Submission Details

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). 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.