RNU4ATAC

Inheritance Pattern: AR

Disease ID:MONDO:0014722

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014722

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0008871

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009191

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0008871

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0100558

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0100558

Submitter: ClinGen

*RNU4ATAC* was first reported in relation to autosomal recessive RNU4ATAC-spectrum disorder in 2011 (He et al., PMID: 21474760 and Edery et al., PMID: 21474761). RNU4ATAC spectrum disorder is characterized by growth restriction, microcephaly, skeletal dysplasia, and cognitive impairment. Less common but variable findings include brain anomalies, seizures, strokes, immunodeficiency, and cardiac anomalies, as well as ophthalmologic, skin, renal, gastrointestinal, hearing, and endocrine involvement (PMID: 36795902). Biallelic (homozygous or compound heterozygous) variants in RNU4ATAC, the noncoding gene encoding the U4atac snRNA component of the minor (U12-dependent) spliceosome, which disrupts minor intron splicing and cause a phenotypic spectrum (Taybi-Linder/MOPD1, Roifman, and Lowry-Wood syndromes) in which immune abnormalities are a core, increasingly recognized feature, with variants in the 5′ stem-loop associated with the most severe/lethal disease and those sparing it with milder, immune-predominant presentations. The immune phenotype extends well beyond the classically described antibody deficiency/hypogammaglobulinemia (Roifman syndrome) to include frank autoimmunity and systemic inflammation in nearly half of patients, T-cell activation/exhaustion (increased HLA-DR and PD-1 expression), impaired B-cell development, chilblain-like lesions with enhanced type I interferon signaling, and syndromic autoimmune (islet-autoantibody–positive) diabetes. Mechanistically, defective U12-type intron splicing dysregulates transcripts governing innate and adaptive immunity, including JAK/STAT signaling linking minor spliceosome dysfunction directly to immune dysregulation (2026, PMID 42322192 and 2026, PMID 41808109). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no differences in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, Lowry-Wood syndrome (OMIM:226960), Roifman syndrome (OMIM:616651), microcephalic osteodysplastic primordial dwarfism, type I (OMIM:210710), and Taybi-Linder syndrome (TALS). Twenty-five variants in a non-protein-coding gene that have been reported in eighteen probands in nine publications (PMIDs: 21474760, 21474761, 22581640, 26522830, 28771251, 29263834, 29265708, 30368667, https://doi.org/10.14785/lymphosign-2016-0015) are included in this curation meeting phenotypic criteria including growth restriction, microcephaly, skeletal dysplasia, and cognitive impairment. Of note, there is a wide variability of phenotypes associated with dysfunction of RNU4ATAC, and there have been reports of affected individuals who do not present with skeletal dysplasia and/or microcephaly (McMillan et al., PMID 34405953, Duker et al., PMID 36795902). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. RNU4ATAC encodes a snRNA (U4atac) part of the U12-dependent minor spliceosome complex involved in splicing of minor introns. The mechanism of pathogenicity is reported to be loss of function. RNA sequencing analysis on blood from affected individuals has revealed significant retention of minor introns in multiple genes, along with other transcriptional anomalies (Merico et al., PMID 26522830), consistent with a dysfunction of RNU4ATAC, which plays a crucial role in the splicing of minor introns. Notably, there is no MANE select transcript for this gene, and there is a discrepancy between Ensembl (Chr2:121,530,881-121,531,007 (Hg38)) and NCBI (Chr2:121,530,880-121,531,009) regarding the exact position of the first nucleotide of this non-coding gene, with a difference of one nucleotide. In summary, RNU4ATAC is definitively associated with autosomal recessive RNU4ATAC-spectrum disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date September 6, 2023 (SOP Version 9) and reviewed by experts from the ClinGen Syndromic Disorders GCEP on August 27, 2024. Data provided by the ClinGen Prenatal GCEP from April 8, 2025 secondary analysis: RNU4ATAC demonstrates consistent prenatal and neonatal phenotypes that include mild to severe fetal growth restriction, short birth length, microcephaly, brachydactyly, tapered fingers, dry skin, and facial dysmorphisms including prominent eyes and nose, sloping forehead, flat philtrum, and micrognathia [PMID: 21815888, 29370840, 27040866, 36622817, 29265708, 30368667, 30455926, 26641461, 22581640, 21990275, 27312855, 36660028]. Other features including contractures and brain anomalies including absent septum pellucidum, agenesis of the corpus callosum, abnormal gyral pattern, ventriculomegaly, hydrocephaly, and intracranial cysts have also been observed [PMID: 21815888, 29370840, 27040866, 27312855, 36660028]. Disproportionate short limbs and other manifestations of the postnatal phenotype are not routinely observed prenatally. The prenatal phenotype of microcephaly was observed in a zebrafish model [PMID:36802443]. Considering RNU4ATAC is a noncoding RNA gene it may not be included on all capture kits and targeted reanalysis may be required, as was reported in several cases with no pathogenic variants reported on exome sequencing [PMID: 29370840, 29265708, 30368667, 36660028].

Inheritance Pattern: AR

Disease ID:MONDO:0100558

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0100558

Submitter: Broad Center for Mendelian Genomics

Inheritance Pattern: AR

Disease ID:MONDO:0014722

Submitter: Illumina

Inheritance Pattern: AR

Disease ID:MONDO:0008871

Submitter: Ambry Genetics