The potential for next-generation sequencing to characterise the genetic variation underlying non-syndromic cleft lip and palate phenotypes

Abstract

Next-generation sequencing is revolutionising the study of genetic variation and its role in disease. Individual DNA samples can now be sequenced cost-effectively enabling analysis of the complete spectrum of genetic variation. This technology has the potential to contribute significantly to the understanding of non-syndromic cleft lip and/or palate. This condition occurs with relatively high frequency and only a proportion of the underlying genetic causal factors have been identified. Many of the genes implicated have been found through genome-wide association studies but further progress is limited because these approaches consider only common genetic variants and neglect rarer variations. Because many of the causal genetic variants remain unknown, the role of gene-environment and gene-gene interaction is difficult to characterise. The identification of novel, low frequency, variants will provide new insights into the biological mechanisms and pathways involved in the condition. Sequence-based analysis will also be invaluable for fine mapping causal variants in the larger regions already identified by linkage and association studies for which positive identification of causal genetic variants has proven difficult. This review considers the available evidence for the genes involved and current understanding of how genetic variation interacts with environmental factors known to influence risk. Only by characterising the underlying genetic factors will the effort to understand gene-environment interaction and underlying functional processes be successful.