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Approximately 50% of all congenital anomalies cannot be linked to any specific cause, but cost effective high throughput sequencing has emerged as an efficient strategy for identifying single nucleotide polymorphisms (SNPs) associated with disease. In many cases, there is not enough evidence to determine if these SNPs underlie disease. To bridge this gap in our understanding, advances in functional analyses are warranted. Several preclinical model systems are currently being utilized to provide such evidence, including the advantageous zebrafish embryo. While every system exhibits disadvantages and caveats, a new era of multidisciplinary research is emerging, which uses a broad spectrum of functional analysis tools. This approach will make it possible to identify potential therapeutic targets for both common and rare human disorders.