Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 105, Issue 3, Pages 573-587Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2019.07.013
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Funding
- National Health and Medical Research Council of Australia [APP1048816, APP1136197, APP1117510, 1080587]
- Muscular Dystrophy New South Wales PhD scholarship
- National Human Genome Research Institute
- National Eye Institute
- National Heart, Lung and Blood Institute grant [UM1 HG008900]
- National Health and Medical Research Council of Australia [1080587] Funding Source: NHMRC
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A precise genetic diagnosis is the single most important step for families with genetic disorders to enable personalized and preventative medicine. In addition to genetic variants in coding regions (exons) that can change a protein sequence, abnormal pre-mRNA splicing can be devastating for the encoded protein, inducing a frameshift or in-frame deletion/insertion of multiple residues. Non-coding variants that disrupt splicing are extremely challenging to identify. Stemming from an initial clinical discovery in two index Australian families, we define 25 families with genetic disorders caused by a class of pathogenic non-coding splice variant due to intronic deletions. These pathogenic intronic deletions spare all consensus splice motifs, though they critically shorten the minimal distance between the 5' splice-site (5'SS) and branchpoint. The mechanistic basis for abnormal splicing is due to biophysical constraint precluding U1/U2 spliceosome assembly, which stalls in A-complexes (that bridge the 5'SS and branchpoint). Substitution of deleted nucleotides with non-specific sequences restores spliceosome assembly and normal splicing, arguing against loss of an intronic element as the primary causal basis. Incremental lengthening of 5'SS-branchpoint length in our index EMD case subject defines 45-47 nt as the critical elongation enabling (inefficient) spliceosome assembly for EMD intron 5. The 5'SS-branchpoint space constraint mechanism, not currently factored by genomic informatics pipelines, is relevant to diagnosis and precision medicine across the breadth of Mendelian disorders and cancer genomics.
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