Talks at the Sanford-Burnham Rare Disease Day Symposium highlight the “transformative potential of exome sequencing” for rare Mendelian diseases
Individually rare yet collectively common, ‘orphan’ or rare diseases affect nearly 30 million Americans every year. Despite the current explosion in genomic data and personalized medicine strategies, little is known about what causes these rare genetic disorders, how they progress or options for treatment. Marking Rare Disease Day, a one-day symposium at the Sanford Burnham Medical Research Institute in La Jolla, CA featured talks by several researchers studying disorders of glycosylation, especially in children. Several of these discussions highlighted how studying rare conditions can enhance the ways we detect, diagnose or research relatively more common diseases.
As genomics makes its tentative way into clinical programs, the value of exome sequencing vs. whole genome sequencing remains a matter of debate. In a presentation demonstrating the continuing value of exomes, Dr. Sessions Cole of Washington University in St. Louis described how analyzing whole exome sequences from one family helped identify the rare Mendelian disease affecting their 9-month-old daughter.
The first child of healthy parents, this young patient suffered multi-organ failure, including renal tubular dysfunction, interstitial lung disease and liver failure with no readily apparent cause. Searching for an underlying genetic condition, Dr. Cole and his research group sequenced the exomes of both parents and the child using Agilent exon arrays and Illumina HiSeq technology, aligned sequences and computationally identified relevant single nucleotide variants.
Assuming a recessive condition inherited from the parents, the group systematically filtered the identified SNVs based on several criteria. Excluding SNPs present in public databases, and searching specifically for variants present in gene loci that had at least two SNPs per gene and were heterozygous in both parents, the group found a single gene with missense mutations in both parents: MARS, or methionyl amino-acyl tRNA synthetase.
Transfer RNA (tRNA) synthetase genes are involved in amino acid transport during protein synthesis. Though MARS has been studied in model animals, mutations of the gene have not so far been associated with any rare human disease. Since each parent had a missense mutation in the gene, it was likely that their child had inherited two defective copies.
Following up on their clinical results, the group tested the variant alleles to identify the impact of the mutations on function. They found that the mutant alleles were transcribed at the same levels as the normal version of the gene, but functional assays in the cell line HK293 showed that the variants were not as efficient functionally as the normal, more common version of the gene. Bringing these experimental results back to the clinic, the team is currently addressing the child’s condition with enzyme therapy to improve the activity of the defective MARS transcripts.
Though exome sequencing has particular advantages for rare conditions where mutations tend to be highly disruptive to protein function, the group’s approach demonstrates the importance of such family analysis to inform genetic counselors, doctors and patients of potential disease risks. And for children with rare Mendelian disorders, exome sequencing can be a “transformative strategy” to identify therapies that treat life-threatening disease.