports (see Table 2).

Developmental delay (DD) and intellectual disability (ID). Some degree of global developmental delay and intellectual disability is observed in all individuals, with approximately 65% being severe, 30% moderate, and 5% in the mild/borderline range.

To date, there have been no reports of global regression in individuals with the most common RNU4-2 pathogenic variant, n.64_65insT. In contrast, one individual (with the RNU4-2 pathogenic variant n.66A>G) was reported to have neurologic regression following a viral infection associated with intractable epilepsy at age two years ten months [Kuroda et al 2025].

Motor milestones tend to be acquired at the following ages: sitting unsupported around age 12 months; walking at around age three years (range: 13 months to 12 years). Many individuals have a wide-based or ataxic-like gait, and a minority (~15%) do not achieve walking [Chen et al 2024, Valenzuela et al 2024, Nava et al 2025]. On the other hand, 10% start to walk within the typical timeline.

Fine motor skills are delayed; most young adults require help with dressing and other activities of daily living [Valenzuela et al 2024].

Although about 60% of individuals reported to date were nonverbal, 23% were able to communicate with few words, and 15% to speak in sentences. Despite significant issues with expressive speech, receptive language skills seem to be preserved, and most children have a strong communicative intent, expressing themselves using alternative methods [Valenzuela et al 2024].

Hypotonia, a very common finding in the neonatal period, tends to improve over time.

Feeding difficulties can be lifelong. In neonates, low muscle tone and weak suck make feeding challenging. Gastroesophageal reflux disease is common and may further complicate feeding issues. Later in childhood, feeding issues may continue, specifically around texture transitions (from liquid to purees and then solids).

Drooling/sialorrhea, observed in many children and young adults [Barbour et al 2024, Valenzuela et al 2024], is likely related to facial hypotonia and difficulty managing saliva.

Epilepsy. Approximately 55% of individuals develop epilepsy and an additional approximately 10% experience at least one seizure. The onset of seizures can be as early as the neonatal period (i.e., birth to age 30 days) and as late as age 13 years (median age: around 3 years). Types of seizures include infantile epileptic spasms syndrome (IESS), febrile seizures, generalized tonic-clonic seizures, absence seizures, and focal seizures. Although epilepsy is typically well controlled with anti-seizure medications, in a cohort of 143 individuals, up to 30% of individuals developed status epilepticus and approximately 15% had refractory epilepsy [Nava et al 2025].

Neurobehavioral/psychiatric manifestations. Autistic features are observed in more than 50% of individuals [Chen et al 2024, Valenzuela et al 2024]. Common findings are midline stereotypies, self-stimulatory repetitive activities using objects, and hand and finger mannerisms, including putting fingers or objects in the mouth, rocking back and forth, or hand flapping [Valenzuela et al 2024].

Frustration – often triggered by difficulty with communication, changes in routine, and anxiety-provoking situations – may be expressed as self-injurious behavior or aggressiveness.

Sleep problems, reported in 15%-45% of individuals, can include difficulty falling asleep, fragmented sleep, night terrors, and obstructive sleep apnea [Chen et al 2024, Nava et al 2025].

In general, caregivers describe their children as happy, friendly, and affectionate. Love for music and water play are often reported [Valenzuela et al 2024, Okamoto et al 2025].

Growth. Congenital microcephaly is observed in up to 30% of individuals, with an additional 40% developing postnatal microcephaly [Valenzuela et al 2024, Nava et al 2025].

About one third of individuals have a prenatal history of intrauterine growth restriction. Typically, these children do not have postnatal catch-up growth. Those children whose growth is appropriate for gestational age often show slow growth with height and weight below the 10th centile for age. Overall, about 60% of individuals will meet the criteria for short stature (i.e., at least 2 standard deviations below the mean) with a proportionate but slender build [Chen et al 2024, Valenzuela et al 2024].

Ophthalmologic findings, seen in most individuals, include strabismus, nystagmus, and refractive errors. Chen et al [2024] reported optic nerve hypoplasia and/or cerebral blindness in about 20% of individuals. Additionally, Chen et al [2024] described one individual with suspected cone-rod dystrophy, and Nava et al [2025] described retinopathy in another seven individuals.

Other associated features

• Conductive hearing loss, seen in a few individuals, tends to be due to recurrent otitis media [Chen et al 2024, Valenzuela et al 2024].
• Gastrointestinal problems also commonly include constipation.
• Endocrine issues include hypothyroidism (diagnosed sometimes in the newborn period or later in childhood), growth hormone deficiency, and panhypopituitarism [Chen et al 2024].
• Skeletal involvement. Talipes equinovarus and/or hip dysplasia can be evident in the neonatal period or become apparent later, as can the progressive findings of scoliosis, kyphosis, and/or pectus carinatum [Chen et al 2024, Valenzuela et al 2024]. Some individuals also have generalized joint hypermobility and pes planus [Valenzuela et al 2024].
• Bone involvement. In late childhood/teenage and young adult years, decreased bone density (osteopenia, osteoporosis) and recurrent fractures or low-impact fractures were reported in 25%-40% of individuals [Chen et al 2024, Valenzuela et al 2024]. Five infants had unexpected fractures during the first year of life [Schot et al 2024, Okamoto et al 2025]. Asymptomatic vertebral fractures in a teenager were reported [Holling et al 2025]. The underlying pathophysiology is not known; however, increased bone turnover has been proposed [Holling et al 2025, Peñafiel-Sam et al 2025].
• Congenital anomalies of the kidneys and urinary tract. Multicystic dysplastic kidney, hydronephrosis, pyelectasis, and vesicoureteral reflux have been observed [Chen et al 2024, Nava et al 2025]. Other kidney issues identified include nephrocalcinosis and kidney stones.
• Cryptorchidism and inguinal hernias have been reported in males [Valenzuela et al 2024, Nava et al 2025].
• Dental issues commonly include malocclusion, malpositioning, widely spaced teeth, decay, hypomineralization, hypoplastic enamel, and early eruption or early loss of primary and/or secondary teeth [Chen et al 2024, Nava et al 2025].
• Cardiac issues commonly include atrial septal defect, ventricular septal defect, bicuspid aortic valve, and mitral regurgitation. A few individuals had arrhythmias (supraventricular tachycardia and sinus tachycardia) [Chen et al 2024, Valenzuela et al 2024, Nava et al 2025].
• Cutaneous features noted in several individuals include acrocyanosis or vasomotor disorders, hypohidrosis, dry skin, keratosis pilaris, hemangioma, hirsutism, and café au lait macules [Chen et al 2024, Nava et al 2025].
• Characteristic facial features in older individuals include myopathic face, deep-set eyes, epicanthus, prominent nasal bridge, anteverted nares, short philtrum, tented open mouth, full lips with downturned corners, high-arched palate, large or protruding tongue, full cheeks, and large, cupped ears. Some features become more obvious with age (e.g., triangular face, prominent nasal bridge with a broad base, lower lip eversion) (see Figure 3 in Chen et al [2024], Figure 1 in Valenzuela et al [2024] and Figure 4 in Nava et [2025]).

Neuroimaging findings that are less common than those included in Suggestive Findings include: reduced volume of white matter, delayed myelination and nonspecific abnormalities of the white matter, abnormal gyral pattern, and periventricular heterotopias [Chen et al 2024, Valenzuela et al 2024, Nava et al 2025]. Valenzuela et al [2024] described two individuals with intracranial arterial tortuosity.

Prognosis. It is unknown if life expectancy in ReNU syndrome is reduced compared to the general population. One reported individual with the RNU4-2 pathogenic variant n.64_65insT was alive at age 45 years and another two individuals were alive in their late thirties [Chen et al 2024, Valenzuela et al 2024, Nava et al 2025], demonstrating that survival into adulthood is possible. A 47-year-old with the RNU4-2 pathogenic variant n.70T>C was reported by Rosenblum et al [2025]. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

RNU4-2 pathogenic variants cluster in two contiguous regions [Greene et al 2024]:

• Region surrounding the quasi-pseudoknot (nucleotides 62-70)
• Stem III duplex-forming region (nucleotides 73-79)

Genotype-phenotype correlation analyses to date suggest that the phenotype varies according to which of the two regions contain the pathogenic variant.

• The region surrounding the quasi-pseudoknot includes nucleotide 62 (Stem I), 63-67 (T loop), and 68-70 (RBM42 interaction domain). The region encompasses the highly recurrent insertion n.64_65insT, which is present in 70%-75% of affected individuals. Variants in this region are associated with a severe phenotype characterized by severe/profound ID with either absent speech or minimal verbal development. Most affected individuals achieve ambulation at a median age of 30 months [Nava et al 2025]. The recurrent variants n.66A>G and n.67A>G are associated with similar features including neonatal hypotonia, microcephaly, epilepsy, and similar dysmorphic facial features [Nava et al 2025]. The clinical phenotype does not appear to vary according to whether the variants are in the Stem I, T loop, or RBM42 interaction domains [Nava et al 2025].
• Variants in the Stem III duplex-forming region, including the recurrent n.76C>T pathogenic variant, are associated with a milder phenotype with fewer brain MRI abnormalities and neonatal findings, less severe DD/ID, and more expressive language skills. Median age at walking is 19 months [Chen et al 2024, Nava et al 2025].

Prevalence

Estimating the prevalence of ReNU syndrome requires a well-estimated, well-defined comparator, combined with a dataset in which both ReNU syndrome and the comparator are represented in reasonably large numbers and with minimal differential ascertainment bias against either condition. Here, we use MECP2-related Rett syndrome as the comparator, which has a global prevalence of ~7.1 in 100,000 females [Petriti et al 2023]. In the United Kingdom, genetic testing of individuals with Rett syndrome, as well as those with unknown neurodevelopmental delays such as ReNU syndrome, is performed by the Genomic Medicine Service (GMS) using genome sequencing. In the GMS, the prevalence of ReNU syndrome was 87.5% of that of MECP2-related Rett syndrome [Greene et al 2024]. The age distributions of the two syndromes in the GMS are similar [E Turro, unpublished data], suggesting minimal ascertainment bias against Rett syndrome due to the possible exclusion of individuals with Rett syndrome diagnosed before the GMS was established in 2018. Assuming the life expectancy of females with MECP2-related Rett syndrome is the same as that of individuals with ReNU syndrome gives a prevalence for ReNU syndrome of ~7.1 × 0.5 × 0.875 = 3.1 in 100,000 individuals of any age and either sex. Using intellectual disability in children as the comparator gives an estimate of ReNU syndrome of slightly more than 3.5 affected individuals in 100,000 children [Barbour et al 2025]. The slightly elevated estimate of prevalence in children relative to the general population is consistent with the effects of a shortened life expectancy, although affected individuals in their forties have been identified.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ReNU syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

Consider avoiding or limiting any substance or medication that may affect bone health (e.g., steroids).

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

RNU4-2–related autosomal dominant neurodevelopmental disorder (ReNU syndrome) is an autosomal dominant disorder. Almost all affected individuals have the disorder as the result of a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Almost all individuals diagnosed with ReNU syndrome have the disorder as the result of a de novo RNU4-2 pathogenic variant.
  • The most common ReNU syndrome–related pathogenic variant (n.64_65insT) occurred as a de novo event in all individuals reported to date whose parents have undergone molecular genetic testing.
  • There exists a strong bias toward a maternal origin of de novo pathogenic variants [Chen et al 2024, Nava et al 2025].
• 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. In two families reported to date with parent-to-child transmission, the maternally transmitted pathogenic variant (n.76C>T) [Greene et al 2024] and the paternally transmitted pathogenic variant (n.72_73del) [Nava et al 2025] were present in individuals with milder phenotypes.
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* (Maternal mosaicism has been reported [Greene et al [2024]). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism for an RNU4-2 pathogenic variant may be mildly/minimally affected or unaffected.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If the RNU4-2 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental mosaicism [Greene et al 2024].
• If a parent of the proband is known to have the RNU4-2 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Note: Based on parent-of-origin studies showing a strong bias toward a maternal origin of de novo pathogenic variants [Chen et al 2024], it has been hypothesized that sperm with an RNU4-2 pathogenic variant are at a disadvantage and, consequently, that the risk to offspring of a male with such a variant may be lower (i.e., less than 50%) [E Turro, personal observation].
• If a parent is known to be mosaic for the RNU4-2 pathogenic variant identified in the proband, the recurrence risk to sibs is up to 50% (mosaicism has been reported in the unaffected mother of a child with ReNU syndrome) [Greene et al 2024].
• If the parents have not been tested for the RNU4-2 pathogenic variant but are clinically unaffected, sibs of a proband are still presumed to be at increased risk for ReNU syndrome because of the possibility of parental gonadal mosaicism.

Offspring of a proband. Each child of an individual with ReNU syndrome has a 50% chance of inheriting the RNU4-2 pathogenic variant. (Note: It has been speculated that sperm with an RNU4-2 pathogenic variant are at a disadvantage and, consequently, that the risk to offspring of a male with such a variant may be lower [i.e., less than 50%].)

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is heterozygous for an RNU4-2 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the RNU4-2 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

RNU4-2 is a close paralog of RNU4-1, a canonical gene that is transcribed into U4 small nuclear RNA (snRNA). RNU4-1 and RNU4-2 are 145 bp in length and differ only at four nucleotides. The functional differences between the two genes are currently unknown. Canonical U4, along with U1, U2, U5, and U6, are noncoding components of the major spliceosome. Pathogenic variants in RNU4-2 that cause the autosomal dominant neurodevelopmental disorder ReNU syndrome occur in nucleotides 62-70 and 73-79 [Greene et al 2024]. A CRISPR-based saturation editing experiment measuring a cell fitness phenotype suggests one of the regions might be slightly narrower, at nucleotides 75-78 rather than 73-79 [De Jonghe et al 2026]. These regions correspond approximately to two structurally and functionally critical elements of the U4 snRNA, the quasi-pseudoknot and the Stem III duplex formed with U6 snRNA, respectively. These two elements surround the critical ACAGAGA loop of U6 snRNA that interacts with 5' splice sites in pre-mRNA during spliceosome activation. Although low-penetrance variants have been reported outside these regions [Bruselles et al 2025], to date the effects of these variants and their interactions with other variants that may modify disease risk remain uncertain.

Emerging evidence from transcriptomic studies of blood cells and fibroblasts suggest pathogenic variants disrupt spliceosome function by altering U4/U6 snRNA structural integrity, leading to aberrant 5' splice site recognition and splicing errors [Chen et al 2024, Nava et al 2025]. However, the reported numbers of abnormal splicing events and their effect sizes are modest. Furthermore, transcriptomic analyses of more disease-relevant cell types, such as neurons, have not been published to date. Therefore, the mechanism of action is suggestive of aberrant splicing but remains to be fully characterized.

Mechanism of disease causation. Most pathogenic RNU4-2 variants responsible for ReNU syndrome occur de novo and cluster in nucleotides 62-70 and 73-79, regions that in the paralog RNU4-1 are thought to be critical for supporting spliceosomal function at 5' splice sites.

RNU4-2-specific laboratory technical considerations

• RNU4-2 is a noncoding gene. Therefore, most available clinical capture kits that target coding regions, including exome sequencing, do not currently include RNU4-2. Genome sequencing or targeted Sanger sequencing are therefore recommended to identify RNU4-2 pathogenic variants that cause ReNU syndrome.
• Pathogenic variants that cause ReNU syndrome occur within nucleotides 62-70 and 73-79 of the gene (chr12[hg38]): 120,291,825–120,291,833 and 120,291,835–120,291,842). These regions contain key domains (see Genotype-Phenotype Correlations). Therefore, careful analysis of these regions (including genome sequencing) is recommended if ReNU syndrome is clinically suspected. There is currently no evidence that variants outside of these regions can cause an autosomal dominant neurodevelopmental disorder with high penetrance. As such, variants outside the regions in monoallelic individuals should be interpreted with care.

Author Notes

Mafalda Barbosa (ude.mssm@asobrab.adlafam), Irene Valenzuela (tac.norbehllav@aleuznelav.eneri), and Maya Chopra (ude.dravrah.snerdlihc@arpohc.ayam) are actively involved in clinical research regarding individuals with RNU4-2–related autosomal dominant neurodevelopmental disorder (ReNU syndrome). They would be happy to communicate with persons who have any questions regarding diagnosis of ReNU syndrome or other considerations.

Acknowledgments

The authors acknowledge the efforts and leadership of the ReNU Syndrome United.

Revision History

• 26 May 2026 (bp) Review posted live
• 16 September 2025 (mb) Original submission

Literature Cited

• Barbour K, Bainbridge MN, Wigby K, Besterman AD, Chuang NA, Tobin LE, Del Campo M, Lenberg J, Bird LM, Friedman J. The face and features of RNU4-2: a new, common, recognizable, yet hidden neurodevelopmental disorder. Pediatr Neurol. 2024;161:188-93. [PubMed: 39423747]
• Barbour K, Friedman J, Bird LM, Del Campo M, Wigby K, Jones M, Chong A, Grinspan ZM. The prevalence of RNU4-2-associated autosomal dominant intellectual disability syndrome. Pediatr Neurol. 2025;164:1-3. [PubMed: 39756185]
• Bruselles A, Mancini C, Chiriatti L, Carvetta M, Baroni MC, Cappelletti C, Caraffi SG, Celario M, Ciolfi A, Cordeddu V, De Falco A, Ferilli M, Garavelli L, Leoni C, Meossi C, Niceta M, Onesimo R, Peluso F, Politano D, Priolo M, Radio FC, Santorelli F, Signorini S, Sirchia F, Valente EM, Zampino G, Tartaglia M. Expanding the mutational spectrum of ReNU syndrome: insights into 5' Stem-loop variants. Eur J Hum Genet. 2025;33:432-40. [PMC free article: PMC11986017] [PubMed: 40011755]
• Chen Y, Dawes R, Kim HC, Ljungdahl A, Stenton SL, Walker S, Lord J, Lemire G, Martin-Geary AC, Ganesh VS, Ma J, Ellingford JM, Delage E, D'Souza EN, Dong S, Adams DR, Allan K, Bakshi M, Baldwin EE, Berger SI, Bernstein JA, Bhatnagar I, Blair E, Brown NJ, Burrage LC, Chapman K, Coman DJ, Compton AG, Cunningham CA, D'Souza P, Danecek P, Delot EC, Dias KR, Elias ER, Elmslie F, Evans CA, Ewans L, Ezell K, Fraser JL, Gallacher L, Genetti CA, Goriely A, Grant CL, Haack T, Higgs JE, Hinch AG, Hurles ME, Kuechler A, Lachlan KL, Lalani SR, Lecoquierre F, Leitao E, Fevre AL, Leventer RJ, Liebelt JE, Lindsay S, Lockhart PJ, Ma AS, Macnamara EF, Mansour S, Maurer TM, Mendez HR, Metcalfe K, Montgomery SB, Moosajee M, Nassogne MC, Neumann S, O'Donoghue M, O'Leary M, Palmer EE, Pattani N, Phillips J, Pitsava G, Pysar R, Rehm HL, Reuter CM, Revencu N, Riess A, Rius R, Rodan L, Roscioli T, Rosenfeld JA, Sachdev R, Shaw-Smith CJ, Simons C, Sisodiya SM, Snell P, St Clair L, Stark Z, Stewart HS, Tan TY, Tan NB, Temple SEL, Thorburn DR, Tifft CJ, Uebergang E, VanNoy GE, Vasudevan P, Vilain E, Viskochil DH, Wedd L, Wheeler MT, White SM, Wojcik M, Wolfe LA, Wolfenson Z, Wright CF, Xiao C, Zocche D, Rubenstein JL, Markenscoff-Papadimitriou E, Fica SM, Baralle D, Depienne C, MacArthur DG, Howson JMM, Sanders SJ, O'Donnell-Luria A, Whiffin N. De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome. Nature. 2024;632:832-40. [PMC free article: PMC11338827] [PubMed: 38991538]
• De Jonghe J, Kim HC, Adedeji A, Leitão E, Dawes R, Kajba CM, Cogné B, Chen Y, Blakes AJM, Simons C, Rius R, Alvi JR, Amblard F, Austin-Tse C, Baer S, Balton EV, Blanc P, Calame DG, Coutton C, Cunningham CA, Dargie N, Dipple KM, Du H, El Chehadeh S, Glass I, Gleeson JG, Grunewald O, Gueguen P, Harbuz R, Jacquemont ML, Leventer RJ, Marijon P, Messaoud O, Sultan T, Thauvin C, Vincent-Delorme C, Yilmaz Gulec E, Thevenon J, Mendez R, MacArthur DG, Depienne C, Nava C, Whiffin N, Findlay GM. Saturation editing of RNU4-2 reveals distinct dominant and recessive disorders. Nature. 2026. Epub ahead of print. [PubMed: 41951737]
• Greene D, De Wispelaere K, Lees J, Codina-Solà M, Jensson BO, Hales E, Katrinecz A, Nieto Molina E, Pascoal S, Pfundt R, Schot R, Sevilla Porras M, Sleutels F, Valenzuela I, Wijngaard R, Arroyo Carrera I, Atton G, Casas-Alba D, Donnelly D, Duat Rodríguez A, Fernández Garoz B, Foulds N, García-Navas Núñez D, González Alguacil E, Jarvis J, Kant SG, Madrigal Bajo I, Martinez-Monseny AF, McKee S, Ortiz Cabrera NV, Rodríguez-Revenga Bodi L, Sariego Jamardo A, Stefansson K, Sulem P, Suri M, Van Karnebeek C, Vasudevan P, Vega Pajares AI, Carracedo Á, Engelen M, Lapunzina P, Morgan NP, Morte B, Rump P, Stirrups K, Tizzano EF, Barakat TS, O'Donoghue M, Pérez-Jurado LA, Freson K, Mumford AD, Turro E. Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsy. Nat Genet. 2025;57:1367-73. [PMC free article: PMC12165851] [PubMed: 40210679]
• Greene D, Mendez R, Lees J, Barbosa M, Bruselles A, Chiriatti L, Ferraro F, Mancini C, Schot R, Sleutels F, Bertini E, Bonner DE, Bouman A, Brooks AS, Cassini TA, Ezell KM, Gomez-Ospina N, Kleefstra T, O'Donoghue M, Rives L, Shashi V, Spillmann RC, Wafik M; Undiagnosed Diseases Network; Freson K, Barakat TS, Tartaglia M, Bernstein JA, Mumford AD, Wheeler MT, Turro E. Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder. Nat Genet. 2026;58:774-81. [PMC free article: PMC13083235] [PubMed: 41912932]
• Greene D, Thys C, Berry IR, Jarvis J, Ortibus E, Mumford AD, Freson K, Turro E. Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders. Nat Med. 2024;30:2165-9. [PMC free article: PMC11333284] [PubMed: 38821540]
• Holling T, von Kroge S, Hecher L, Amling M, Schinke T, Kutsche K, Oheim R. Assessment and treatment of osteoporosis in a patient with a neurodevelopmental disorder caused by a RNU4-2 pathogenic variant (ReNU syndrome). JBMR Plus. 2025;9:ziaf084. [PMC free article: PMC12161495] [PubMed: 40510867]
• Kuroda Y, Nagai K, Kawai Y, Naruto T, Saijou H, Morikawa S, Goto T, Sato M, Kurosawa K. Genotype-phenotype correlations and phenotypic expansion in a case series of ReNU syndrome associated with RNU4-2 variants. J Med Genet. 2025;62:531-5. [PubMed: 40413032]
• Manickam K, McClain MR, Demmer LA, Biswas S, Kearney HM, Malinowski J, Massingham LJ, Miller D, Yu TW, Hisama FM, et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23:2029-37. [PubMed: 34211152]
• Nava C, Cogne B, Santini A, Leitao E, Lecoquierre F, Chen Y, Stenton SL, Besnard T, Heide S, Baer S, Jakhar A, Neuser S, Keren B, Faudet A, Forlani S, Faoucher M, Uguen K, Platzer K, Afenjar A, Alessandri JL, Andres S, Angelini C, Aral B, Arveiler B, Attie-Bitach T, Aubert Mucca M, Banneau G, Barakat TS, Barcia G, Baulac S, Beneteau C, Benkerdou F, Bernard V, Bezieau S, Bonneau D, Bonnet-Dupeyron MN, Boussion S, Boute O, Brischoux-Boucher E, Bryen SJ, Buratti J, Busa T, Caliebe A, Capri Y, Cassinari K, Caumes R, Cenni C, Chambon P, Charles P, Christodoulou J, Colson C, Conrad S, Cospain A, Coursimault J, Courtin T, Couse M, Coutton C, Creveaux I, D'Gama AM, Dauriat B, de Sainte Agathe JM, Del Gobbo G, Delahaye-Duriez A, Delanne J, Denomme-Pichon AS, Dieux-Coeslier A, Do Souto Ferreira L, Doco-Fenzy M, Drukewitz S, Duboc V, Dubourg C, Duffourd Y, Dyment D, El Chehadeh S, Elmaleh M, Faivre L, Fennelly S, Fischer H, Fradin M, Galludec Vaillant C, Ganne B, Ghoumid J, Goel H, Gokce-Samar Z, Goldenberg A, Gonfreville Robert R, Gorokhova S, Goujon L, Granier V, Gras M, Greally JM, Greiten B, Gueguen P, Guerrot AM, Guha S, Guimier A, Haack TB, Hadj Abdallah H, Halleb Y, Harbuz R, Harris M, Hentschel J, Heron B, Hitz MP, Innes AM, Jadas V, Januel L, Jean-Marcais N, Jobanputra V, Jobic F, Jornea L, Jost C, Julia S, Kaiser FJ, Kaschta D, Kaya S, Ketteler P, Khadija B, Kilpert F, Knopp C, Kraft F, Krey I, Lackmy M, Laffargue F, Lambert L, Lamont R, Laugel V, Laurie S, Lauzon JL, Lebreton L, Lebrun M, Legendre M, Leguern E, Lehalle D, Lejeune E, Lesca G, Lesieur-Sebellin M, Levy J, Linglart A, Lyonnet S, Luthy K, Ma AS, Mach C, Mandel JL, Mansour-Hendili L, Marcadier J, Marin V, Margot H, Marquet V, May A, Mayr JA, Meridda C, Michaud V, Michot C, Nadeau G, Naudion S, Nguyen L, Nizon M, Nowak F, Odent S, Olin V, Osei-Owusu IA, Osmond M, Ounap K, Pasquier L, Passemard S, Pauly M, Patat O, Pensec M, Perrin-Sabourin L, Petit F, Philippe C, Planes M, Poduri A, Poirsier C, Pouzet A, Prince B, Prouteau C, Pujol A, Racine C, Rama M, Ramond F, Ranguin K, Raway M, Reis A, Renaud M, Revencu N, Richard AC, Riera-Navarro L, Rius R, Rodriguez D, Rodriguez-Palmero A, Rondeau S, Roser-Unruh A, Rougeot Jung C, Safraou H, Satre V, Saugier-Veber P, Sauvestre C, Schaefer E, Shao W, Schanze I, Schlump JU, Schluter Martin A, Schluth-Bolard C, Schuhmann S, Schroder C, Sebastin M, Sigaudy S, Spielmann M, Spodenkiewicz M, St Clair L, Steffann J, Stoeva R, Surowy H, Tarnopolsky MA, Todosi C, Toutain A, Tran Mau-Them F, Unterlauft A, Van-Gils J, Vanlerberghe C, Vasileiou G, Vera G, Verdel A, Verloes A, Vial Y, Vignal C, Vincent M, Vincent-Delorme C, Vincent-Devulder A, Vitobello A, Weber S, Willems M, Zaafrane-Khachnaoui K, Zacher P, Zeltner L, Ziegler A, Galej WP, Dollfus H, Thauvin C, Boycott KM, Marijon P, Lermine A, Malan V, Rio M, Kuechler A, Isidor B, Drunat S, Smol T, Chatron N, Piton A, Nicolas G, Wagner M, Abou Jamra R, Heron D, Mignot C, Blanc P, O'Donnell-Luria A, Whiffin N, Charbonnier C, Charenton C, Thevenon J, Depienne C. Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption. Nat Genet. 2025;57:1374-88. [PMC free article: PMC12165858] [PubMed: 40379786]
• Okamoto N, Nishi E, Hasegawa Y, Higuchi S, Kuki I, Yanagi K, Kaname T, Uchiyama Y, Matsumoto N. A clinical study of nine patients with ReNU syndrome. Am J Med Genet A. 2025;197:e64151. [PubMed: 40546132]
• Peñafiel-Sam J, Valenzuela I, Peris P. Severe osteoporosis in an adult subject with RNU4-2 gene mutation. Calcif Tissue Int. 2025;116:40. [PubMed: 39961815]
• Petriti U, Dudman DC, Scosyrev E, Lopez-Leon S. Global prevalence of Rett syndrome: systematic review and meta-analysis. Syst Rev. 2023;12:5. [PMC free article: PMC9841621] [PubMed: 36642718]
• Quinodoz M, Rodenburg K, Cvackova Z, Kaminska K, de Bruijn SE, Iglesias-Romero AB, Boonen EGM, Ullah M, Zomer N, Folcher M, Bijon J, Holtes LK, Tsang SH, Corradi Z, Freund KB, Shliaga S, Panneman DM, Hitti-Malin RJ, Ali M, AlTalbishi A, Andreasson S, Ansari G, Arno G, Astuti GDN, Ayuso C, Ayyagari R, Banfi S, Banin E, Barakat TS, Barboni MTS, Bauwens M, Ben-Yosef T, Bernard V, Birch DG, Biswas P, Blanco-Kelly F, Bocquet B, Boon CJF, Branham K, Bremond-Gignac D, Britten-Jones AC, Bujakowska KM, Burin des Roziers C, Cadena EL, Calzetti G, Cancellieri F, Cattaneo L, Chadderton N, Charbel Issa P, Coutinho-Santos L, Daiger SP, De Baere E, De Bruyne M, de la Cerda B, De Roach JN, De Zaeytijd J, Derks R, Dhaenens CM, Dudakova L, Duncan JL, Farrar GJ, Feltgen N, Fenner BJ, Fernandez-Caballero L, Ferraz Sallum JM, Gana S, Garanto A, Gardner JC, Gilissen C, Gonzalez-Duarte R, Goto K, Griffiths-Jones S, Haack TB, Haer-Wigman L, Hardcastle AJ, Hayashi T, Heon E, Hoefsloot LH, Hoischen A, Holtan JP, Hoyng CB, Ibanez MBBt, Inglehearn CF, Iwata T, Jensson BO, Jones K, Kalatzis V, Kamakari S, Karali M, Kellner U, Klaver CCW, Knezy K, Koenekoop RK, Kohl S, Kominami T, Kuhlewein L, Lamey TM, Leibu R, Leroy BP, Liskova P, Lopez I, Lopez-Rodriguez VRJ, Mahieu Q, Mahroo OA, Manes G, Mansard L, Martin-Gutierrez MP, Martins N, Mauring L, McKibbin M, McLaren TL, Meunier I, Michaelides M, Millan JM, Mizobuchi K, Mukherjee R, Nagy ZZ, Neveling K, Oldak M, Oorsprong M, Pan Y, Papachristou A, Percesepe A, Pfau M, Pierce EA, Place E, Ramesar R, Ramond F, Rasquin FA, Rice GI, Roberts L, Rodriguez-Hidalgo M, Ruiz-Ederra J, Sabir AH, Sajiki AF, Sanchez-Barbero AI, Sarma AS, Sangermano R, Santos CM, Scarpato M, Scholl HPN, Sharon D, Signorini SG, Simonelli F, Sousa AB, Stefaniotou M, Stefansson K, Stingl K, Suga A, Sulem P, Sullivan LS, Szabo V, Szaflik JP, Taurina G, Thiadens A, Toomes C, Tran VH, Tsilimbaris MK, Tsoka P, Vaclavik V, Vajter M, Valeina S, Valente EM, Valentine C, Valero R, Valleix S, van Aerschot J, van den Born LI, Van Heetvelde M, Verhoeven VJM, Vincent AL, Webster AR, Whelan L, Wissinger B, Yioti GG, Yoshitake K, Zenteno JC, Zeuli R, Zuleger T, Landau C, Jacob AI, Lin S, Cremers FPM, Lee W, Ellingford JM, Stanek D, Roosing S, Rivolta C. De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa. Nat Genet. 2026;58:169-79. [PMC free article: PMC12807869] [PubMed: 41513982]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Rius R, Blakes AJM, Chen Y, De Jonghe J, Lecoquierre F, Dawes R, Cogne B, Kim HC, Alvi JR, Amblard F, Ansari M, Arlt A, Austin-Tse C, Baer S, Balasubramanian M, Balton EV, Barcia G, Beleza-Meireles A, Bernstein JA, Beygo J, Blanc P, Bramswig NC, Braun F, Buchzik D, Calame DG, Campbell J, Coutton C, Cunningham CA, Dargie N, Depienne C, Dipple KM, Dieux A, Dixit A, Dreyer L, Du H, El Chehadeh S, Field M, Ewans LJ, Geiger V, Gibbs RA, Glass I, Grunewald O, Gueguen P, Haack TB, Hadj Abdallah H, Harbuz R, Helbig I, Horvath J, Hustinx A, Isidor B, Jacquemont ML, Jamie F, Jeanne M, Kessler R, Klinkhammer H, Korenke GC, Kotzaeridou U, Krawitz P, Laurie S, Leventer RJ, Levy RJ, Lupski JR, Marijon P, McGinnis KE, Mendez R, Messaoud O, Nava C, Nizard M, O'Donnell-Luria A, O'Leary MC, Olivieri S, Parida A, Pehlivan D, Prentice AJ, Posey JE, Reuter CM, Satre V, Schluth-Bolard C, Smol T, Sultan T, Taylor J, Thauvin-Robinet C, Thevenon J, Uebergang E, Ueberberg S, Vincent-Delorme C, Wassmer E, Westwood E, Wheeler MT, Gulec EY, Vanderver A, Vossough A, Sanders SJ, Banka S, Findlay GM, MacArthur DG, Simons C, Whiffin N. Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes. Nat Genet. 2026;58:761-73. [PMC free article: PMC13083247] [PubMed: 41951959]
• Rodan LH, Stoler J, Chen E, Geleske T; Council on Genetics. Genetic evaluation of the child with intellectual disability or global developmental delay: clinical report. Pediatrics. 2025;156:e2025072219. [PubMed: 40545261]
• Rosenblum J, Beysen D, Jansen AC, De Rademaeker M, Reyniers E, Janssens K, Meuwissen M. RNU4-2-related neurodevelopmental disorder is associated with a recognisable facial gestalt. Clin Genet. 2025;107:104-12. [PubMed: 39434505]
• Schot R, Ferraro F, Geeven G, Diderich KEM, Barakat TS. Re-analysis of whole genome sequencing ends a diagnostic odyssey: case report of an RNU4-2 related neurodevelopmental disorder. Clin Genet. 2024;106:512-7. [PubMed: 38859706]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Valenzuela I, Codina-Sola M, Vazquez E, Cueto-Gonzalez A, Leno-Colorado J, Lasa-Aranzasti A, Trujillano L, Masotto B, Masas M, Escobar M, Garcia-Arumi E, Tizzano EF. Deep phenotyping of 11 individuals with pathogenic variants in RNU4-2 reveals a clinically recognizable syndrome. Genet Med. 2024;26:101288. [PubMed: 39369315]
• van der Sanden BPGH, Schobers G, Corominas Galbany J, Koolen DA, Sinnema M, van Reeuwijk J, Stumpel CTRM, Kleefstra T, de Vries BBA, Ruiterkamp-Versteeg M, Leijsten N, Kwint M, Derks R, Swinkels H, den Ouden A, Pfundt R, Rinne T, de Leeuw N, Stegmann AP, Stevens SJ, van den Wijngaard A, Brunner HG, Yntema HG, Gilissen C, Nelen MR, Vissers LELM. The performance of genome sequencing as a first-tier test for neurodevelopmental disorders. Eur J Hum Genet. 2023;31:81-8. [PMC free article: PMC9822884] [PubMed: 36114283]