|dc.description.abstract||Humans are afflicted by an enormous number of diseases with a genetic component, of which roughly 7,000 are thought to follow Mendelian inheritance. As these Mendelian diseases often have a large impact on normal development and quality of life, many studies are conducted using the affected individual’s genetic sequence in an effort to determine what has changed in which gene to cause them. If successful, this can then aid in understanding the disease and how best to manage it, as well as furthering the effort towards understanding the function of every gene in the human genome. Many techniques are used to locate the causative changes, or variants, that are causing a given Mendelian disease, such as using exome sequencing to search the coding regions of the genome, or comparative genomic hybridization to arrays (array-CGH) to identify large deletions or duplications.
This analysis attempted to identify the genetic cause of unexplained disorders in two families, one affected with Otopalatodigital Syndrome Type 1 (OPD1) and the other affected with Larsen Syndrome. Both disorders are usually caused by variants in the genes that code for filamin proteins (FLNA and FLNB respectively). These families are atypical in that no causative variants in these genes had been found despite significant previous attempts. In the OPD1 family, the exons of the FLNA gene have previously been sequenced using the Sanger methodology and array-CGH had been performed, but no causal variant had been located. In the family affected by Larsen Syndrome, the Sanger methodology has been used to sequence across the exons and exon/intron boundaries of the FLNB gene and Multiplex Ligation-dependent Probe Amplification (MLPA) has been performed over the FLNB gene. Ultimately, the whole exome of this family trio was examined, but no causal variant had been identified.
In this study, an analysis of whole genome sequence data was undertaken in an attempt to resolve the causation of the disorders in these two families. In the case of the family thought to be affected by OPD1, the child in fact had Rubinstein-Taybi syndrome; a disease with a similar phenotype but that is caused by mutations in the CREBBP gene, in this case a loss of a splice donor sequence at the beginning of exon 20. For the family affected by Larsen Syndrome multiple variants remain that could be causal, although none are particularly compelling. For this reason, it is not possible to definitively determine the cause of the disease and so no inferences about the genes with which FLNB interacts can be made. It is suggested that the analysis be repeated with further families as they become available, as the strength of the candidate genes would be greatly increased if they were also found in another family. Currently the cause of the disease in this family remains an enigma, despite the use of whole genome sequencing.||