Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing

Abstract

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.Clin Genet. 2012 Aug;82(2):140-6. (PMID: 21815888); Science. 2012 Dec 21;338(6114):1587-93. (PMID: 23258890); Genome Res. 2013 Mar;23(3):519-29. (PMID: 23204306); Am J Med Genet A. 2015 Apr;167A(4):919-21. (PMID: 25735804); Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9851-5. (PMID: 23696674); Elife. 2013;2:e00780. (PMID: 23908766); Nucleic Acids Res. 2014 Jan;42(Database issue):D986-92. (PMID: 24174537); Nat Genet. 2014 Mar;46(3):310-5. (PMID: 24487276); EMBO Mol Med. 2014 Mar;6(3):299-306. (PMID: 24480542); RNA. 2014 Jul;20(7):1078-89. (PMID: 24865609); Nucleic Acids Res. 2014 Jun;42(11):7358-69. (PMID: 24848017); Genome Res. 2014 Nov;24(11):1774-86. (PMID: 25258385); Cell. 2014 Dec 18;159(7):1511-23. (PMID: 25525873); Bioinformatics. 2015 Jan 15;31(2):166-9. (PMID: 25260700); Bioinformatics. 2000 Jan;16(1):16-23. (PMID: 10812473); Clin Genet. 2000 Jun;57(6):435-8. (PMID: 10905663); Cardiol Young. 2001 Mar;11(2):240-3. (PMID: 11293748); Genome Res. 2001 May;11(5):863-74. (PMID: 11337480); J Biol Chem. 2002 Jul 12;277(28):25815-22. (PMID: 11983712); EMBO J. 2002 Jul 15;21(14):3804-15. (PMID: 12110592); Nucleic Acids Res. 2002 Nov 1;30(21):4650-7. (PMID: 12409455); Proc Int Conf Intell Syst Mol Biol. 1994;2:28-36. (PMID: 7584402); Nature. 1996 Aug 8;382(6591):551-5. (PMID: 8700231); Cell. 1996 Aug 9;86(3):379-89. (PMID: 8756720); Science. 1996 Sep 27;273(5283):1824-32. (PMID: 8791582); Am J Med Genet. 1998 Oct 30;80(1):16-24. (PMID: 9800907); Clin Genet. 1999 Feb;55(2):103-9. (PMID: 10189087); RNA. 1999 Apr;5(4):525-38. (PMID: 10199569); Science. 1999 Jun 18;284(5422):2003-5. (PMID: 10373121); J Intellect Disabil Res. 2006 Sep;50(Pt 9):690-6. (PMID: 16901296); RNA. 2006 Oct;12(10):1883-92. (PMID: 16957280); Nucleic Acids Res. 2007 Jan;35(Database issue):D110-5. (PMID: 17082203); Am J Hum Genet. 2007 Mar;80(3):485-94. (PMID: 17273969); Science. 2007 Apr 6;316(5821):115-20. (PMID: 17412961); Science. 2008 Jul 11;321(5886):218-23. (PMID: 18621663); Am J Hum Genet. 2008 Nov;83(5):610-5. (PMID: 18950739); Bioinformatics. 2009 May 1;25(9):1105-11. (PMID: 19289445); Bioinformatics. 2010 Jan 1;26(1):139-40. (PMID: 19910308); Science. 2010 Jan 1;327(5961):78-81. (PMID: 19892942); Genome Res. 2010 Jan;20(1):110-21. (PMID: 19858363); Nat Methods. 2010 Apr;7(4):248-9. (PMID: 20354512); Nature. 2010 Apr 22;464(7292):1214-7. (PMID: 20383123); Nat Biotechnol. 2010 May;28(5):511-5. (PMID: 20436464); Nucleic Acids Res. 2010 Sep;38(16):e164. (PMID: 20601685); Nature. 2010 Oct 28;467(7319):1061-73. (PMID: 20981092); Genome Biol. 2010;11(10):R106. (PMID: 20979621); Science. 2011 Apr 8;332(6026):238-40. (PMID: 21474760); Science. 2011 Apr 8;332(6026):240-3. (PMID: 21474761); RNA. 2011 Sep;17(9):1655-63. (PMID: 21784869); Mol Cell. 2011 Aug 19;43(4):624-37. (PMID: 21855801); Nucleic Acids Res. 2011 Sep 1;39(17):e118. (PMID: 21727090); Am J Med Genet A. 2011 Oct;155A(10):2560-5. (PMID: 21910238); Am J Med Genet A. 2011 Nov;155A(11):2885-96. (PMID: 21990275); Int J Immunogenet. 2011 Dec;38(6):501-5. (PMID: 21977988); J Comput Biol. 2012 Mar;19(3):279-92. (PMID: 22175250); Am J Med Genet A. 2012 Jun;158A(6):1455-61. (PMID: 22581640); Science. 2012 Jul 6;337(6090):64-9. (PMID: 22604720); Wiley Interdiscip Rev RNA. 2013 Jan-Feb;4(1):61-76. (PMID: 23074130). Linking ISSN: 20411723. Subset: MEDLINE; Grant Information: Canada Canadian Institutes of Health Research Date of Electronic Publication: 2015 Nov 02. ; Original Imprints: Publication: [London] : Nature Pub. Group <br />