Isabelle Thiffault
Children's Mercy Kansas City, USA
Posters & Accepted Abstracts: J Genet Syndr Gene Ther
Molecular diagnostic testing is commonly used to confirm clinical suspicion of mitochondrial diseases and has been greatly facilitated by the advent of next generation sequencing, including whole genome and exome sequencing (WGS/WES). Many factors make WGS/WES attractive, including the cost-effectiveness, the ability to identify patients with a typical clinical presentation, as well as the identification of novel disease genes. One group of conditions especially amenable to WGS/WES is mitochondrial diseases, which collectively represent a significant source of morbidity and mortality in children, with a conservative estimate for prevalence being 1 in 5000 live births. The diverse clinical presentation of mitochondrial disease in conjunction with the large number of both nuclear and mitochondrial gene disease targets make the molecular diagnosis of mitochondrial diseases challenging. At least 265 disease genes have been identified to date, with up to 20 new disease genes described every year. We have been offering WES since 2011 as part of an undiagnosed disease program at The Center for Pediatric Genomic Medicine at Children's Mercy Hospital. Like many other centers, we have published diagnostic yields of ~50%. However, challenges remain in diagnosing the remaining half of these patients with rare disorders, which may harbor variants refractory to standard diagnosis. An important adjunct to WES/ WGS is transcriptomics (RNA-seq.), which is emerging as a powerful tool to examine the impact of genomic variants on transcript expression, identify the potential pathways involved in pathogenesis, and assess the impact of a disease-causing variant on transcripts in other genes. In the last year, we have collectively published the identification of four novel causal genes for mitochondrial disorders, and provided insight into the molecular pathogenesis leading to mitochondrial dysfunction. Currently, we have 6 additional putative novel genes. Characterization of the impact of variants by biochemical and/or functional studies will lead to a better understanding of the process of mitochondrial dysfunction, shedding light on potential therapeutic strategies that could potentially be applicable to the more common acquired mitochondrial diseases.
Email: ithiffault@cmh.edu
