Authors
Dena R Matalon, Angela L Duker, Taylor M Arriaga, Kathryn Russell, Hector Rodrigo Mendez, Devon E Bonner, Margaret E Harley, Moriel Singer-Berk, Monica H Wojcik, Lynn Pais, Stephanie DiTroia, Melanie O'Leary, Thomas Cassini, Kimberly Ezell, Anne D Niehaus, Julie Kaplan, David S Wargowski, Cory J Smid, Emily D Longenecker, Ana Maria Rodriguez Barreto, Danny E Miller, Alexandra C Keefe, Laurel Calderwood, Gregory M Enns, Mustafa Tekin, Stephanie A Bivona, Neeta L Vora, Kelly L Gilmore, Tahir N Khan, Erica E Davis, Amber W Wang, Sameena Khan, Sateesh Maddirevula, Lama AlAbdi, Omar Abuyousef, Hanan E Shamseldin, Salwa Alkhalifi, Firdous Abdulwahab, Mashael Alqahtani, Zainab A Alhumaidi, Seba Nadeef, Amal M Al Hashem, Khadijah Bakur, Eissa A Faqeih, Ebtesam Abdalla, Angus Clarke, Elaine Fletcher, Wee Teik Keng, Lilian Bomme Ousager, Deepthi C de Silva, Muzhirah Haniffa, Francesca Mari, Wayne Lam, Jennifer Campbell, Tessa Homfray, Sheela Nampoothiri, Chumei Li, Bimal P Chaudhari, Kristen Truxal, Genomics Research to Elucidate the Genetics of Rare Diseases consortium, Undiagnosed Diseases Network, Jonathan A Bernstein, Stephen B Montgomery, Matthew T Wheeler, Fowzan S Alkuraya, Anne O'Donnell-Luria, Andrew P Jackson, Ian M Campbell, Vijay S Ganesh, Nic Robertson, Gabrielle Lemire
Published in
Genetics in medicine : official journal of the American College of Medical Genetics. Pages 102633. Jun 19, 2026. Epub Jun 19, 2026.
Abstract
We aim to better define the genotype and phenotype spectrum of RNU4ATAC-opathy, demonstrate the utility of RNA sequencing for variant classification, and highlight challenges in detecting variants in this noncoding gene.
Sixty individuals with molecularly confirmed RNU4ATAC-opathy were recruited from multiple clinical and research centers internationally. RNA sequencing was available for seven affected individuals.
We report the clinical and molecular findings of 60 individuals, including 42 not previously described, and 33 distinct RNU4ATAC variants, 13 of which are novel. Core features in this cohort-present in most individuals assessed and varying in severity-include microcephaly, short stature, skeletal anomalies, developmental delay, cerebral anomalies, skin conditions and immune deficiency. Additional findings such as diabetes, holoprosencephaly, and absence of various core features in some individuals highlight the broad phenotypic spectrum. All individuals with RNA sequencing showed a consistent pattern of minor intron retention. In six, RNA-seq enabled reclassification of variants of uncertain significance as likely pathogenic. While RNU4ATAC variants are generally covered by clinical exomes, they are often overlooked in analysis due to the noncoding nature.
This study further highlights the variability of phenotypes and genotypes associated with RNU4ATAC-opathy. Laboratories should ensure RNU4ATAC and other noncoding genes are appropriately assessed by their analysis pipelines.
PMID:
42322193
Bibliographic data and abstract were imported from PubMed on 20 Jun 2026.
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