Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: RNU4ATAC

Green List (high evidence)

Comment on list classification: Immunodeficiency is a consistent finding in RNU4ATAC-related Roifman syndrome. In some cases, it may be the sole presenting feature, as other characteristics become apparent later. There are more than 3 unrelated cases reported in literature with biallelic RNU4ATAC variants and syndromic immunodeficiency, Hence, this gene should be promoted to Green at the next GMS update.

Created: 13 Mar 2026, 4:04 p.m. | Last Modified: 13 Mar 2026, 4:04 p.m.

Panel Version: 8.83

PMID: 26522830 Merico et al., 2015
6 cases with Roifman syndrome from 4 unrelated families (English, Italian, Lebanese, Albanian). All 6 had history of repeat infections.

PMID: 28623346 Bogaert et al., 2017
Report of two siblings that presented with a phenotype resembling early-onset common variable immunodeficiency - extra-immunological characteristics were not apparent at that time. Additional features were diagnosed later, including skeletal and organ anomalies and mild facial dysmorphism. Whole exome sequencing revealed c.13 C > T and c.116 A > T RNU4ATAC variants, which is consistent with diagnosis of Roifman syndrome.

PMID: 29391254 Heremans et al., 2018
3 patients from 2 unrelated kindreds harboring compound heterozygous or homozygous stem II variants in RNU4ATAC. All patients have a common phenotype of moderate psychomotor delay and autism spectrum disorder, retinal dystrophy with hypovascularization, severe growth retardation, spondyloepiphysial dysplasia with irregularly shaped vertebral bodies with platyspondyly and flattened proximal femoral epiphyses, pruritic ichthyosis-like skin rash, brachydactyly, hyperlaxity, hypotonia, and hepatosplenomegaly.
All 3 patients have hypogammaglobulinemia and B-cell lymphopenia, and they experience recurrent viral infections, necessitating immunoglobulin substitution therapy. P2 had mucocutaneous Herpes simplex infection, and P3 presented a pneumococcal sepsis on discontinuation of therapy. Study showed abnormal differentiation of B cells and megakaryocytes in the patients.

PMID: 33059947 Hagiwara et al., 2020
18-year-old woman exhibiting congenital dwarfism and microcephaly with structural brain anomaly. She suffered human herpesvirus 6 (HHV-6)-associated acute necrotizing encephalopathy at age one, resulting in severe psychomotor disabilities. Genetic analysis revealed comp het variants in RNU4ATAC (NR_023343.1:n.[50G > A];[55G > A]). Immunological findings showed decreases in total lymphocytes, CD4+ T cells, and T cell regenerative activity, and little response to vaccinations.

MedRxiv preprint Johnson et al., 2025 doi: https://doi.org/10.1101/2025.09.12.25335567
identified 19 individuals with early-onset diabetes (diagnosed <5 years) and additional clinical features who had biallelic pathogenic variants in the novel disease gene RNU6ATAC (n=7) or in RNU4ATAC (n=12). 12/19 had additional immune features of immune dysregulation.

RNU4ATAC is associated with multiple AR conditions in OMIM: Lowry-Wood syndrome, MIM:226960; Microcephalic osteodysplastic primordial dwarfism, type I, MIM:210710; Roifman syndrome, OMIM:616651. Only Roifman syndrome features immunodeficiency.

Created: 13 Mar 2026, 4:02 p.m. | Last Modified: 13 Mar 2026, 4:07 p.m.

Panel Version: 8.84

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Roifman syndrome, OMIM:616651

Publications

• 26522830
• 28623346
• 29391254
• 33059947

The following PubMed IDs were added to gene RNU4ATAC (OMIM gene MIM#601428): 21474760;26522830. These publications have been associated with the gene by the immunodeficiencies subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.

Created: 13 Oct 2020, 9:36 a.m. | Last Modified: 13 Oct 2020, 9:36 a.m.

Panel Version: 2.208

Publications

• 21474760
• 26522830

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): RNU4ATAC .PanelApp HGNC gene symbol check: RNU4ATAC . IUIS Disease: MOPD1 deficiency . IUIS Inheritance: AR .T cells: Normal, .B cells: Normal, .IUIS Other affected cells: N/A. IUIS Associated features: Recurrent bacterial infections, lymphadenopathy, Spondyloepiphyseal dysplasia, extreme intrauterine growth retardation, retinal dystrophy, facial dysmorphism, may present with microcephaly. IUIS Major category: Combined immunodeficiencies with associated or syndromic features. IUIS Subcategory: Immuno-osseous Dysplasias

Created: 6 Jul 2018, 12:35 p.m.