Disruption of a large intergenic noncoding RNA in subjects with neurodevelopmental disabilities.

Large intergenic noncoding (linc) RNAs represent a newly described class of ribonucleic acid whose importance in human disease remains undefined. We identified a severely developmentally delayed 16-year-old female with karyotype 46,XX,t(2;11)(p25.1;p15.1)dn in the absence of clinically significant copy number variants (CNVs). DNA capture followed by next-generation sequencing of the translocation breakpoints revealed disruption of a single noncoding gene on chromosome 2, LINC00299, whose RNA product is expressed in all tissues measured, but most abundantly in brain. Among a series of additional, unrelated subjects referred for clinical diagnostic testing who showed CNV affecting this locus, we identified four with exon-crossing deletions in association with neurodevelopmental abnormalities. No disruption of the LINC00299 coding sequence was seen in almost 14,000 control subjects. Together, these subjects with disruption of LINC00299 implicate this particular noncoding RNA in brain development and raise the possibility that, as a class, abnormalities of lincRNAs may play a significant role in human developmental disorders.

[1]  J. Rinn,et al.  Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells , 2010, Nature Genetics.

[2]  Toshiro K. Ohsumi,et al.  Sequencing Chromosomal Abnormalities Reveals Neurodevelopmental Loci that Confer Risk across Diagnostic Boundaries , 2012, Cell.

[3]  Ira M. Hall,et al.  Complex reorganization and predominant non-homologous repair following chromosomal breakage in karyotypically balanced germline rearrangements and transgenic integration , 2012, Nature Genetics.

[4]  J. Rashbass.  Online Mendelian Inheritance in Man. , 1995, Trends in genetics : TIG.

[5]  Michael F. Lin,et al.  Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals , 2009, Nature.

[6]  Howard Y. Chang,et al.  A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression , 2011, Nature.

[7]  J. Rinn,et al.  Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression , 2009, Proceedings of the National Academy of Sciences.

[8]  Howard Y. Chang,et al.  Long noncoding RNA HOTAIR reprograms chromatin state to promote cancer metastasis , 2010, Nature.

[9]  Yiping Shen,et al.  Next-generation sequencing strategies enable routine detection of balanced chromosome rearrangements for clinical diagnostics and genetic research. , 2011, American journal of human genetics.

[10]  James A. Cuff,et al.  Distinguishing protein-coding and noncoding genes in the human genome , 2007, Proceedings of the National Academy of Sciences.

[11]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..

[12]  J. Shendure,et al.  Characterization of apparently balanced chromosomal rearrangements from the developmental genome anatomy project. , 2008, American journal of human genetics.

[13]  Richard Durbin,et al.  Sequence analysis Fast and accurate short read alignment with Burrows – Wheeler transform , 2009 .

[14]  S. Haggarty,et al.  Epigenetic Characterization of the FMR1 Gene and Aberrant Neurodevelopment in Human Induced Pluripotent Stem Cell Models of Fragile X Syndrome , 2011, PloS one.

[15]  J. Rinn,et al.  A Large Intergenic Noncoding RNA Induced by p53 Mediates Global Gene Repression in the p53 Response , 2010, Cell.

[16]  William R. Jeck,et al.  Expression of Linear and Novel Circular Forms of an INK4/ARF-Associated Non-Coding RNA Correlates with Atherosclerosis Risk , 2010, PLoS genetics.