Compound heterozygous mutations in the noncoding RNU4ATAC gene 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. Given its prevalence in males, it was originally postulated to be X-linked. Whole genome sequencing revealed compound heterozygous rare variants disrupting highly conserved positions of the autosomal non-coding RNU4ATAC gene, a minor spliceosome component essential for minor intron splicing. Targeted sequencing confirmed allele segregation in six cases from four unrelated families. RNU4ATAC has been recently reported to cause Microcephalic osteodysplastic primordial dwarfism, type I (MOPD1), whose phenotype is distinct from Roifman Syndrome. Strikingly, all the six Roifman Syndrome cases have one RNU4ATAC variant overlapping MOPD1-implicated structural elements, while the other variant overlaps a highly conserved element not previously implicated in disease. RNA-seq analysis confirmed defects of minor intron splicing. Available allele frequency data suggests that recessive genetic disorders caused by RNU4ATAC may be more prevalent than reported in the literature.

• Type: Other
• Archive: European Genome-phenome Archive (EGA)