@article{00641584548b40e19415083f5e01ce8c,
title = "Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro-costo-mandibular syndrome",
abstract = "Elucidating the function of highly conserved regulatory sequences is a significant challenge in genomics today. Certain intragenic highly conserved elements have been associated with regulating levels of core components of the spliceosome and alternative splicing of downstream genes. Here we identify mutations in one such element, a regulatory alternative exon of SNRPB as the cause of cerebro-costo-mandibular syndrome. This exon contains a premature termination codon that triggers nonsense-mediated mRNA decay when included in the transcript. These mutations cause increased inclusion of the alternative exon and decreased overall expression of SNRPB. We provide evidence for the functional importance of this conserved intragenic element in the regulation of alternative splicing and development, and suggest that the evolution of such a regulatory mechanism has contributed to the complexity of mammalian development.",
author = "Lynch, {Danielle C.} and Timoth{\'e}e Revil and Jeremy Schwartzentruber and Bhoj, {Elizabeth J.} and Innes, {A. Micheil} and Lamont, {Ryan E.} and Lemire, {Edmond G.} and Chodirker, {Bernard N.} and Taylor, {Juliet P.} and Zackai, {Elaine H.} and McLeod, {D. Ross} and Kirk, {Edwin P.} and Julie Hoover-Fong and Leah Fleming and Ravi Savarirayan and Kym Boycott and Alex MacKenzie and Jacek Majewski and Michael Brudno and Dennis Bulman and David Dyment and Jerome-Majewska, {Loydie A.} and Parboosingh, {Jillian S.} and Bernier, {Francois P.}",
note = "Funding Information: Exome sequencing. DNA was extracted from whole blood. Exome sequencing was performed for six unrelated cases and seven family members at the McGill University and G{\'e}nome Qu{\'e}bec Innovation Centre. The SureSelect 50 Mb Human All Exon kit (Agilent) was used for exon capture; v3 was used for families A, B and C, and v5 was used for families D, E and F. Captured regions were sequenced on a HiSeq 2000 sequencer (Illumina) with 100 bp paired-end reads. Reads were aligned to the hg19/GRCh37 human reference sequence using the Burrows-Wheeler Aligner34, and indel realignment was done with GATK35. Duplicate reads were then marked using Picard (http://picard.sourceforge.net/) and excluded from downstream analyses. Coverage of consensus coding sequence (CCDS) bases was assessed using the GATK, which showed that samples had on average >94% of CCDS bases covered by at least 10 reads, and >90% of CCDS bases covered by at least 20 reads. Single-nucleotide variants and short insertions and deletions were called with SAMtools mpileup36 with the extended base alignment quality adjustment (-E). Only variants that were supported by Z20% of reads were returned. These were annotated using both Annovar37 and custom scripts to identify whether they affected protein-coding sequence, and whether they had previously been seen in the 1,000 genomes data set (April 2012), the National Institutes of Health Heart, Lung, Blood Institute, Grand Opportunity Exome Sequencing Project (NHLBI GO) exomes, or in B700 exomes previously sequenced at our center. Publisher Copyright: {\textcopyright} 2014 Macmillan Publishers Limited. All rights res.",
year = "2014",
month = jul,
day = "22",
doi = "10.1038/ncomms5483",
language = "English (US)",
volume = "5",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}