Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing.
Roifman Syndrome is a rare congenital disorder characterized by growth retardation, cognitive delay, spondyloepiphyseal dysplasia and antibody deficiency. Here we utilize whole-genome sequencing of Roifman Syndrome patients to reveal compound heterozygous rare variants that disrupt highly conserved positions of the RNU4ATAC small nuclear RNA gene, a minor spliceosome component that is essential for minor intron splicing. Targeted sequencing confirms allele segregation in six cases from four unrelated families. RNU4ATAC rare variants have been recently reported to cause microcephalic osteodysplastic primordial dwarfism, type I (MOPD1), whose phenotype is distinct from Roifman Syndrome. Strikingly, all six of the Roifman Syndrome cases have one variant that overlaps MOPD1-implicated structural elements, while the other variant overlaps a highly conserved structural element not previously implicated in disease. RNA-seq analysis confirms extensive and specific defects of minor intron splicing. Available allele frequency data suggest that recessive genetic disorders caused by RNU4ATAC rare variants may be more prevalent than previously reported.
Pubmed ID: 26522830
Research resources used in this publication
None foundAdditional research tools detected in this publication
- FastQ Screen (RRID:SCR_000141)
- Trim Galore (RRID:SCR_011847)
- FastQC (RRID:SCR_014583)
- MEME Suite - Motif-based sequence analysis tools (RRID:SCR_001783)
- RefSeq (RRID:SCR_003496)
- iReckon (RRID:SCR_005232)
- HTSeq (RRID:SCR_005514)
- edgeR (RRID:SCR_012802)
- SIFT (RRID:SCR_012813)
- TopHat (RRID:SCR_013035)
- CummeRbund (RRID:SCR_014568)
- Mutation Assessor (RRID:SCR_024502)
Antibodies used in this publication
None foundAssociated grants
- Agency: Canadian Institutes of Health Research, Canada
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FastQ Screen (tool)
RRID:SCR_000141
Software that allows you to screen a library of sequences in FastQ format against a set of sequence databases so you can see if the composition of the library matches with what you expect.
View all literature mentionsTrim Galore (tool)
RRID:SCR_011847
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RRID:SCR_014583
Quality control software that perform checks on raw sequence data coming from high throughput sequencing pipelines. This software also provides a modular set of analyses which can give a quick impression of the quality of the data prior to further analysis.
View all literature mentionsMEME Suite - Motif-based sequence analysis tools (tool)
RRID:SCR_001783
Suite of motif-based sequence analysis tools to discover motifs using MEME, DREME (DNA only) or GLAM2 on groups of related DNA or protein sequences; search sequence databases with motifs using MAST, FIMO, MCAST or GLAM2SCAN; compare a motif to all motifs in a database of motifs; associate motifs with Gene Ontology terms via their putative target genes, and analyze motif enrichment using SpaMo or CentriMo. Source code, binaries and a web server are freely available for noncommercial use.
View all literature mentionsRefSeq (tool)
RRID:SCR_003496
Collection of curated, non-redundant genomic DNA, transcript RNA, and protein sequences produced by NCBI. Provides a reference for genome annotation, gene identification and characterization, mutation and polymorphism analysis, expression studies, and comparative analyses. Accessed through the Nucleotide and Protein databases.
View all literature mentionsiReckon (tool)
RRID:SCR_005232
An algorithm for the simultaneous isoform reconstruction and abundance estimation. In addition to modelling novel isoforms, multi-mapped reads and read duplicates, this method takes into account the possible presence of unspliced pre-mRNA and intron retention. iReckon only requires a set of transcription start and end sites, but can use known full isoforms to improve sensitivity. Starting from the set of nearly all possible isoforms, iReckon uses a regularized EM algorithm to determine those actually present in the sequenced sample, together with their abundances. iReckon is multi-threaded to increase efficiency in all its time consuming steps.
View all literature mentionsHTSeq (tool)
RRID:SCR_005514
THIS RESOURCE IS NO LONGER IN SERVICE. Documented on February 28,2023. Software Python package that provides infrastructure to process data from high-throughput sequencing assays. While the main purpose of HTSeq is to allow you to write your own analysis scripts, customized to your needs, there are also a couple of stand-alone scripts for common tasks that can be used without any Python knowledge.
View all literature mentionsedgeR (tool)
RRID:SCR_012802
Bioconductor software package for Empirical analysis of Digital Gene Expression data in R. Used for differential expression analysis of RNA-seq and digital gene expression data with biological replication.
View all literature mentionsSIFT (tool)
RRID:SCR_012813
Data analysis service to predict whether an amino acid substitution affects protein function based on sequence homology and the physical properties of amino acids. SIFT can be applied to naturally occurring nonsynonymous polymorphisms and laboratory-induced missense mutations. (entry from Genetic Analysis Software) Web service is also available.
View all literature mentionsTopHat (tool)
RRID:SCR_013035
Software tool for fast and high throughput alignment of shotgun cDNA sequencing reads generated by transcriptomics technologies. Fast splice junction mapper for RNA-Seq reads. Aligns RNA-Seq reads to mammalian-sized genomes using ultra high-throughput short read aligner Bowtie, and then analyzes mapping results to identify splice junctions between exons.TopHat2 is accurate alignment of transcriptomes in presence of insertions, deletions and gene fusions.
View all literature mentionsCummeRbund (tool)
RRID:SCR_014568
Software R package used for simplifying and analyzing Cufflink RNA-Seq output. This program takes various output files from a cuffdiff run and creates a SQLite database of the results that will describe the appropriate relationships between the genes, transcripts, transcription start sites and CDS regions.
View all literature mentionsMutation Assessor (tool)
RRID:SCR_024502
Web server predicts functional impact of amino-acid substitutions in proteins, such as mutations discovered in cancer or missense polymorphisms. Functional impact is assessed based on evolutionary conservation of affected amino acid in protein homologs.
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