Journal
HUMAN MUTATION
Volume 42, Issue 1, Pages 19-24Publisher
WILEY-HINDAWI
DOI: 10.1002/humu.24135
Keywords
aberrant splicing; mitochondrial disease; genomics; proteomics; RNA sequencing
Categories
Funding
- National Human Genome Research Institute [R01 HG009141, UM1 HG008900]
- Medical Research Future Fund [ARG76368]
- National Health and Medical Research Council [1072662, 1140851, 1140906, 1155244, 1164479]
- National Health and Medical Research Council of Australia [1140851, 1072662, 1140906, 1155244, 1164479] Funding Source: NHMRC
Ask authors/readers for more resources
The study identified a deep intronic variant associated with a mitochondrial disease in two individuals, leading to isolated Complex I deficiency. Transcriptomic and proteomic analyses were highlighted as complementary diagnostic tools in patients undergoing genome-wide diagnostic evaluation.
The diagnosis of Mendelian disorders following uninformative exome and genome sequencing remains a challenging and often unmet need. Following uninformative exome and genome sequencing of a family quartet including two siblings with suspected mitochondrial disorder, RNA sequencing (RNAseq) was pursued in one sibling. Long-read amplicon sequencing was used to determine and quantify transcript structure. Immunoblotting studies and quantitative proteomics were performed to demonstrate functional impact. Differential expression analysis of RNAseq data identified significantly decreased expression of the mitochondrial OXPHOS Complex I subunit NDUFB10 associated with a cryptic exon in intron 1 of NDUFB10, that included an in-frame stop codon. The cryptic exon contained a rare intronic variant that was homozygous in both affected siblings. Immunoblot and quantitative proteomic analysis of fibroblasts revealed decreased abundance of Complex I subunits, providing evidence of isolated Complex I deficiency. Through multiomic analysis we present data implicating a deep intronic variant in NDUFB10 as the cause of mitochondrial disease in two individuals, providing further support of the gene-disease association. This study highlights the importance of transcriptomic and proteomic analyses as complementary diagnostic tools in patients undergoing genome-wide diagnostic evaluation.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available