RNU4-2-Related Autosomal Recessive Neurodevelopmental Disorder

Mendelian Pathograph 32 Show in embeddings browser Neurodevelopmental Disorder

RNU4-2-related autosomal recessive neurodevelopmental disorder is a moderate to severe syndromic neurodevelopmental disorder caused by homozygous or compound heterozygous variants in RNU4-2, the gene for the U4 small nuclear RNA of the major spliceosome. The variants lie outside the 18-nucleotide critical region mutated in ReNU syndrome and cluster in other functional elements of U4: stem II, which pairs with U6; the k-turn of the 5' stem loop, which binds SNU13 (15.5K); and the Sm protein binding site needed for snRNA biogenesis and stability, with a few in the terminal stem loop. The disorder was first found from saturation genome editing of RNU4-2 in a haploid human cell line and then characterized in 38 individuals from 28 families, 31 with detailed clinical data. All have global developmental delay or intellectual disability and delayed language, about half are nonverbal, and most have hypotonia; seizures, spasticity, strabismus, microcephaly, short stature and male genital anomalies are common. The distinguishing feature is brain MRI: dilated perivascular spaces in the periventricular and deep white matter, in severe cases coalescing into a tightly packed microcystic pattern, with white matter volume loss, thin corpus callosum and cerebellar atrophy, which can progress on serial imaging. Blood RNA sequencing shows strongly reduced RNU4-2 RNA with upregulation of the paralog RNU4-1, so the disorder acts by loss of function. ReNU syndrome is different on each axis: it is dominant, usually de novo, caused by critical-region variants in the T-loop and stem III, shows raised rather than reduced RNU4-2 levels and a systematic 5' splice site signature that the recessive disorder lacks, and has a different facial gestalt and no comparable microcystic white matter pattern. No splicing defect has yet been detected in the recessive disorder. It is much rarer than ReNU syndrome in outbred populations (0.08% versus 0.69% of undiagnosed neurodevelopmental disorder in the Genomics England 100,000 Genomes Project) and more frequent with parental consanguinity. MONDO has no class for this disease, so disease_term carries a free-text preferred term with no binding and the Mendelian neurodevelopmental disorder class is recorded as a broad match.

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Mappings

MONDO
MONDO:0100500 Mendelian neurodevelopmental disorder Not Yet Curated
skos:broadMatch MONDO
This entry is one recessive Mendelian neurodevelopmental disorder, so the Mendelian neurodevelopmental disorder class, which is also the direct MONDO parent of the ReNU syndrome class MONDO:0971172, is broader than it. A narrower MONDO class was searched for on 2026-11-01 with the OLS4 search API restricted to MONDO. The query "RNU4-2" returned one class, MONDO:0008871 microcephalic osteodysplastic primordial dwarfism type I, which is an RNU4ATAC disease. The queries "U4 snRNA", "recessive neurodevelopmental white matter snRNA" and "RNU4-2 recessive" returned no classes.
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Affected individuals carry two RNU4-2 variants, either homozygous or compound heterozygous. In the expanded cohort of 43 individuals, 15 from 11 families were homozygous and 27 from 22 families compound heterozygous, and all eight individuals with consanguineous parents were homozygous. Heterozygous carriers of variants with significant saturation editing scores are unaffected parents, and UK Biobank participants carrying biallelic variants, almost all with weak function scores, had no neurodevelopmental phenotype. No parent-of-origin bias was found among compound heterozygous variants.
Autosomal recessive inheritance
Show evidence (4 references)
PMID:41951959 SUPPORT Human clinical
"Here we describe a new recessive NDD associated with homozygous and compound heterozygous variants in RNU4-2."
States the recessive inheritance of the disorder.
PMID:41951959 SUPPORT Human clinical
"Fifteen individuals from 11 families had homozygous variants, and 27 individuals from 22 families had compound heterozygous variants."
Counts of homozygous and compound heterozygous individuals.
PMID:41951959 SUPPORT Human clinical
"Eight individuals from five families, all of whom had homozygous variants, had consanguineous parents."
Homozygosity tracks parental consanguinity, as expected for a recessive disorder.
+ 1 more reference
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Discussions and Knowledge Gaps

1
What splicing defect, if any, links the reduction in U4 snRNA to the neurodevelopmental and white matter phenotype?
KNOWLEDGE GAP OPEN recessive_rnu4_2_splicing_defect_undetected
Attached to
pathophysiology#Reduced RNU4-2 U4 snRNA Level pathophysiology#Impaired Brain Development
Blood RNA sequencing from biallelic individuals shows neither the ReNU 5' splice site signature nor the intron retention that equivalent RNU4ATAC variants cause, so no splicing consequence is in this entry's pathograph and the entry does not conform to the module's mis-splicing node. The authors suggest the defect is subtle because a global defect in U2-type introns would not be viable, and that it may only be visible with deeper sequencing or in brain-relevant cells. Whether RNU4-1 upregulation compensates in blood but not in brain is part of the same question.
Show evidence (2 references)
PMID:41951959 SUPPORT Human clinical
"we found no significant intron retention events in either individuals with biallelic variants in RNU4-2 or individuals with ReNU syndrome"
No intron retention signal was found.
PMID:41951959 SUPPORT Human clinical
"We suggest that the splicing defect associated with this disorder may be more subtle, as a global defect across U2-type introns is likely to be nonviable."
The authors' account of why no defect was detected.
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Pathophysiology

6
Biallelic RNU4-2 Stem II, K-Turn or Sm-Site Variants
Two germline RNU4-2 variants, one on each allele, alter U4 snRNA outside the ReNU critical region, in the elements that bind other spliceosome components: stem II, which pairs with U6; the k-turn in the 5' stem loop, which binds SNU13 (15.5K); and the Sm protein binding site, which is needed for snRNA biogenesis and stability. Variants also occur in the terminal stem loop. UK Biobank biallelic variants sit elsewhere, half of them in the 3' stem loop, where no case variant was found. For about a third of case variants the equivalent nucleotide in RNU4ATAC carries a pathogenic variant causing a recessive RNU4atac-opathy. Evidence for the variant spectrum and its structural mapping is from human genetic cohorts; the function scores come from saturation genome editing in haploid HAP1 cells.
RNU4-2 hgnc:10193 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RNU4-2 (hgnc:10193). hgnc:10193 is a gene from the HUGO Gene Nomenclature Committee.
U4/U6 snRNP GO:0071001 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves U4/U6 snRNP (GO:0071001). GO:0071001 is a cellular component from the Gene Ontology.
Downstream
Reduced RNU4-2 U4 snRNA Level
Show evidence (3 references)
PMID:41951959 SUPPORT Human clinical
"We identify 38 individuals with biallelic variants outside the 18-nucleotide ReNU syndrome region that cluster within other functionally important elements of U4: Stem II, the k-turn and the Sm protein binding site."
Defines the genotype and the structural elements affected.
PMID:41951959 SUPPORT Human clinical
"These biallelic variants map to regions of U4 that are important for binding to other spliceosome components: the Stem II region of interaction with U6, the Sm protein binding site that is essential for snRNA biogenesis and stability, and the k-turn structure in the 5′ stem loop that binds to..."
Names what each affected element does in the spliceosome.
PMID:41951737 SUPPORT In vitro / ex vivo
"we identify variants affecting function in regions of RNU4-2 that are critical for interactions with other spliceosome components. We show that these variants cause a new recessive neurodevelopmental disorder that is distinct from ReNU syndrome."
The saturation editing screen that first identified the functionally damaging variants outside the critical region.
Reduced RNU4-2 U4 snRNA Level
In blood RNA sequencing from the Genomics England National Genomic Research Library, three individuals with biallelic variants had RNU4-2 expression about one fifth of controls (mean 314 versus 1,645 TPM), and heterozygous carriers of significant variants a more moderate reduction. Individuals with ReNU syndrome instead had raised RNU4-2. The authors read this as loss of function. Whether the reduction comes from impaired Sm ring loading and snRNP assembly, consistent with where the variants lie, or from another step in U4 biogenesis or decay has not been tested. Evidence is from patient blood transcriptomes.
RNU4-2 hgnc:10193 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RNU4-2 (hgnc:10193). hgnc:10193 is a gene from the HUGO Gene Nomenclature Committee.
U4 snRNP GO:0005687 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves U4 snRNP (GO:0005687). GO:0005687 is a cellular component from the Gene Ontology.
Downstream
Compensatory RNU4-1 Upregulation
Periventricular Perivascular Space Dilation and White Matter Loss
Progressive Cerebellar Atrophy
Impaired Brain Development
Show evidence (3 references)
PMID:41951959 SUPPORT Human clinical
"Using RNA-seq data, we show that individuals with biallelic variants in RNU4-2 have dramatically reduced levels of RNU4-2 RNA, which is consistent with a loss-of-function mechanism."
The measured reduction and its loss-of-function reading.
PMID:41951959 SUPPORT Human clinical
"In contrast, individuals with ReNU syndrome had significantly higher RNU4-2 levels than controls"
The opposite direction in ReNU syndrome separates the two mechanisms.
PMID:41951737 SUPPORT BACKGROUND Human clinical
"Furthermore, biallelic individuals have notably decreased RNU4-2 expression, which is not observed in individuals with ReNU syndrome, supporting a distinct loss-of-function molecular mechanism."
The companion saturation editing paper restates the patient RNA-seq finding reported in PMID:41951959.
Compensatory RNU4-1 Upregulation
In the same blood transcriptomes, expression of the paralog RNU4-1 rose more than fivefold (mean 1,952 versus 346 TPM), so the RNU4-2 to RNU4-1 ratio fell from 5.4 to 0.2. The authors take this as possible compensatory upregulation, and suggest it is incomplete because the disease still occurs; whether RNU4-1 differs functionally, cannot rise far enough, or is not upregulated in brain is unknown. The ratio is proposed as a diagnostic biomarker. Evidence is from patient blood transcriptomes.
Show evidence (2 references)
PMID:41951959 SUPPORT Human clinical
"This is accompanied by an elevation in RNU4-1 levels, which is consistent with potential compensatory upregulation."
The paralog is upregulated in biallelic individuals.
PMID:41951959 SUPPORT Human clinical
"Our data suggest that RNU4-1 cannot fully compensate for loss of RNU4-2."
Compensation is incomplete.
Periventricular Perivascular Space Dilation and White Matter Loss
The defining imaging finding. On review of 13 MRIs by one neuroradiologist every individual had cerebral white matter changes, most often dilated perivascular spaces in the periventricular and deep white matter, which in six severe cases resembled tightly packed microcysts. White matter volume loss, patchy signal abnormality, ventriculomegaly and a thin corpus callosum accompany it. Two siblings imaged serially showed only ventriculomegaly in infancy and progressive perivascular space dilation and white matter loss later, and scans before age 2 showed minimal dilation. Mildly dilated spaces occur in some individuals with ReNU syndrome, but the confluent microcystic pattern was not seen in any. How reduced U4 snRNA produces this is not known. Evidence is from patient MRI.
cerebral white matter UBERON:0002437 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebral white matter, annotated with cerebral hemisphere white matter (UBERON:0002437). UBERON:0002437 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Dilation of Virchow-Robin spaces
Cerebral white matter atrophy
Abnormal cerebral white matter morphology
Thin corpus callosum
Ventriculomegaly
Show evidence (3 references)
PMID:41951959 SUPPORT Human clinical
"Cerebral white matter changes were the most consistent feature, present in 100% (13 of 13), most frequently manifesting as dilation of perivascular spaces in the periventricular and deep white matter."
The white matter pattern on expert MRI review.
PMID:41951959 SUPPORT Human clinical
"their initial scans showed only ventriculomegaly, but follow-up studies revealed progressive pathology, including perivascular space dilation, white matter volume loss and cerebellar atrophy"
The change progresses on serial imaging.
PMID:41951959 SUPPORT Human clinical
"While three of nine individuals with ReNU syndrome had mildly dilated perivascular spaces in the periventricular region, none had the severe dilation mimicking a confluent microcystic appearance that is characteristic of the recessive disorder."
Separates the recessive pattern from ReNU syndrome on the same reviewer's reading.
Progressive Cerebellar Atrophy
Cerebellar atrophy, involving both hemispheres and vermis, is found in half of those imaged and is significantly enriched over ReNU syndrome, where the same reviewer found it in none of nine cases. It appeared on follow-up imaging in serially scanned siblings. The mechanism linking reduced U4 to cerebellar loss is not known. Evidence is from patient MRI.
cerebellum UBERON:0002037 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebellum (UBERON:0002037). UBERON:0002037 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cerebellar atrophy
Ataxia
Show evidence (2 references)
PMID:41951959 SUPPORT Human clinical
"Cerebellar atrophy was not limited to a specific portion of the cerebellum and both cerebellar hemispheres and vermis could be involved."
Extent of the cerebellar involvement.
PMID:41951959 SUPPORT Human clinical
"Furthermore, none of the nine individuals with ReNU had cerebellar atrophy."
The finding distinguishes the recessive disorder from ReNU syndrome.
Impaired Brain Development
Global developmental delay or intellectual disability is universal, with language most affected, and is accompanied by hypotonia, seizures, spasticity, movement disorders and microcephaly. Onset is congenital, neonatal or infantile in most individuals. Siblings share a similar severity, though walking can differ within a sibship. The cellular route from reduced U4 snRNA to these outcomes is not known; this node records the organism-level neurodevelopmental outcome rather than a demonstrated cellular mechanism. Evidence is from patient clinical data.
nervous system development GO:0007399 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased nervous system development (GO:0007399). GO:0007399 is a biological process from the Gene Ontology.
Downstream
Global developmental delay
Intellectual disability
Delayed speech and language development
Absent speech
Delayed gross motor development
Inability to walk
Hypotonia
Seizure
Spasticity
Ataxia
Dystonia
Microcephaly
Atypical behavior
Autistic behavior
Feeding difficulties
Show evidence (2 references)
PMID:41951959 SUPPORT Human clinical
"In summary, we have characterized the phenotype associated with biallelic variants in RNU4-2 as a moderate-to-severe syndromic neurodevelopmental disorder with distinct white matter abnormalities."
The overall clinical outcome.
PMID:41951959 SUPPORT Human clinical
"Most individuals had infantile-onset phenotypes (n = 16; 51.6%), while ten (32.2%) had congenital or neonatal onset and five (16.1%) had childhood onset."
The developmental onset of the disorder.
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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for RNU4-2-Related Autosomal Recessive Neurodevelopmental Disorder Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

31
Cardiovascular 1
Dilation of Virchow-Robin spaces FREQUENT HP:0012520 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated perivascular spaces, annotated with Dilation of Virchow-Robin spaces (HP:0012520). HP:0012520 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"the recessive disorder frequently presents dilated perivascular spaces that can mimic a compact microcystic appearance (18 of 23; 78.3%"
Frequency of the characteristic perivascular space dilation.
Digestive 1
Feeding difficulties FREQUENT HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"Feeding difficulties57.1% (4/7)44.4% (8/18)48.0% (12/25)Short stature14.3%"
Table 1 row; the last figure is the whole cohort (12 of 25).
Eye 1
Strabismus FREQUENT HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41951959 SUPPORT Human clinical
"Strabismus/esotropia42.9% (3/7)57.1% (12/21)53.6% (15/28)Seizure62.5% (5/8)"
Table 1 row; the third figure is the whole cohort (15 of 28), before the next row begins.
PMID:41951959 SUPPORT Human clinical
"synophrys (individuals 2, 4, 11, 18, 32), strabismus (individuals 2, 4, 11, 18, 28, 31)"
Strabismus is recurrent among photographed individuals.
Genitourinary 2
Micropenis HP:0000054 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micropenis (HP:0000054). HP:0000054 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"Genital anomalies were observed in 9 of 21 males (42.8%), including micropenis, cryptorchidism, hypoplastic scrotum and testicular ectopia."
Micropenis among the male genital anomalies.
Cryptorchidism HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"Genital anomalies were observed in 9 of 21 males (42.8%), including micropenis, cryptorchidism, hypoplastic scrotum and testicular ectopia."
Cryptorchidism among the male genital anomalies.
Head and Neck 6
Microcephaly FREQUENT HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"Microcephaly42.9% (3/7)43.5% (10/23)43.3% (13/30)Feeding difficulties57.1%"
Table 1 row; the last figure is the whole cohort (13 of 30), after the biallelic pathogenic and the VUS-containing subsets.
Abnormal facial shape VERY_FREQUENT HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysmorphic facial features, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41951959 SUPPORT Human clinical
"Dysmorphic facial features57.1% (4/7)87.0% (20/23)80.0% (24/30)Abnormality of the eye62.5%"
Table 1 row; the last figure is the whole cohort (24 of 30).
PMID:41951959 SUPPORT Human clinical
"These data indicate there is convergence within, but distinction between, the facial phenotypes of the dominant and recessive disorders."
Facial gestalt analysis separates the recessive disorder from ReNU syndrome.
Synophrys HP:0000664 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Synophrys (HP:0000664). HP:0000664 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"Dysmorphic features were variable across individuals but commonly included a high anterior hairline (seen in individuals 2, 18, 28, 31), synophrys (individuals 2, 4, 11, 18, 32)"
Synophrys among the recurrent facial features in photographed individuals.
High anterior hairline HP:0009890 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High anterior hairline (HP:0009890). HP:0009890 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"Dysmorphic features were variable across individuals but commonly included a high anterior hairline (seen in individuals 2, 18, 28, 31), synophrys (individuals 2, 4, 11, 18, 32)"
High anterior hairline among the recurrent facial features in photographed individuals.
Upslanted palpebral fissure HP:0000582 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Upslanted palpebral fissures, annotated with Upslanted palpebral fissure (HP:0000582). HP:0000582 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"upslanted palpebral fissures (individuals 11, 18, 28, 31), broad nasal bridge and base (individuals 11, 18, 28), thin upper lip (individuals 2, 28, 31) and dental diastema (individuals 2, 11, 28, 31)"
Upslanted palpebral fissures among the recurrent facial features.
Diastema HP:0000699 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dental diastema, annotated with Diastema (HP:0000699). HP:0000699 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41951959 SUPPORT Human clinical
"upslanted palpebral fissures (individuals 11, 18, 28, 31), broad nasal bridge and base (individuals 11, 18, 28), thin upper lip (individuals 2, 28, 31) and dental diastema (individuals 2, 11, 28, 31)"
Dental diastema among the recurrent features.
PMID:41951959 SUPPORT Human clinical
"Dental anomalies0% (0/7)57.9% (11/19)42.3% (11/26)Abnormality of the genitalia14.3%"
Table 1 row for dental anomalies overall; the last figure is the whole cohort (11 of 26).
Musculoskeletal 2
Hypotonia VERY_FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"Most individuals had a history of hypotonia (83.9%; 26 of 31), with neonatal onset in 64% (19 of 26), which was commonly associated with feeding difficulties."
Frequency and onset of hypotonia.
Spasticity FREQUENT HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"Spasticity was present in 15 of 30 individuals (50.0%)"
Frequency of spasticity.
Nervous System 16
Global developmental delay OBLIGATE HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41951959 SUPPORT Human clinical
"Global developmental delay (GDD) or intellectual disability (ID) was present in all individuals (n = 30)."
Universal developmental delay or intellectual disability.
PMID:41951959 SUPPORT Human clinical
"Severity data, available for 29 individuals, revealed severe GDD in 15 (51.7%) and moderate GDD in 13 (44.8%)."
Severity distribution.
Intellectual disability OBLIGATE HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41951959 SUPPORT Human clinical
"Global developmental delay (GDD) or intellectual disability (ID) was present in all individuals (n = 30)."
Universal developmental delay or intellectual disability.
PMID:41408479 SUPPORT Human clinical
"individuals with biallelic variants exhibited developmental delay and intellectual disability that were similar to but milder than those with monoallelic variants, notably lacking extracerebral organ involvement"
Independent cohort; intellectual disability present but milder than in ReNU syndrome.
Delayed speech and language development OBLIGATE HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed language development, annotated with Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"All individuals (n = 29; 100%) exhibited delayed language development."
Language delay is universal.
Absent speech FREQUENT HP:0001344 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nonverbal, annotated with Absent speech (HP:0001344). HP:0001344 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"Fifteen (51.7%) individuals older than 2 years were nonverbal or had no meaningful spoken language."
Frequency of absent speech.
Delayed gross motor development VERY_FREQUENT HP:0002194 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed walking, annotated with Delayed gross motor development (HP:0002194). HP:0002194 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"Among the 18 individuals who achieved ambulation, first steps were consistently delayed, with a median of 2.5 years ranging from 1.4 years to over 5 years."
Walking is delayed in all who achieve it.
Inability to walk OCCASIONAL HP:0002540 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inability to walk (HP:0002540). HP:0002540 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"Inability to walk was reported in 7 of 25 individuals older than 5 years (28.0%)."
Frequency of non-ambulation.
Seizure FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizures, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41951959 SUPPORT Human clinical
"Seizures occurred in 19 of 31 individuals (63.3%) with a median onset of 2.2 years."
Frequency and onset of seizures.
PMID:41951959 SUPPORT Human clinical
"Three individuals (15.8%) had pharmacoresistant epilepsy with persistent daily seizures."
A minority have drug-resistant epilepsy.
Ataxia FREQUENT HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"movement and coordination abnormalities were observed in 13 of 30 individuals (43.3%), nine with ataxia, three with dystonia"
Frequency of ataxia.
Dystonia OCCASIONAL HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"movement and coordination abnormalities were observed in 13 of 30 individuals (43.3%), nine with ataxia, three with dystonia"
Frequency of dystonia.
Abnormal cerebral white matter morphology FREQUENT HP:0002500 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of cerebral white matter, annotated with Abnormal cerebral white matter morphology (HP:0002500). HP:0002500 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41951959 SUPPORT Human clinical
"demonstrating that the recessive disorder is clinically distinct from ReNU syndrome and is associated with distinctive white matter abnormalities, including enlarged perivascular spaces"
White matter abnormality is the distinguishing feature of the disorder.
PMID:41951959 SUPPORT Human clinical
"Abnormality of cerebral white matter57.1% (4/7)85.0% (17/20)77.8% (21/27)"
Table 1 row giving cerebral white matter abnormality in 21 of 27 individuals with brain imaging data (4 of 7 with both alleles pathogenic or likely pathogenic, 17 of 20 with one or both alleles of uncertain significance).
Cerebral white matter atrophy HP:0012762 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is White matter volume loss, annotated with Cerebral white matter atrophy (HP:0012762). HP:0012762 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"most commonly including dilation of perivascular spaces in the periventricular white matter and white matter volume loss"
White matter volume loss is among the most common MRI findings.
Thin corpus callosum HP:0033725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin corpus callosum (HP:0033725). HP:0033725 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41951959 SUPPORT Human clinical
"Thinning of the corpus callosum was a common feature in both ReNU syndrome and the recessive NDD."
Corpus callosum thinning is common.
PMID:41951959 SUPPORT Human clinical
"Abnormality of the corpus callosum57.1% (4/7)50.0% (7/14)52.4% (11/21)"
Table 1 row giving a corpus callosum abnormality in 11 of 21 individuals. The row counts any corpus callosum abnormality, not thinning alone, so no frequency is set on this thinning phenotype.
Ventriculomegaly HP:0002119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventriculomegaly (HP:0002119). HP:0002119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"their initial scans showed only ventriculomegaly, but follow-up studies revealed progressive pathology, including perivascular space dilation, white matter volume loss and cerebellar atrophy"
Ventriculomegaly is the earliest imaging finding in serially scanned siblings.
Cerebellar atrophy FREQUENT HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272). HP:0001272 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"Cerebellar atrophy is observed in 50.0% (12 of 24) of the recessive individuals showing a significant enrichment in the recessive disorder"
Frequency and enrichment of cerebellar atrophy.
Atypical behavior FREQUENT HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Behavioral abnormality, annotated with Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"Behavioral abnormalities were reported in 14 of 23 (60.9%)"
Frequency of behavioral abnormality.
Autistic behavior OCCASIONAL HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autism spectrum disorder, annotated with Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"Autism spectrum disorder14.3% (1/7)35.7% (5/14)28.6% (6/21)Failure to thrive28.6% (2/7)26.3% (5/19)26.9% (7/26)"
Table 1 row for autism; the last figure before the next row is the whole cohort (6 of 21).
Growth 2
Short stature FREQUENT HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"Short stature14.3% (1/7)52.2% (12/23)43.3% (13/30)Abnormality of"
Table 1 row; the last figure is the whole cohort (13 of 30).
Failure to thrive OCCASIONAL HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"Autism spectrum disorder14.3% (1/7)35.7% (5/14)28.6% (6/21)Failure to thrive28.6% (2/7)26.3% (5/19)26.9% (7/26)"
Table 1 row for failure to thrive; the last figure is the whole cohort (7 of 26).
🧬

Genetic Associations

1
RNU4-2
Gene: RNU4-2 hgnc:10193 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RNU4-2 (hgnc:10193). hgnc:10193 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:41951959 SUPPORT Human clinical
"we identified biallelic RNU4-2 variants in six of 5,386 trios with undiagnosed NDD, compared to zero of 4,776 trios with non-NDD phenotypes"
Case-control enrichment of biallelic variants in undiagnosed neurodevelopmental disorder.
PMID:41951737 SUPPORT In vitro / ex vivo
"we identify variants affecting function in regions of RNU4-2 that are critical for interactions with other spliceosome components. We show that these variants cause a new recessive neurodevelopmental disorder that is distinct from ReNU syndrome."
The saturation editing study that established the gene-disease link.
PMID:41408479 SUPPORT Human clinical
"These results suggest that pathogenic RNU4-2 variants act in both dominant and recessive manners, and that non-critical regions may also harbor disease-causing variants."
Independent replication in a Japanese cohort.
Variants (3)
n.7G>C
single nucleotide variant
In stem II (n.3-n.16), the region of U4 that pairs with U6. Seen both homozygous and compound heterozygous.
Show evidence (2 references)
PMID:41951959 SUPPORT Human clinical
"Three variants (n.127C>T, n.119A>G and n.7G>C) were observed in both homozygous and compound heterozygous genotypes."
Recurrence in homozygous and compound heterozygous cases.
PMID:41951959 SUPPORT Human clinical
"Variants were annotated with the region of RNU4-2 to which they map using the following nucleotides: Stem II (n.3 to n.16)"
Places n.7 in stem II.
n.119A>G
single nucleotide variant
In the Sm protein binding site (n.118-n.126), needed for snRNA biogenesis and stability. Seen both homozygous and compound heterozygous.
Show evidence (2 references)
PMID:41951959 SUPPORT Human clinical
"Three variants (n.127C>T, n.119A>G and n.7G>C) were observed in both homozygous and compound heterozygous genotypes."
Recurrence in homozygous and compound heterozygous cases.
PMID:41951959 SUPPORT Human clinical
"Sm protein (n.118 to n.126); and terminal stem loop (n.127 to n.144)"
Places n.119 in the Sm site.
n.127C>T
single nucleotide variant
At the first nucleotide of the terminal stem loop (n.127-n.144), next to the Sm site. Seen both homozygous and compound heterozygous.
Show evidence (2 references)
PMID:41951959 SUPPORT Human clinical
"Three variants (n.127C>T, n.119A>G and n.7G>C) were observed in both homozygous and compound heterozygous genotypes."
Recurrence in homozygous and compound heterozygous cases.
PMID:41951959 SUPPORT Human clinical
"Sm protein (n.118 to n.126); and terminal stem loop (n.127 to n.144)"
Places n.127 in the terminal stem loop.
💊

Medical Actions

1
Anti-seizure pharmacotherapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: anticonvulsant NCIT:C264 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses anticonvulsant, annotated with Anticonvulsant Agent (NCIT:C264). NCIT:C264 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Of 19 individuals with seizures, 17 received antiseizure medication; 13 were controlled on monotherapy and four needed more than one drug. No disease-modifying treatment exists.
Mechanism Target:
Seizure — Symptomatic control of seizures.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"Most were treatment-responsive: 13 received monotherapy and four required more than one antiseizure medication."
Response to antiseizure medication.
🔬

Diagnosis

1
Genome sequencing with RNU4-2 interrogation
RNU4-2 is a short snRNA gene found by genome sequencing. The marked periventricular perivascular space dilation on MRI should prompt analysis of RNU4-2. Because saturation editing scores are less sensitive for recessive variants, a normal score is not evidence of benignity in this setting, and the authors recommend only supporting-level weight for significant scores. A reduced RNU4-2 to RNU4-1 expression ratio in blood RNA sequencing is a candidate diagnostic biomarker that still needs validation.
clinical whole genome sequencing NCIT:C101294 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:41951959 SUPPORT Human clinical
"The presence of these changes on MRI, particularly the marked periventricular perivascular space dilation, should prompt sequencing and analysis of variants in RNU4-2."
MRI pattern as a trigger for RNU4-2 testing.
PMID:41951959 SUPPORT Human clinical
"As such, normal SGE scores should not be used as evidence of benignity in a recessive context."
Limit of the functional assay for variant interpretation.
PMID:41951959 SUPPORT Human clinical
"The RNU4-2 to RNU4-1 ratio discriminates strongly between cases and controls; therefore, it could be a useful diagnostic biomarker for the recessive disorder, if validated in additional cohorts."
Candidate expression biomarker.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from RNU4-2-Related Autosomal Recessive Neurodevelopmental Disorder:

ReNU syndrome MONDO:0971172
Overlapping Features The dominant RNU4-2 disorder, caused by usually de novo heterozygous variants in the 18-nucleotide critical region (T-loop and stem III). It shares developmental delay, language impairment and seizures, but differs in facial gestalt, lacks the confluent microcystic perivascular space pattern and cerebellar atrophy, shows raised rather than reduced RNU4-2 levels, and has a systematic 5' splice site signature that the recessive disorder lacks.
Distinguishing Features
  • Dominant, usually de novo heterozygous rather than biallelic
  • Variants inside the 18-nucleotide critical region
  • Raised rather than reduced RNU4-2 transcript
  • Systematic 5' splice site changes on blood RNA sequencing
  • No confluent microcystic perivascular space pattern and no cerebellar atrophy
Show evidence (2 references)
PMID:41951959 SUPPORT Human clinical
"We showed that the recessive NDD is distinct from dominant ReNU syndrome at the genetic, phenotypic and mechanistic levels."
The two disorders differ on every axis.
PMID:41951959 SUPPORT Human clinical
"the three biallelic RNU4-2 cases clustered with the controls rather than patients with ReNU syndrome, which is consistent with them not having the same systematic changes to 5′ splice site usage as observed in ReNU syndrome"
The ReNU splicing signature is absent in the recessive disorder.
RNU4atac-opathy
Overlapping Features Recessive disorders (microcephalic osteodysplastic primordial dwarfism type I, Lowry-Wood and Roifman syndromes) caused by variants at structurally equivalent positions of the minor spliceosome U4atac snRNA, which, unlike this disorder, show retention of U12-type introns.
Show evidence (1 reference)
PMID:41951959 SUPPORT Human clinical
"Strikingly, variants in the equivalent regions and nucleotides of U4ATAC (the minor spliceosome homolog of U4) cause the RNU4atac-opathies"
The minor spliceosome counterpart affects the equivalent structural regions.
{ }

Source YAML

click to show 
name: RNU4-2-Related Autosomal Recessive Neurodevelopmental Disorder
creation_date: "2026-11-01T22:08:20Z"
category: Mendelian
synonyms:
- Recessive RNU4-2-related neurodevelopmental disorder
- Recessive RNU4-2-associated neurodevelopmental disorder
- Recessive RNU4-2 syndrome
- Biallelic RNU4-2 neurodevelopmental syndrome
parents:
- Neurodevelopmental Disorder
description: >-
  RNU4-2-related autosomal recessive neurodevelopmental disorder is a moderate
  to severe syndromic neurodevelopmental disorder caused by homozygous or
  compound heterozygous variants in RNU4-2, the gene for the U4 small nuclear
  RNA of the major spliceosome. The variants lie outside the 18-nucleotide
  critical region mutated in ReNU syndrome and cluster in other functional
  elements of U4: stem II, which pairs with U6; the k-turn of the 5' stem
  loop, which binds SNU13 (15.5K); and the Sm protein binding site needed for
  snRNA biogenesis and stability, with a few in the terminal stem loop. The
  disorder was first found from saturation genome editing of RNU4-2 in a
  haploid human cell line and then characterized in 38 individuals from 28
  families, 31 with detailed clinical data. All have global developmental
  delay or intellectual disability and delayed language, about half are
  nonverbal, and most have hypotonia; seizures, spasticity, strabismus,
  microcephaly, short stature and male genital anomalies are common. The
  distinguishing feature is brain MRI: dilated perivascular spaces in the
  periventricular and deep white matter, in severe cases coalescing into a
  tightly packed microcystic pattern, with white matter volume loss, thin
  corpus callosum and cerebellar atrophy, which can progress on serial
  imaging. Blood RNA sequencing shows strongly reduced RNU4-2 RNA with
  upregulation of the paralog RNU4-1, so the disorder acts by loss of
  function. ReNU syndrome is different on each axis: it is dominant, usually
  de novo, caused by critical-region variants in the T-loop and stem III,
  shows raised rather than reduced RNU4-2 levels and a systematic 5' splice
  site signature that the recessive disorder lacks, and has a different facial
  gestalt and no comparable microcystic white matter pattern. No splicing
  defect has yet been detected in the recessive disorder. It is much rarer
  than ReNU syndrome in outbred populations (0.08% versus 0.69% of
  undiagnosed neurodevelopmental disorder in the Genomics England 100,000
  Genomes Project) and more frequent with parental consanguinity. MONDO has
  no class for this disease, so disease_term carries a free-text preferred
  term with no binding and the Mendelian neurodevelopmental disorder class is
  recorded as a broad match.
disease_term:
  preferred_term: RNU4-2-related autosomal recessive neurodevelopmental disorder
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0100500
      label: Mendelian neurodevelopmental disorder
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      This entry is one recessive Mendelian neurodevelopmental disorder, so
      the Mendelian neurodevelopmental disorder class, which is also the
      direct MONDO parent of the ReNU syndrome class MONDO:0971172, is broader
      than it. A narrower MONDO class was searched for on 2026-11-01 with the
      OLS4 search API restricted to MONDO. The query "RNU4-2" returned one
      class, MONDO:0008871 microcephalic osteodysplastic primordial dwarfism
      type I, which is an RNU4ATAC disease. The queries "U4 snRNA", "recessive
      neurodevelopmental white matter snRNA" and "RNU4-2 recessive" returned no
      classes.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals carry two RNU4-2 variants, either homozygous or
    compound heterozygous. In the expanded cohort of 43 individuals, 15 from 11
    families were homozygous and 27 from 22 families compound heterozygous, and
    all eight individuals with consanguineous parents were homozygous.
    Heterozygous carriers of variants with significant saturation editing
    scores are unaffected parents, and UK Biobank participants carrying
    biallelic variants, almost all with weak function scores, had no
    neurodevelopmental phenotype. No parent-of-origin bias was found among
    compound heterozygous variants.
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe a new recessive NDD associated with homozygous and compound heterozygous variants in RNU4-2."
    explanation: States the recessive inheritance of the disorder.
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fifteen individuals from 11 families had homozygous variants, and 27 individuals from 22 families had compound heterozygous variants."
    explanation: Counts of homozygous and compound heterozygous individuals.
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eight individuals from five families, all of whom had homozygous variants, had consanguineous parents."
    explanation: Homozygosity tracks parental consanguinity, as expected for a recessive disorder.
  - reference: PMID:41408479
    reference_title: "Monoallelic and biallelic RNU4-2 variants in neurodevelopmental disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "4 from two families with compound heterozygous variants in non-critical regions (stem II, the k-turn, and the Sm-binding site)"
    explanation: An independent Japanese cohort reports compound heterozygous families in the same structural elements.
pathophysiology:
- name: Biallelic RNU4-2 Stem II, K-Turn or Sm-Site Variants
  conforms_to: "spliceosome_component_dysfunction#Germline Spliceosome Component Variant"
  description: >-
    Two germline RNU4-2 variants, one on each allele, alter U4 snRNA outside
    the ReNU critical region, in the elements that bind other spliceosome
    components: stem II, which pairs with U6; the k-turn in the 5' stem loop,
    which binds SNU13 (15.5K); and the Sm protein binding site, which is
    needed for snRNA biogenesis and stability. Variants also occur in the
    terminal stem loop. UK Biobank biallelic variants sit elsewhere, half of
    them in the 3' stem loop, where no case variant was found. For about a
    third of case variants the equivalent nucleotide in RNU4ATAC carries a
    pathogenic variant causing a recessive RNU4atac-opathy. Evidence for the
    variant spectrum and its structural mapping is from human genetic cohorts;
    the function scores come from saturation genome editing in haploid HAP1
    cells.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: RNU4-2
    term:
      id: hgnc:10193
      label: RNU4-2
  cellular_components:
  - preferred_term: U4/U6 snRNP
    term:
      id: GO:0071001
      label: U4/U6 snRNP
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identify 38 individuals with biallelic variants outside the 18-nucleotide ReNU syndrome region that cluster within other functionally important elements of U4: Stem II, the k-turn and the Sm protein binding site."
    explanation: Defines the genotype and the structural elements affected.
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These biallelic variants map to regions of U4 that are important for binding to other spliceosome components: the Stem II region of interaction with U6, the Sm protein binding site that is essential for snRNA biogenesis and stability, and the k-turn structure in the 5′ stem loop that binds to SNU13/15.5k."
    explanation: Names what each affected element does in the spliceosome.
  - reference: PMID:41951737
    reference_title: "Saturation editing of RNU4-2 reveals distinct dominant and recessive disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we identify variants affecting function in regions of RNU4-2 that are critical for interactions with other spliceosome components. We show that these variants cause a new recessive neurodevelopmental disorder that is distinct from ReNU syndrome."
    explanation: The saturation editing screen that first identified the functionally damaging variants outside the critical region.
  downstream:
  - target: Reduced RNU4-2 U4 snRNA Level
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41951959
      reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we find reduced RNU4-2 transcript levels in individuals with the recessive disorder, suggesting a loss-of-function disease mechanism that is distinct from the mechanism underlying ReNU syndrome"
      explanation: Biallelic variant carriers have reduced RNU4-2 transcript.
- name: Reduced RNU4-2 U4 snRNA Level
  description: >-
    In blood RNA sequencing from the Genomics England National Genomic
    Research Library, three individuals with biallelic variants had RNU4-2
    expression about one fifth of controls (mean 314 versus 1,645 TPM), and
    heterozygous carriers of significant variants a more moderate reduction.
    Individuals with ReNU syndrome instead had raised RNU4-2. The authors read
    this as loss of function. Whether the reduction comes from impaired Sm
    ring loading and snRNP assembly, consistent with where the variants lie,
    or from another step in U4 biogenesis or decay has not been tested.
    Evidence is from patient blood transcriptomes.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: RNU4-2
    term:
      id: hgnc:10193
      label: RNU4-2
  cellular_components:
  - preferred_term: U4 snRNP
    term:
      id: GO:0005687
      label: U4 snRNP
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using RNA-seq data, we show that individuals with biallelic variants in RNU4-2 have dramatically reduced levels of RNU4-2 RNA, which is consistent with a loss-of-function mechanism."
    explanation: The measured reduction and its loss-of-function reading.
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, individuals with ReNU syndrome had significantly higher RNU4-2 levels than controls"
    explanation: The opposite direction in ReNU syndrome separates the two mechanisms.
  - reference: PMID:41951737
    reference_title: "Saturation editing of RNU4-2 reveals distinct dominant and recessive disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Furthermore, biallelic individuals have notably decreased RNU4-2 expression, which is not observed in individuals with ReNU syndrome, supporting a distinct loss-of-function molecular mechanism."
    explanation: >-
      The companion saturation editing paper restates the patient RNA-seq
      finding reported in PMID:41951959.
  downstream:
  - target: Compensatory RNU4-1 Upregulation
    causal_link_type: UNKNOWN
  - target: Periventricular Perivascular Space Dilation and White Matter Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Progressive Cerebellar Atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Impaired Brain Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Compensatory RNU4-1 Upregulation
  description: >-
    In the same blood transcriptomes, expression of the paralog RNU4-1 rose
    more than fivefold (mean 1,952 versus 346 TPM), so the RNU4-2 to RNU4-1
    ratio fell from 5.4 to 0.2. The authors take this as possible compensatory
    upregulation, and suggest it is incomplete because the disease still
    occurs; whether RNU4-1 differs functionally, cannot rise far enough, or is
    not upregulated in brain is unknown. The ratio is proposed as a diagnostic
    biomarker. Evidence is from patient blood transcriptomes.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is accompanied by an elevation in RNU4-1 levels, which is consistent with potential compensatory upregulation."
    explanation: The paralog is upregulated in biallelic individuals.
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data suggest that RNU4-1 cannot fully compensate for loss of RNU4-2."
    explanation: Compensation is incomplete.
- name: Periventricular Perivascular Space Dilation and White Matter Loss
  description: >-
    The defining imaging finding. On review of 13 MRIs by one neuroradiologist
    every individual had cerebral white matter changes, most often dilated
    perivascular spaces in the periventricular and deep white matter, which in
    six severe cases resembled tightly packed microcysts. White matter volume
    loss, patchy signal abnormality, ventriculomegaly and a thin corpus
    callosum accompany it. Two siblings imaged serially showed only
    ventriculomegaly in infancy and progressive perivascular space dilation
    and white matter loss later, and scans before age 2 showed minimal
    dilation. Mildly dilated spaces occur in some individuals with ReNU
    syndrome, but the confluent microcystic pattern was not seen in any. How
    reduced U4 snRNA produces this is not known. Evidence is from patient MRI.
  biological_scale: TISSUE
  locations:
  - preferred_term: cerebral white matter
    term:
      id: UBERON:0002437
      label: cerebral hemisphere white matter
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cerebral white matter changes were the most consistent feature, present in 100% (13 of 13), most frequently manifesting as dilation of perivascular spaces in the periventricular and deep white matter."
    explanation: The white matter pattern on expert MRI review.
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "their initial scans showed only ventriculomegaly, but follow-up studies revealed progressive pathology, including perivascular space dilation, white matter volume loss and cerebellar atrophy"
    explanation: The change progresses on serial imaging.
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While three of nine individuals with ReNU syndrome had mildly dilated perivascular spaces in the periventricular region, none had the severe dilation mimicking a confluent microcystic appearance that is characteristic of the recessive disorder."
    explanation: Separates the recessive pattern from ReNU syndrome on the same reviewer's reading.
  downstream:
  - target: Dilation of Virchow-Robin spaces
  - target: Cerebral white matter atrophy
  - target: Abnormal cerebral white matter morphology
  - target: Thin corpus callosum
  - target: Ventriculomegaly
- name: Progressive Cerebellar Atrophy
  description: >-
    Cerebellar atrophy, involving both hemispheres and vermis, is found in half
    of those imaged and is significantly enriched over ReNU syndrome, where the
    same reviewer found it in none of nine cases. It appeared on follow-up
    imaging in serially scanned siblings. The mechanism linking reduced U4 to
    cerebellar loss is not known. Evidence is from patient MRI.
  biological_scale: TISSUE
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cerebellar atrophy was not limited to a specific portion of the cerebellum and both cerebellar hemispheres and vermis could be involved."
    explanation: Extent of the cerebellar involvement.
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, none of the nine individuals with ReNU had cerebellar atrophy."
    explanation: The finding distinguishes the recessive disorder from ReNU syndrome.
  downstream:
  - target: Cerebellar atrophy
  - target: Ataxia
- name: Impaired Brain Development
  description: >-
    Global developmental delay or intellectual disability is universal, with
    language most affected, and is accompanied by hypotonia, seizures,
    spasticity, movement disorders and microcephaly. Onset is congenital,
    neonatal or infantile in most individuals. Siblings share a similar
    severity, though walking can differ within a sibship. The cellular route
    from reduced U4 snRNA to these outcomes is not known; this node records the
    organism-level neurodevelopmental outcome rather than a demonstrated
    cellular mechanism. Evidence is from patient clinical data.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: nervous system development
    term:
      id: GO:0007399
      label: nervous system development
    modifier: DECREASED
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In summary, we have characterized the phenotype associated with biallelic variants in RNU4-2 as a moderate-to-severe syndromic neurodevelopmental disorder with distinct white matter abnormalities."
    explanation: The overall clinical outcome.
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most individuals had infantile-onset phenotypes (n = 16; 51.6%), while ten (32.2%) had congenital or neonatal onset and five (16.1%) had childhood onset."
    explanation: The developmental onset of the disorder.
  downstream:
  - target: Global developmental delay
  - target: Intellectual disability
  - target: Delayed speech and language development
  - target: Absent speech
  - target: Delayed gross motor development
  - target: Inability to walk
  - target: Hypotonia
  - target: Seizure
  - target: Spasticity
  - target: Ataxia
  - target: Dystonia
  - target: Microcephaly
  - target: Atypical behavior
  - target: Autistic behavior
  - target: Feeding difficulties
phenotypes:
- name: Global developmental delay
  category: Neurologic
  frequency: OBLIGATE
  description: >-
    Present in all 30 individuals assessed; severe in 15 of 29 and moderate in
    13 of 29.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Global developmental delay (GDD) or intellectual disability (ID) was present in all individuals (n = 30)."
    explanation: Universal developmental delay or intellectual disability.
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severity data, available for 29 individuals, revealed severe GDD in 15 (51.7%) and moderate GDD in 13 (44.8%)."
    explanation: Severity distribution.
- name: Intellectual disability
  category: Neurologic
  frequency: OBLIGATE
  description: >-
    Present in all individuals assessed (29 of 29), usually moderate or
    severe. In a Japanese cohort, individuals with biallelic variants were
    milder than those with ReNU syndrome.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Global developmental delay (GDD) or intellectual disability (ID) was present in all individuals (n = 30)."
    explanation: Universal developmental delay or intellectual disability.
  - reference: PMID:41408479
    reference_title: "Monoallelic and biallelic RNU4-2 variants in neurodevelopmental disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "individuals with biallelic variants exhibited developmental delay and intellectual disability that were similar to but milder than those with monoallelic variants, notably lacking extracerebral organ involvement"
    explanation: Independent cohort; intellectual disability present but milder than in ReNU syndrome.
- name: Delayed speech and language development
  category: Neurologic
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Delayed language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All individuals (n = 29; 100%) exhibited delayed language development."
    explanation: Language delay is universal.
- name: Absent speech
  category: Neurologic
  frequency: FREQUENT
  description: Nonverbal or no meaningful spoken language in 15 of 29 individuals older than 2 years.
  phenotype_term:
    preferred_term: Nonverbal
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fifteen (51.7%) individuals older than 2 years were nonverbal or had no meaningful spoken language."
    explanation: Frequency of absent speech.
- name: Delayed gross motor development
  category: Neurologic
  frequency: VERY_FREQUENT
  description: >-
    Gross motor delay or delayed walking in 28 of 30; those who walked took
    first steps at a median of 2.5 years.
  phenotype_term:
    preferred_term: Delayed walking
    term:
      id: HP:0002194
      label: Delayed gross motor development
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the 18 individuals who achieved ambulation, first steps were consistently delayed, with a median of 2.5 years ranging from 1.4 years to over 5 years."
    explanation: Walking is delayed in all who achieve it.
- name: Inability to walk
  category: Neurologic
  frequency: OCCASIONAL
  description: Not walking in 7 of 25 individuals older than 5 years.
  phenotype_term:
    preferred_term: Inability to walk
    term:
      id: HP:0002540
      label: Inability to walk
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inability to walk was reported in 7 of 25 individuals older than 5 years (28.0%)."
    explanation: Frequency of non-ambulation.
- name: Hypotonia
  category: Neurologic
  frequency: VERY_FREQUENT
  description: In 26 of 31, with neonatal onset in 19 of 26, often with feeding difficulties.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most individuals had a history of hypotonia (83.9%; 26 of 31), with neonatal onset in 64% (19 of 26), which was commonly associated with feeding difficulties."
    explanation: Frequency and onset of hypotonia.
- name: Seizure
  category: Neurologic
  frequency: FREQUENT
  description: >-
    In 19 of 31, median onset 2.2 years, with varied and evolving seizure
    types. Most respond to treatment; three had pharmacoresistant epilepsy,
    and none had status epilepticus.
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizures occurred in 19 of 31 individuals (63.3%) with a median onset of 2.2 years."
    explanation: Frequency and onset of seizures.
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three individuals (15.8%) had pharmacoresistant epilepsy with persistent daily seizures."
    explanation: A minority have drug-resistant epilepsy.
- name: Spasticity
  category: Neurologic
  frequency: FREQUENT
  description: In 15 of 30 individuals.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spasticity was present in 15 of 30 individuals (50.0%)"
    explanation: Frequency of spasticity.
- name: Ataxia
  category: Neurologic
  frequency: FREQUENT
  description: Nine of 30 individuals had ataxia, within 13 of 30 with movement or coordination abnormalities.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "movement and coordination abnormalities were observed in 13 of 30 individuals (43.3%), nine with ataxia, three with dystonia"
    explanation: Frequency of ataxia.
- name: Dystonia
  category: Neurologic
  frequency: OCCASIONAL
  description: Three of 30 individuals.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "movement and coordination abnormalities were observed in 13 of 30 individuals (43.3%), nine with ataxia, three with dystonia"
    explanation: Frequency of dystonia.
- name: Dilation of Virchow-Robin spaces
  category: Neurologic
  frequency: FREQUENT
  description: >-
    Dilated perivascular spaces in 18 of 23 individuals, periventricular and
    deep, in severe cases with a compact microcystic appearance. Not reported
    in this form in ReNU syndrome.
  phenotype_term:
    preferred_term: Dilated perivascular spaces
    term:
      id: HP:0012520
      label: Dilation of Virchow-Robin spaces
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the recessive disorder frequently presents dilated perivascular spaces that can mimic a compact microcystic appearance (18 of 23; 78.3%"
    explanation: Frequency of the characteristic perivascular space dilation.
- name: Abnormal cerebral white matter morphology
  category: Neurologic
  frequency: FREQUENT
  description: Cerebral white matter abnormality in 21 of 27 individuals with imaging data.
  phenotype_term:
    preferred_term: Abnormality of cerebral white matter
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "demonstrating that the recessive disorder is clinically distinct from ReNU syndrome and is associated with distinctive white matter abnormalities, including enlarged perivascular spaces"
    explanation: White matter abnormality is the distinguishing feature of the disorder.
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormality of cerebral white matter57.1% (4/7)85.0% (17/20)77.8% (21/27)"
    explanation: >-
      Table 1 row giving cerebral white matter abnormality in 21 of 27
      individuals with brain imaging data (4 of 7 with both alleles
      pathogenic or likely pathogenic, 17 of 20 with one or both alleles of
      uncertain significance).
- name: Cerebral white matter atrophy
  category: Neurologic
  phenotype_term:
    preferred_term: White matter volume loss
    term:
      id: HP:0012762
      label: Cerebral white matter atrophy
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "most commonly including dilation of perivascular spaces in the periventricular white matter and white matter volume loss"
    explanation: White matter volume loss is among the most common MRI findings.
- name: Thin corpus callosum
  category: Neurologic
  description: Corpus callosum abnormality in 11 of 21; thinning is common in both this disorder and ReNU syndrome.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thinning of the corpus callosum was a common feature in both ReNU syndrome and the recessive NDD."
    explanation: Corpus callosum thinning is common.
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormality of the corpus callosum57.1% (4/7)50.0% (7/14)52.4% (11/21)"
    explanation: >-
      Table 1 row giving a corpus callosum abnormality in 11 of 21 individuals.
      The row counts any corpus callosum abnormality, not thinning alone, so
      no frequency is set on this thinning phenotype.
- name: Ventriculomegaly
  category: Neurologic
  description: Seen alone on early infant scans before perivascular space dilation develops.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "their initial scans showed only ventriculomegaly, but follow-up studies revealed progressive pathology, including perivascular space dilation, white matter volume loss and cerebellar atrophy"
    explanation: Ventriculomegaly is the earliest imaging finding in serially scanned siblings.
- name: Cerebellar atrophy
  category: Neurologic
  frequency: FREQUENT
  description: In 12 of 24 individuals, significantly enriched over ReNU syndrome.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cerebellar atrophy is observed in 50.0% (12 of 24) of the recessive individuals showing a significant enrichment in the recessive disorder"
    explanation: Frequency and enrichment of cerebellar atrophy.
- name: Microcephaly
  category: Neurologic
  frequency: FREQUENT
  description: In 13 of 30 individuals.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microcephaly42.9% (3/7)43.5% (10/23)43.3% (13/30)Feeding difficulties57.1%"
    explanation: >-
      Table 1 row; the last figure is the whole cohort (13 of 30), after the
      biallelic pathogenic and the VUS-containing subsets.
- name: Strabismus
  category: Ophthalmologic
  frequency: FREQUENT
  description: Strabismus or esotropia in 15 of 28 individuals.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Strabismus/esotropia42.9% (3/7)57.1% (12/21)53.6% (15/28)Seizure62.5% (5/8)"
    explanation: Table 1 row; the third figure is the whole cohort (15 of 28), before the next row begins.
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "synophrys (individuals 2, 4, 11, 18, 32), strabismus (individuals 2, 4, 11, 18, 28, 31)"
    explanation: Strabismus is recurrent among photographed individuals.
- name: Feeding difficulties
  category: Gastrointestinal
  frequency: FREQUENT
  description: In 12 of 25 individuals, commonly with neonatal hypotonia.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Feeding difficulties57.1% (4/7)44.4% (8/18)48.0% (12/25)Short stature14.3%"
    explanation: Table 1 row; the last figure is the whole cohort (12 of 25).
- name: Short stature
  category: Growth
  frequency: FREQUENT
  description: In 13 of 30 individuals.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Short stature14.3% (1/7)52.2% (12/23)43.3% (13/30)Abnormality of"
    explanation: Table 1 row; the last figure is the whole cohort (13 of 30).
- name: Failure to thrive
  category: Growth
  frequency: OCCASIONAL
  description: In 7 of 26 individuals.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autism spectrum disorder14.3% (1/7)35.7% (5/14)28.6% (6/21)Failure to thrive28.6% (2/7)26.3% (5/19)26.9% (7/26)"
    explanation: Table 1 row for failure to thrive; the last figure is the whole cohort (7 of 26).
- name: Atypical behavior
  category: Behavioral
  frequency: FREQUENT
  description: >-
    Behavioral abnormalities in 14 of 23, including obsessive-compulsive
    traits, aggression or self-injury, and emotional lability or tantrums,
    six individuals each.
  phenotype_term:
    preferred_term: Behavioral abnormality
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Behavioral abnormalities were reported in 14 of 23 (60.9%)"
    explanation: Frequency of behavioral abnormality.
- name: Autistic behavior
  category: Behavioral
  frequency: OCCASIONAL
  description: Autism spectrum disorder in 6 of 21 individuals.
  phenotype_term:
    preferred_term: Autism spectrum disorder
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autism spectrum disorder14.3% (1/7)35.7% (5/14)28.6% (6/21)Failure to thrive28.6% (2/7)26.3% (5/19)26.9% (7/26)"
    explanation: Table 1 row for autism; the last figure before the next row is the whole cohort (6 of 21).
- name: Abnormal facial shape
  category: Craniofacial
  frequency: VERY_FREQUENT
  description: >-
    Dysmorphic facial features in 24 of 30. The features are variable but
    form a facial gestalt distinct from that of ReNU syndrome on
    GestaltMatcher analysis; recurrent ones are a high anterior hairline,
    synophrys, upslanted palpebral fissures, a broad nasal bridge and base, a
    thin upper lip and dental diastema.
  phenotype_term:
    preferred_term: Dysmorphic facial features
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysmorphic facial features57.1% (4/7)87.0% (20/23)80.0% (24/30)Abnormality of the eye62.5%"
    explanation: Table 1 row; the last figure is the whole cohort (24 of 30).
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data indicate there is convergence within, but distinction between, the facial phenotypes of the dominant and recessive disorders."
    explanation: Facial gestalt analysis separates the recessive disorder from ReNU syndrome.
- name: Synophrys
  category: Craniofacial
  phenotype_term:
    preferred_term: Synophrys
    term:
      id: HP:0000664
      label: Synophrys
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysmorphic features were variable across individuals but commonly included a high anterior hairline (seen in individuals 2, 18, 28, 31), synophrys (individuals 2, 4, 11, 18, 32)"
    explanation: Synophrys among the recurrent facial features in photographed individuals.
- name: High anterior hairline
  category: Craniofacial
  phenotype_term:
    preferred_term: High anterior hairline
    term:
      id: HP:0009890
      label: High anterior hairline
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysmorphic features were variable across individuals but commonly included a high anterior hairline (seen in individuals 2, 18, 28, 31), synophrys (individuals 2, 4, 11, 18, 32)"
    explanation: High anterior hairline among the recurrent facial features in photographed individuals.
- name: Upslanted palpebral fissure
  category: Craniofacial
  phenotype_term:
    preferred_term: Upslanted palpebral fissures
    term:
      id: HP:0000582
      label: Upslanted palpebral fissure
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "upslanted palpebral fissures (individuals 11, 18, 28, 31), broad nasal bridge and base (individuals 11, 18, 28), thin upper lip (individuals 2, 28, 31) and dental diastema (individuals 2, 11, 28, 31)"
    explanation: Upslanted palpebral fissures among the recurrent facial features.
- name: Diastema
  category: Craniofacial
  description: Dental anomalies overall in 11 of 26 individuals; diastema recurs among photographed individuals.
  phenotype_term:
    preferred_term: Dental diastema
    term:
      id: HP:0000699
      label: Diastema
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "upslanted palpebral fissures (individuals 11, 18, 28, 31), broad nasal bridge and base (individuals 11, 18, 28), thin upper lip (individuals 2, 28, 31) and dental diastema (individuals 2, 11, 28, 31)"
    explanation: Dental diastema among the recurrent features.
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dental anomalies0% (0/7)57.9% (11/19)42.3% (11/26)Abnormality of the genitalia14.3%"
    explanation: Table 1 row for dental anomalies overall; the last figure is the whole cohort (11 of 26).
- name: Micropenis
  category: Genitourinary
  description: >-
    Genital anomalies in 9 of 21 males, including micropenis, cryptorchidism,
    hypoplastic scrotum and testicular ectopia; none in females.
  phenotype_term:
    preferred_term: Micropenis
    term:
      id: HP:0000054
      label: Micropenis
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genital anomalies were observed in 9 of 21 males (42.8%), including micropenis, cryptorchidism, hypoplastic scrotum and testicular ectopia."
    explanation: Micropenis among the male genital anomalies.
- name: Cryptorchidism
  category: Genitourinary
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genital anomalies were observed in 9 of 21 males (42.8%), including micropenis, cryptorchidism, hypoplastic scrotum and testicular ectopia."
    explanation: Cryptorchidism among the male genital anomalies.
genetic:
- name: RNU4-2
  gene_term:
    preferred_term: RNU4-2
    term:
      id: hgnc:10193
      label: RNU4-2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    RNU4-2 encodes U4 snRNA of the major spliceosome. The 38 characterized
    individuals carried 35 unique variants: seven homozygous in 13 individuals
    and 31 in the compound heterozygous state in 25. Only 20 of the 35 scored
    significantly in saturation genome editing, which measures fitness in
    haploid HAP1 cells and is less sensitive for recessive variants than for
    ReNU variants; the rest lie in the same structural elements. Under ACMG/AMP
    criteria one variant was pathogenic, eight likely pathogenic and the rest
    of uncertain significance, and only 10 of 38 individuals had two
    pathogenic or likely pathogenic alleles, so some cohort members may prove
    to be false positives. The authors use the region boundaries stem II
    n.3-n.16, 5' stem loop n.20-n.52 with the k-turn at n.27-n.35 and
    n.41-n.46, Sm site n.118-n.126 and terminal stem loop n.127-n.144. No
    ClinGen gene-disease validity record exists for this pair. RNU4-2 is a
    non-coding gene, so the snRNA has no protein molecular function.
  variants:
  - name: n.7G>C
    variant_type: single nucleotide variant
    description: >-
      In stem II (n.3-n.16), the region of U4 that pairs with U6. Seen both
      homozygous and compound heterozygous.
    evidence:
    - reference: PMID:41951959
      reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Three variants (n.127C>T, n.119A>G and n.7G>C) were observed in both homozygous and compound heterozygous genotypes."
      explanation: Recurrence in homozygous and compound heterozygous cases.
    - reference: PMID:41951959
      reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Variants were annotated with the region of RNU4-2 to which they map using the following nucleotides: Stem II (n.3 to n.16)"
      explanation: Places n.7 in stem II.
  - name: n.119A>G
    variant_type: single nucleotide variant
    description: >-
      In the Sm protein binding site (n.118-n.126), needed for snRNA
      biogenesis and stability. Seen both homozygous and compound
      heterozygous.
    evidence:
    - reference: PMID:41951959
      reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Three variants (n.127C>T, n.119A>G and n.7G>C) were observed in both homozygous and compound heterozygous genotypes."
      explanation: Recurrence in homozygous and compound heterozygous cases.
    - reference: PMID:41951959
      reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sm protein (n.118 to n.126); and terminal stem loop (n.127 to n.144)"
      explanation: Places n.119 in the Sm site.
  - name: n.127C>T
    variant_type: single nucleotide variant
    description: >-
      At the first nucleotide of the terminal stem loop (n.127-n.144), next to
      the Sm site. Seen both homozygous and compound heterozygous.
    evidence:
    - reference: PMID:41951959
      reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Three variants (n.127C>T, n.119A>G and n.7G>C) were observed in both homozygous and compound heterozygous genotypes."
      explanation: Recurrence in homozygous and compound heterozygous cases.
    - reference: PMID:41951959
      reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sm protein (n.118 to n.126); and terminal stem loop (n.127 to n.144)"
      explanation: Places n.127 in the terminal stem loop.
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified biallelic RNU4-2 variants in six of 5,386 trios with undiagnosed NDD, compared to zero of 4,776 trios with non-NDD phenotypes"
    explanation: Case-control enrichment of biallelic variants in undiagnosed neurodevelopmental disorder.
  - reference: PMID:41951737
    reference_title: "Saturation editing of RNU4-2 reveals distinct dominant and recessive disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we identify variants affecting function in regions of RNU4-2 that are critical for interactions with other spliceosome components. We show that these variants cause a new recessive neurodevelopmental disorder that is distinct from ReNU syndrome."
    explanation: The saturation editing study that established the gene-disease link.
  - reference: PMID:41408479
    reference_title: "Monoallelic and biallelic RNU4-2 variants in neurodevelopmental disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results suggest that pathogenic RNU4-2 variants act in both dominant and recessive manners, and that non-critical regions may also harbor disease-causing variants."
    explanation: Independent replication in a Japanese cohort.
diagnosis:
- name: Genome sequencing with RNU4-2 interrogation
  description: >-
    RNU4-2 is a short snRNA gene found by genome sequencing. The marked
    periventricular perivascular space dilation on MRI should prompt analysis
    of RNU4-2. Because saturation editing scores are less sensitive for
    recessive variants, a normal score is not evidence of benignity in this
    setting, and the authors recommend only supporting-level weight for
    significant scores. A reduced RNU4-2 to RNU4-1 expression ratio in blood
    RNA sequencing is a candidate diagnostic biomarker that still needs
    validation.
  diagnosis_term:
    preferred_term: clinical whole genome sequencing
    term:
      id: NCIT:C101294
      label: Whole Genome Sequencing
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of these changes on MRI, particularly the marked periventricular perivascular space dilation, should prompt sequencing and analysis of variants in RNU4-2."
    explanation: MRI pattern as a trigger for RNU4-2 testing.
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As such, normal SGE scores should not be used as evidence of benignity in a recessive context."
    explanation: Limit of the functional assay for variant interpretation.
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The RNU4-2 to RNU4-1 ratio discriminates strongly between cases and controls; therefore, it could be a useful diagnostic biomarker for the recessive disorder, if validated in additional cohorts."
    explanation: Candidate expression biomarker.
treatments:
- name: Anti-seizure pharmacotherapy
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Of 19 individuals with seizures, 17 received antiseizure medication; 13
    were controlled on monotherapy and four needed more than one drug. No
    disease-modifying treatment exists.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticonvulsant
      term:
        id: NCIT:C264
        label: Anticonvulsant Agent
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most were treatment-responsive: 13 received monotherapy and four required more than one antiseizure medication."
    explanation: Response to antiseizure medication.
  target_mechanisms:
  - target: Seizure
    description: Symptomatic control of seizures.
differential_diagnoses:
- name: ReNU syndrome
  description: >-
    The dominant RNU4-2 disorder, caused by usually de novo heterozygous
    variants in the 18-nucleotide critical region (T-loop and stem III). It
    shares developmental delay, language impairment and seizures, but differs
    in facial gestalt, lacks the confluent microcystic perivascular space
    pattern and cerebellar atrophy, shows raised rather than reduced RNU4-2
    levels, and has a systematic 5' splice site signature that the recessive
    disorder lacks.
  disease_term:
    preferred_term: ReNU syndrome
    term:
      id: MONDO:0971172
      label: neurodevelopmental disorder with hypotonia, brain anomalies, distinctive facies, and absent language
  distinguishing_features:
  - Dominant, usually de novo heterozygous rather than biallelic
  - Variants inside the 18-nucleotide critical region
  - Raised rather than reduced RNU4-2 transcript
  - Systematic 5' splice site changes on blood RNA sequencing
  - No confluent microcystic perivascular space pattern and no cerebellar atrophy
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We showed that the recessive NDD is distinct from dominant ReNU syndrome at the genetic, phenotypic and mechanistic levels."
    explanation: The two disorders differ on every axis.
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the three biallelic RNU4-2 cases clustered with the controls rather than patients with ReNU syndrome, which is consistent with them not having the same systematic changes to 5′ splice site usage as observed in ReNU syndrome"
    explanation: The ReNU splicing signature is absent in the recessive disorder.
- name: RNU4atac-opathy
  description: >-
    Recessive disorders (microcephalic osteodysplastic primordial dwarfism type
    I, Lowry-Wood and Roifman syndromes) caused by variants at structurally
    equivalent positions of the minor spliceosome U4atac snRNA, which, unlike
    this disorder, show retention of U12-type introns.
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Strikingly, variants in the equivalent regions and nucleotides of U4ATAC (the minor spliceosome homolog of U4) cause the RNU4atac-opathies"
    explanation: The minor spliceosome counterpart affects the equivalent structural regions.
discussions:
- discussion_id: recessive_rnu4_2_splicing_defect_undetected
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced RNU4-2 U4 snRNA Level
  - pathophysiology#Impaired Brain Development
  prompt: >-
    What splicing defect, if any, links the reduction in U4 snRNA to the
    neurodevelopmental and white matter phenotype?
  rationale: >-
    Blood RNA sequencing from biallelic individuals shows neither the ReNU 5'
    splice site signature nor the intron retention that equivalent RNU4ATAC
    variants cause, so no splicing consequence is in this entry's pathograph
    and the entry does not conform to the module's mis-splicing node. The
    authors suggest the defect is subtle because a global defect in U2-type
    introns would not be viable, and that it may only be visible with deeper
    sequencing or in brain-relevant cells. Whether RNU4-1 upregulation
    compensates in blood but not in brain is part of the same question.
  evidence:
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we found no significant intron retention events in either individuals with biallelic variants in RNU4-2 or individuals with ReNU syndrome"
    explanation: No intron retention signal was found.
  - reference: PMID:41951959
    reference_title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We suggest that the splicing defect associated with this disorder may be more subtle, as a global defect across U2-type introns is likely to be nonviable."
    explanation: The authors' account of why no defect was detected.
references:
- reference: PMID:41951959
  title: "Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes."
- reference: PMID:41951737
  title: "Saturation editing of RNU4-2 reveals distinct dominant and recessive disorders."
- reference: PMID:41408479
  title: "Monoallelic and biallelic RNU4-2 variants in neurodevelopmental disorders."
- reference: PMID:42190036
  title: "RNU4-2–Related Autosomal Dominant Neurodevelopmental Disorder."
  tags:
  - GeneReviews
notes: >-
  The GeneReviews chapter RNU4-2-Related Autosomal Dominant Neurodevelopmental
  Disorder (NBK622730) covers ReNU syndrome only; no GeneReviews chapter covers
  this recessive disorder in the Bookshelf index snapshot of 2026-09-10. The
  chapter (PMID:42190036) is listed in references as a GeneReviews source for
  the same gene, not as a phenotype baseline for this disorder.
📚

References & Deep Research

References

4
PMID:41951959
Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes.
No top-level findings curated for this source.
PMID:41951737
Saturation editing of RNU4-2 reveals distinct dominant and recessive disorders.
No top-level findings curated for this source.
PMID:41408479
Monoallelic and biallelic RNU4-2 variants in neurodevelopmental disorders.
No top-level findings curated for this source.
PMID:42190036
RNU4-2–Related Autosomal Dominant Neurodevelopmental Disorder.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Review round: Table 1 imaging counts quoted; GeneReviews chapter tagged; claude_code deep research · 2026-11-01T23:08:49Z · View source

Answered the automated review on PR 16292. The cerebral white matter (21 of 27) and corpus callosum (11 of 21) counts, previously only in description prose, are now quoted from the Table 1 rows of PMID:41951959 as evidence on Abnormal cerebral white matter morphology and Thin corpus callosum. The corpus callosum row counts any abnormality of the corpus callosum, so the thinning phenotype still carries no frequency. The GeneReviews chapter for the dominant disorder (PMID:42190036, NBK622730) is now listed in references with the GeneReviews tag, which clears the CITED_UNTAGGED finding from just check-genereviews; notes still say the chapter covers ReNU syndrome and not this recessive disorder. The 0.08% versus 0.69% figures stay in description prose: they are diagnostic yields among 8,841 undiagnosed NDD cases in the 100,000 Genomes Project, and no PrevalenceMeasureEnum value describes that measure. Ran just research-disorder claude_code for this entry (research/RNU4-2-Related_Autosomal_Recessive_Neurodevelopmental_Disorder-deep-research-claude_code.md and its citations sidecar). All references resolved and no term was unresolved; three term names in the report were frequency strings beside correct CURIEs. It drew on the three studies the entry already cites (PMID:41951959, PMID:41951737, PMID:41408479). It also listed PMID:42502410, but that paper's recessive cases are RNU2-2 and RNU4ATAC, not RNU4-2, so it added no new cohort. Its other leads (the milder Japanese series, the RNU4-2 to RNU4-1 ratio as a candidate biomarker) were already in the entry, so the report added nothing new.

Claude Code ▸
RNU4-2-Related Autosomal Recessive Neurodevelopmental Disorder: Research Report
claude-haiku-5-5, claude-opus-5-5 9 citations 2026-11-01T23:06:06.086198

RNU4-2-Related Autosomal Recessive Neurodevelopmental Disorder: Research Report

Scope. This disorder is caused by biallelic variants in RNU4-2 (hgnc:10193). RNU4-2 is a non-protein-coding gene that makes the U4 small nuclear RNA (snRNA), a core part of the major spliceosome. This is a different disease from the dominant, usually de novo ReNU syndrome, even though both come from the same 145-nucleotide gene.

Where the evidence comes from. Almost everything known rests on three studies, all from 2026:

  • Rius et al. 2026, Nat Genet (PMID:41951959): the disease-defining clinical cohort.
  • De Jonghe et al. 2026, Nature (PMID:41951737): the companion saturation-editing study that found the disease.
  • Hayashi et al. 2026, J Hum Genet (PMID:41408479): an independent Japanese/international series.

All three are already in references_cache/. Quotes below are copied from those cached files. A kb/disorders/RNU4-2-Related_Autosomal_Recessive_Neurodevelopmental_Disorder.yaml entry already exists and already uses most of this material.

1. Disease information

Overview. This is a moderate-to-severe syndromic neurodevelopmental disorder (NDD) caused by homozygous or compound heterozygous RNU4-2 variants. The variants lie outside the 18-nucleotide ReNU critical region. Its hallmark is a distinctive pattern of white-matter change on brain MRI.

  • Rius et al.: "Here we describe a new recessive NDD associated with homozygous and compound heterozygous variants in RNU4-2." (PMID:41951959)
  • Rius et al.: "we have characterized the phenotype associated with biallelic variants in RNU4-2 as a moderate-to-severe syndromic neurodevelopmental disorder with distinct white matter abnormalities." (PMID:41951959)
  • De Jonghe et al.: "We show that these variants cause a new recessive neurodevelopmental disorder that is distinct from ReNU syndrome." (PMID:41951737)

Identifiers

Resource Status
MONDO No specific class found. The existing entry records that an OLS4 search on 2026-11-01 found none. It uses MONDO:0100500 (Mendelian neurodevelopmental disorder) as a skos:broadMatch. The ReNU syndrome class is MONDO:0971172.
OMIM Not recorded. No OMIM phenotype entry turned up in web searches.
Orphanet, ICD-10, ICD-11, MeSH No disease-specific codes found. MeSH indexing uses "Neurodevelopmental Disorders/genetics" and "RNA, Small Nuclear/genetics".
Gene RNU4-2, hgnc:10193, RefSeq NR_003137.3, chr12 (GRCh38 chr12:120291753–120291903, from the SGE paper's methods)

Synonyms: recessive RNU4-2-related (or -associated) NDD; recessive RNU4-2 syndrome; biallelic RNU4-2 neurodevelopmental syndrome.

Data source. The data are aggregated cohort data from individual patients in rare-disease sequencing programmes, not EHR data. The programmes are Genomics England 100,000 Genomes Project and NHS GMS, CaRDinal, SeqOIA/Auragen (PFMG 2025), UDN, Broad CMG and GREGoR. Controls came from UK Biobank and All of Us.

2. Etiology

Cause. The disease is caused by biallelic loss-of-function variants in RNU4-2. The variants fall in parts of U4 that bind other spliceosome components:

  • "We identify 38 individuals with biallelic variants outside the 18-nucleotide ReNU syndrome region that cluster within other functionally important elements of U4: Stem II, the k-turn and the Sm protein binding site." (PMID:41951959)
  • "These biallelic variants map to regions of U4 that are important for binding to other spliceosome components: the Stem II region of interaction with U6, the Sm protein binding site that is essential for snRNA biogenesis and stability, and the k-turn structure in the 5′ stem loop that binds to SNU13/15.5k." (PMID:41951959)

Genetic risk factors

  • Parental consanguinity. "Eight individuals from five families, all of whom had homozygous variants, had consanguineous parents." (PMID:41951959)
  • High mutation rate at the locus. "RNU4-2, like other snRNA genes, has a substantially elevated mutation rate" (PMID:41951959). The same paper notes that negative selection keeps every variant very rare. This lowers the chance of homozygosity in outbred populations.

Modifier genes. None established. RNU4-1, the paralog, is upregulated in affected people but does not compensate fully (see section 6).

Environmental, protective and gene–environment factors. None reported. The disease is purely genetic.

3. Phenotypes

The figures below come from 31 individuals with detailed data (21 male, 10 female; median age at last follow-up 10 years, range 6 weeks to 32 years) in Rius et al. 2026, Table 1 (PMID:41951959). All suggested HP IDs were checked against cache/hp/terms.csv.

Phenotype Frequency Suggested HPO Key quote / note
Global developmental delay / ID 30/30 (100%); severe 51.7%, moderate 44.8% HP:0001263 Global developmental delay; HP:0001249 Intellectual disability "Global developmental delay (GDD) or intellectual disability (ID) was present in all individuals (n = 30)."
Delayed language 29/29 (100%) HP:0000750 "All individuals (n = 29; 100%) exhibited delayed language development."
Absent speech 15/29 (51.7%) HP:0001344 "Fifteen (51.7%) individuals older than 2 years were nonverbal or had no meaningful spoken language."
Delayed walking 28/30; median first steps at 2.5 years HP:0031936 Inability to walk at age 5 or older: 7/25 (28%)
Hypotonia (neonatal onset in 64%) 26/31 (83.9%) HP:0001252 "Most individuals had a history of hypotonia (83.9%; 26 of 31), with neonatal onset in 64% (19 of 26), which was commonly associated with feeding difficulties."
Feeding difficulties 12/25 (48%) HP:0011968
Seizures (median onset 2.2 years) 19/31 (61–63%) HP:0001250 Mostly respond to treatment; 3/19 are pharmacoresistant; no status epilepticus
Spasticity 15/30 (50%) HP:0001257
Movement disorder 13/30 (43.3%) HP:0001251 Ataxia (n=9); HP:0001332 Dystonia (n=3); HP:0001266 Choreoathetosis (n=1)
Abnormal brain MRI 24/27 (88.9%) HP:0002500 Abnormal cerebral white matter morphology
Dilated perivascular spaces 18/23 (78.3%) No HP term in the local cache; search HPO for "perivascular space" before binding "the recessive disorder frequently presents dilated perivascular spaces that can mimic a compact microcystic appearance (18 of 23; 78.3%"
White matter volume loss common, not counted separately HP:0034295 Reduced cerebral white matter volume
Cerebellar atrophy 12/24 (50%); OR 22.0 vs ReNU HP:0001272 Both the hemispheres and the vermis can be involved
Corpus callosum abnormality 11/21 (52.4%) HP:0033725 Thin corpus callosum Also common in ReNU syndrome
Ventriculomegaly (early scans) seen in several individuals HP:0002119
Strabismus 15/28 (53.6%); eye involved 77.4% HP:0000486
Facial dysmorphism 24/30 (80%) HP:0009890 High anterior hairline; HP:0000664 Synophrys; HP:0000582 Upslanted palpebral fissure; HP:0000219 Thin upper lip vermilion; HP:0000699 Diastema GestaltMatcher distinguishes this face from the ReNU face
Microcephaly 13/30 (43.3%) HP:0000252
Short stature 13/30 (43.3%) HP:0004322
Male genital anomalies 9/21 males (42.8%) HP:0000054 Micropenis; HP:0000028 Cryptorchidism None reported in females
Skin and nail findings 17/28 (60.7%) HP:0000998 Hypertrichosis; HP:0033505 Livedo reticularis Also acrokeratosis verruciformis, hypoplastic nails
Behavioural abnormality 14/23 (60.9%) HP:0000718 Aggressive behavior; HP:0100716 Self-injurious behavior; HP:0000712 Emotional lability OCD traits in 6
Autism spectrum disorder 6/21 (28.6%) HP:0000717
Failure to thrive 7/26 (26.9%) HP:0001508
Dental, skeletal and endocrine anomalies 42%, 30%, 31% —

Onset. "Most individuals had infantile-onset phenotypes (n = 16; 51.6%), while ten (32.2%) had congenital or neonatal onset and five (16.1%) had childhood onset." (PMID:41951959)

Severity relative to ReNU syndrome. The two available sources differ:

  • Hayashi et al. describe their biallelic cases as milder: "individuals with biallelic variants exhibited developmental delay and intellectual disability that were similar to but milder than those with monoallelic variants, notably lacking extracerebral organ involvement" (PMID:41408479). That cohort had only 4 individuals from 2 families.
  • Rius et al. report GDD, speech delay and seizure frequencies similar to ReNU, plus extracerebral involvement (genital, skin, dental).

Quality of life. No validated QoL instrument data exist. Lifelong dependence can be inferred from the high rates of nonverbal status and non-ambulation.

4. Genetic and molecular information

Gene. RNU4-2 (hgnc:10193) encodes the U4 snRNA. Alignment with its paralog RNU4-1 shows mismatches at "only 4 of the 145 nt" (PMID:41951737).

Variant spectrum (Rius et al.)

  • 35 unique variants in 38 included individuals: 7 homozygous variants (13 individuals) and 31 compound heterozygous variants (25 individuals).
  • Variants seen in both the homozygous and compound heterozygous state: n.127C>T, n.119A>G and n.7G>C.
  • The broader search found 43 individuals from 33 families. "Fifteen individuals from 11 families had homozygous variants, and 27 individuals from 22 families had compound heterozygous variants." Five were later excluded because their SGE scores were similar to those in the population.

Variant types. Mostly single-nucleotide variants, plus small indels such as n.7_8insA and n.43_44insT. This is a noncoding RNA, so "missense" and "nonsense" do not apply.

Structural regions. The SGE paper defines these coordinates (PMID:41951737):

Region Nucleotides Binding partner / role
Stem II n.3–16 (central core n.6–11) Pairs with U6
k-turn of the 5′ stem loop n.27–35 and n.41–46 Binds SNU13/15.5K
Sm site n.118–126 Sm protein ring; biogenesis and stability
Terminal stem loop n.127–144 (pairing n.129–131 with n.140–142) —

The ReNU critical region (T-loop n.62–70, Stem III n.75–78) is spared in this disorder. Population variants are instead enriched in the 3′ stem loop (n.85–117): 7 of 14 UK Biobank variants versus 0 of 35 case variants, P = 5.0×10⁻⁴.

Equivalent RNU4ATAC variants. Thirteen of the 35 variants (37.1%) sit at nucleotides where the equivalent RNU4ATAC variant is pathogenic or likely pathogenic. Five exact equivalents are listed in the SGE paper: n.32G>A, n.45G>C, n.46G>A, n.119A>G and n.122T>G. For n.119A>G, the RNU4ATAC equivalent n.117A>G is ClinVar ID 1525441. n.119A>G was homozygous in two individuals and compound heterozygous in three (PMID:41951737).

ACMG/AMP classification

  • Of the 35 variants: 1 pathogenic, 8 likely pathogenic, the rest VUS.
  • Per individual: 10/38 (26.3%) had P/LP variants on both alleles, 4/38 had one P/LP allele, and 24/38 (63.2%) had VUS on both alleles (PMID:41951959).
  • No phenotype frequency differed between the P/LP–P/LP group and everyone else.

Using the SGE function scores clinically

  • A variant counts as significantly depleted (deleterious) when its function score is below −0.302.
  • The SGE authors recommend that "PS3 supporting evidence be assigned to significantly depleted variants outside the CR" (PMID:41951737).
  • A normal score does not show a variant is benign: "normal SGE scores should not be used as evidence of benignity in a recessive context" (PMID:41951959).
  • Only 20 of 35 case variants (57.1%) were SGE-significant.

Population frequency

  • SGE-depleted variants outside the critical region are carried by 0.12% of UK Biobank and 0.094% of All of Us participants (PMID:41951737).
  • Only 11 UK Biobank participants were biallelic; none had a neurodevelopmental phenotype.
  • Only one UK Biobank / All of Us individual was homozygous for an SGE-depleted variant (n.31T>G, score −0.730). That person reported cognitive and functional difficulties suggestive of possible ID (PMID:41951737).

Other genetic features

  • Origin: germline, inherited from carrier parents.
  • Parental origin of alleles: maternal and paternal alleles had similar SGE scores (P = 0.095).
  • Heterozygous carriers: carriers of depleted variants outside the critical region (n = 592 in UK Biobank) showed no differences in fluid intelligence, developmental diagnoses or education.
  • Epigenetics and chromosomal abnormalities: none reported. The disease is not caused by copy-number change.

5. Environmental information

Not applicable. No environmental, lifestyle or infectious contributors are reported.

6. Mechanism and pathophysiology

Causal chain

  1. Biallelic germline variants arise in RNU4-2 in Stem II, the 5′-stem-loop k-turn, the Sm site or the terminal stem loop. These variants disrupt U4's binding to U6, SNU13/15.5K or the Sm ring. This step is inferred from structure, from yeast U4 mutagenesis and from in vitro SNU13 binding data, as cited in PMID:41951737.
  2. → This leads to reduced steady-state U4 (RNU4-2) RNA. This is shown in blood RNA-seq: mean 314 TPM versus 1,645 TPM in controls, P = 0.012 (PMID:41951959). Impaired biogenesis or stability is the presumed route, which is inferred, especially for Sm-site variants.
  3. → This is accompanied by compensatory upregulation of RNU4-1 (1,952 vs 346 TPM). The RNU4-2:RNU4-1 ratio shifts from 5.4 in controls to 0.2 (P = 0.003). Rius et al.: "Our data suggest that RNU4-1 cannot fully compensate for loss of RNU4-2." The reason is not known. Their three candidate explanations are functional divergence, insufficient upregulation, or tissue-specific failure in the brain.
  4. → The net result is partial loss of function of U4-containing complexes (U4/U6 di-snRNP and U4/U6·U5 tri-snRNP) and the major spliceosome. Cell-fitness loss is shown in haploid HAP1 cells by SGE. The specific splicing defect has not been demonstrated:
  5. No ReNU-type 5′ splice-site signature appears in lymphocyte RNA-seq.
  6. No excess intron retention appears in blood, unlike RNU4ATAC disease.
  7. The authors suggest the defect is subtle, because a global defect across U2-type introns would be nonviable.
  8. → In the nervous system this results in abnormal development and white-matter integrity: dilated perivascular spaces, white-matter volume loss, cerebellar atrophy and a thin corpus callosum. Serial imaging shows these can be progressive. The cell-level link between U4 loss and these findings is unknown. Oligodendrocyte or glial vulnerability is a hypothesis only.
  9. → This produces the clinical picture: GDD/ID, absent speech, hypotonia, spasticity and ataxia, and seizures.
  10. Branch: an extracerebral, multisystem arm (genital, skin, dental, growth). Its mechanism is not studied.

How it differs from ReNU syndrome

  • ReNU variants (T-loop and Stem III) mis-position the U6 ACAGAGA box. This alters 5′ splice-site selection, a dominant mechanism.
  • In ReNU, RNU4-2 RNA is raised (2,699 TPM) rather than reduced.
  • "Together, these data suggest that dominant and recessive RNU4-2 disorders are driven by different molecular processes and are consistent with a loss-of-function mechanism in the recessive condition." (PMID:41951959)

Suggested ontology terms (checked against the local caches)

  • GO:
  • GO:0005687 U4 snRNP
  • GO:0046540 U4/U6 x U5 tri-snRNP complex
  • GO:0000244 spliceosomal tri-snRNP complex assembly
  • GO:0000387 spliceosomal snRNP assembly
  • "mRNA splicing, via spliceosome" is not in the local cache; look it up before use.
  • CL: CL:0000540 neuron; CL:0000128 oligodendrocyte; CL:0000127 astrocyte; CL:0000121 Purkinje cell (relevant given cerebellar atrophy; speculative); CL:0000542 lymphocyte (the tissue in which RNA changes were measured).
  • Model and assay context: the SGE assay was run in HAP1-LIG4-KO cells; evidence from it is IN_VITRO.

Omics

  • Blood RNA-seq from the Genomics England NGRL (n = 7,826; 3 biallelic cases).
  • Lymphocyte RNA-seq (3 biallelic cases, 19 ReNU, 20 controls).
  • No proteomic, metabolomic, single-cell or spatial data exist.

7. Anatomical structures affected

  • Primary: brain.
  • Cerebral white matter: periventricular and deep, peritrigonal.
  • Cerebellum (UBERON:0002037): both hemispheres and vermis.
  • Corpus callosum (UBERON:0002336).
  • Lateral ventricles (ventriculomegaly).
  • "Cerebral white matter" is not in the local UBERON cache; look it up before use.
  • Secondary: eye (strabismus), male external genitalia, skin and nails, teeth, skeleton, endocrine system, and growth.
  • Subcellular: nucleus, specifically the spliceosomal snRNPs (GO:0005687, GO:0046540).
  • Laterality: the white-matter changes are bilateral and symmetric (for example, "peritrigonal region bilaterally").

8. Temporal development

  • Onset: congenital or neonatal in 32%, infantile in 52%, childhood in 16%. Hypotonia is often neonatal.
  • Course: a static neurodevelopmental disorder in which imaging can progress. Two siblings imaged serially from infancy at first showed only ventriculomegaly. Follow-up "revealed progressive pathology, including perivascular space dilation, white matter volume loss and cerebellar atrophy." Perivascular dilation also increased between 32 months and 7 years in another individual (PMID:41951959).
  • Within families: siblings were largely concordant, but expressivity varied. In three sibships, one child walked and the other did not.
  • Duration: lifelong. The oldest reported individual was 32. No remission has been described.
  • Critical period: early childhood, when white-matter change appears to evolve. This is not formally established.

9. Inheritance and population

  • Inheritance: autosomal recessive (HP:0000007), homozygous or compound heterozygous.
  • Penetrance: not established. Rius et al. note that some included individuals may be false positives and that some excluded individuals may be true cases.
  • Expressivity: variable, including within sibships.
  • Anticipation and germline mosaicism: none reported.
  • Founder effects: none reported.
  • Consanguinity: important. All five consanguineous families carried homozygous variants.
  • Frequency: much rarer than ReNU syndrome. "while we identified 61 individuals with ReNU syndrome in 8,841 individuals (0.69%) with previously undiagnosed NDD in the Genomics England 100,000 Genomes Project, we only identified seven (0.08%) with biallelic variants in the same cohort." (PMID:41951959)
  • Case enrichment: 6/5,386 undiagnosed NDD trios versus 0/4,776 non-NDD trios (P = 3.3×10⁻³).
  • Population prevalence and incidence: unknown. The authors expect higher frequency in populations with more consanguinity.
  • Carrier frequency: about 0.1% carry SGE-depleted variants outside the critical region (UK Biobank 0.12%, All of Us 0.094%). This is a ceiling on the frequency of deleterious alleles, not a confirmed carrier rate.
  • Sex: 21 male and 10 female in the clinical cohort. This is probably ascertainment, not biology; a recessive autosomal locus should affect both sexes.
  • Geography: cases from the UK, France, Germany, the USA, Australia, Turkey and Pakistan, plus a Japanese/Israeli/Malaysian/Brazilian series in Hayashi et al. No endemic clustering has been reported.

10. Diagnostics

  • Genetic testing is required. RNU4-2 is noncoding and is missed by standard exome capture.
  • Whole-genome sequencing (NCIT:C101294) is the recommended test.
  • Extended-exome designs that capture snRNA genes also work. PMID:42502410 reports WGS reanalysis of 1,578 unsolved probands that found RNU4-2 cases, and recommends extended-exome screening.
  • Variant calling must allow for paralog and pseudogene homology with RNU4-1.
  • Phasing: use parental testing, or read-backed phasing in IGV when parents are unavailable.
  • Variant interpretation:
  • Use the SGE function scores at supporting strength (PS3_supporting) for significantly depleted variants outside the critical region.
  • Check whether the equivalent RNU4ATAC nucleotide is pathogenic.
  • Check the structural region.
  • Imaging: MRI (NCIT:C16809). Marked periventricular perivascular-space dilation with a "tightly packed microcystic" appearance should prompt RNU4-2 analysis: "The presence of these changes on MRI, particularly the marked periventricular perivascular space dilation, should prompt sequencing and analysis of variants in RNU4-2." (PMID:41951959)
  • Candidate RNA biomarker (not yet validated): the RNU4-2:RNU4-1 expression ratio in rRNA-depleted blood RNA-seq. "it could be a useful diagnostic biomarker for the recessive disorder, if validated in additional cohorts." (PMID:41951959)
  • Facial gestalt: GestaltMatcher separates biallelic cases from ReNU cases (biallelic–biallelic pairs P = 1.8×10⁻⁵; ReNU–biallelic pairs P = 0.37).
  • EEG: obtain one when seizures occur. No characteristic pattern has been reported.
  • Differential diagnosis:
  • ReNU syndrome. Distinguished by a heterozygous T-loop or Stem III variant, the 5′ splice-site signature, raised RNU4-2 RNA, myopathic facies and no cerebellar atrophy.
  • Recessive RNU2-2 disorder.
  • RNU4ATAC disorders (MOPD I, Lowry–Wood, Roifman).
  • RNU12 disorder.
  • Other leukodystrophies and metabolic disorders with enlarged perivascular spaces, such as mucopolysaccharidoses.
  • Hypomyelinating leukodystrophies.
  • Screening: there is no newborn screening. Carrier and prenatal testing are possible once the familial variants are known.

11. Prognosis

  • No mortality or survival data exist. Individuals up to 32 years old have been reported.
  • Disability is substantial: about half are nonverbal, and 28% are non-ambulatory after age 5.
  • Epilepsy is mostly controllable: 13 of 17 treated individuals were on monotherapy, 3 were pharmacoresistant, and none had status epilepticus.
  • Prognostic factors are not established. More severe perivascular dilation went with lower mean SGE scores, but not significantly (P = 0.056, n = 5 per group).

12. Treatment

No disease-specific treatment exists. Management is symptomatic.

  • Antiseizure medication: NCIT:C15986 Pharmacotherapy, with NCIT:C264 Anticonvulsant Agent as the agent class.
  • Therapies: physical therapy (NCIT:C15302), occupational therapy (NCIT:C121351) and speech-language therapy (NCIT:C159273), including AAC for nonverbal patients.
  • Supportive care (NCIT:C15747) for feeding difficulties, plus ophthalmology for strabismus, and urology or endocrine follow-up.
  • Genetic counselling: NCIT:C15240.
  • Experimental: no clinical trials were found. Because the disease is loss of function, restoring or augmenting U4 (for example, upregulating RNU4-1) is a conceivable future approach. This is speculative, and the SGE authors frame their data only as a resource for "therapeutic development."
  • Pharmacogenomics: none known.

13. Prevention

  • Primary prevention: genetic counselling. The recurrence risk is 25% for carrier couples.
  • Carrier, prenatal and preimplantation testing: possible once both familial variants are identified. Carrier screening is especially relevant in consanguineous families.
  • Tertiary prevention: seizure control, orthopaedic care for spasticity, and nutritional support.
  • Vaccines and public-health measures: not applicable.

14. Other species

No naturally occurring animal disease has been reported, and there is no OMIA entry. U4 snRNA is deeply conserved. The RNU4-2 upstream region "is both unique and poorly conserved across species" (PMID:41951737). Yeast U4 mutagenesis implicates the same regions (stem II, k-turn, Sm site) as essential for function. Copy-number and paralog structure differ between species, so a one-to-one ortholog mapping needs care. No NCBI Gene orthology details were checked here.

15. Model systems

  • In vitro: saturation genome editing in HAP1-LIG4-KO haploid human cells. All possible SNVs across the 145-nt transcript plus 6 nt 3′ (539 variants) were tested, with a cell-fitness readout (PMID:41951737).
  • Strength: it found the recessive disease and gives variant-level function scores.
  • Limitations:
    • It does not separate dominant from recessive effects; a diploid HAP1 screen did not either.
    • It does not measure the splicing mechanism.
    • It reports nothing about brain cells.
    • It is less sensitive for recessive variants.
  • Patient-derived samples: lymphocyte cultures and whole blood (RNA-seq).
  • Animal models: none reported (no mouse, zebrafish or fly).
  • Gaps: neural iPSC models, organoids, or oligodendrocyte or glial models are needed to find the splicing defect and explain the white-matter pathology. Rius et al. say a splicing defect "may require additional samples sequenced at higher depth or sequencing of disease-relevant cell types and tissues."

Points for the curator

  • No MONDO or OMIM identifiers exist yet. Keep the broadMatch to MONDO:0100500 until MONDO adds a class.
  • Two sources disagree on severity. Hayashi et al. (n = 4) describe the disorder as milder and without extracerebral involvement; Rius et al. (n = 31) report extracerebral features. Record this as a disagreement rather than resolving it.
  • No splicing signature has been shown. The loss-of-function claim rests on reduced RNU4-2 RNA and on analogy with RNU4ATAC disease, not on any demonstrated splicing defect. The KNOWLEDGE_GAP and HUMAN_MODEL_MISMATCH discussion kinds both fit here.
  • Two terms need lookup before binding. "Dilated perivascular spaces" (HPO) and "mRNA splicing, via spliceosome" (GO) are not in the local caches. Look both up rather than writing an ID.

Sources

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome Count
References checked 6
Resolved 6
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 17
Quoted claims found in source 17
Quoted claims not found in source 0
References weighed for topical relevance 6
On topic 6
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 57
Resolved 57
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 10
Terms named correctly 5
Terms named as a different term 3
Terms whose name is worth a second look 2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0031936 (1 mention) - the report calls it "28/30; median first steps at 2.5 years"; HP calls it Delayed ability to walk
  • HP:0001272 (1 mention) - the report calls it "12/24 (50%); OR 22.0 vs ReNU"; HP calls it Cerebellar atrophy
  • HP:0000486 (1 mention) - the report calls it "15/28 (53.6%); eye involved 77.4%"; HP calls it Strabismus

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • NCIT:C16809 (1 mention) - the report calls it "Imaging: MRI"; NCIT calls it Magnetic Resonance Imaging**, and lists "MR Imaging" among its other names
  • NCIT:C15302 (1 mention) - the report calls it "Therapies: physical therapy"; NCIT calls it Physical Therapy**