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Here we utilize whole-genome sequencing of Roifman Syndrome patients to reveal compound heterozygous rare variants that disrupt highly conserved positions of the <jats:italic>RNU4ATAC<\/jats:italic> 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. <jats:italic>RNU4ATAC<\/jats:italic> 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 <jats:italic>RNU4ATAC<\/jats:italic> rare variants may be more prevalent than previously reported.<\/jats:p>","DOI":"10.1038\/ncomms9718","type":"journal-article","created":{"date-parts":[[2015,11,2]],"date-time":"2015-11-02T10:09:38Z","timestamp":1446458978000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":158,"title":["Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing"],"prefix":"10.1038","volume":"6","author":[{"given":"Daniele","family":"Merico","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maian","family":"Roifman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6653-0926","authenticated-orcid":false,"given":"Ulrich","family":"Braunschweig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan K. 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