Abstract:
:Next-generation sequencing (NGS) enables analysis of the human genome on a scale previously unachievable by Sanger sequencing. Exome sequencing of the coding regions and conserved splice sites has been very successful in the identification of disease-causing mutations, and targeting of these regions has extended clinical diagnostic testing from analysis of fewer than ten genes per phenotype to more than 100. Noncoding mutations have been less extensively studied despite evidence from mRNA analysis for the existence of deep intronic mutations in >20 genes. We investigated individuals with hyperinsulinaemic hypoglycaemia and biochemical or genetic evidence to suggest noncoding mutations by using NGS to analyze the entire genomic regions of ABCC8 (117 kb) and HADH (94 kb) from overlapping ~10 kb PCR amplicons. Two deep intronic mutations, c.1333-1013A>G in ABCC8 and c.636+471G>T HADH, were identified. Both are predicted to create a cryptic splice donor site and an out-of-frame pseudoexon. Sequence analysis of mRNA from affected individuals' fibroblasts or lymphoblastoid cells confirmed mutant transcripts with pseudoexon inclusion and premature termination codons. Testing of additional individuals showed that these are founder mutations in the Irish and Turkish populations, accounting for 14% of focal hyperinsulinism cases and 32% of subjects with HADH mutations in our cohort. The identification of deep intronic mutations has previously focused on the detection of aberrant mRNA transcripts in a subset of disorders for which RNA is readily obtained from the target tissue or ectopically expressed at sufficient levels. Our approach of using NGS to analyze the entire genomic DNA sequence is applicable to any disease.
journal_name
Am J Hum Genetjournal_title
American journal of human geneticsauthors
Flanagan SE,Xie W,Caswell R,Damhuis A,Vianey-Saban C,Akcay T,Darendeliler F,Bas F,Guven A,Siklar Z,Ocal G,Berberoglu M,Murphy N,O'Sullivan M,Green A,Clayton PE,Banerjee I,Clayton PT,Hussain K,Weedon MN,Ellard Sdoi
10.1016/j.ajhg.2012.11.017subject
Has Abstractpub_date
2013-01-10 00:00:00pages
131-6issue
1eissn
0002-9297issn
1537-6605pii
S0002-9297(12)00630-1journal_volume
92pub_type
杂志文章abstract::Prior to the implementation of predictive-testing programs for Huntington disease (HD), significant concern was raised concerning the likelihood of catastrophic events (CEs), particularly in those persons receiving an increased-risk result. We have investigated the frequency of CEs-that is, suicide, suicide attempt, a...
journal_title:American journal of human genetics
pub_type: 杂志文章,多中心研究
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journal_title:American journal of human genetics
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doi:
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