Abstract
The success of whole-exome sequencing to identify mutations causing single-gene disorders has been well documented. In contrast whole-exome sequencing has so far had limited success in the identification of variants causing more complex phenotypes that seem unlikely to be due to the disruption of a single gene. We describe a family where two male offspring of healthy first cousin parents present a complex phenotype consisting of peripheral neuropathy and bronchiectasis that has not been described previously in the literature. Due to the fact that both children had the same problems in the context of parental consanguinity we hypothesised illness resulted from either X-linked or autosomal recessive inheritance. Through the use of whole-exome sequencing we were able to simplify this complex phenotype and identified a causative mutation (p.R1070*) in the gene periaxin (PRX), a gene previously shown to cause peripheral neuropathy (Dejerine–Sottas syndrome) when this mutation is present. For the bronchiectasis phenotype we were unable to identify a causal single mutation or compound heterozygote, reflecting the heterogeneous nature of this phenotype. In conclusion, in this study we show that whole-exome sequencing has the power to disentangle complex phenotypes through the identification of causative genetic mutations for distinct clinical disorders that were previously masked.
Highlights
The utility of whole-exome sequencing (WES) for the identification of known and novel disease genes in families segregating rare Mendelian forms of disease is well established
Of the remaining variants only two were located within genes functionally related to the phenotype under study; these were periaxin (PRX) for the peripheral neuropathy and Interleukin-33 (IL33) for the bronchiectasis
We present here the results of a study that aimed to identify the genetic cause of a novel phenotype that included peripheral neuropathy and bronchiectasis
Summary
The utility of whole-exome sequencing (WES) for the identification of known and novel disease genes in families segregating rare Mendelian forms of disease is well established. Bronchiectasis is a term used to describe a clinicopathological phenotype with multiple routes to causation These include local causes such as damage due to previous infection, foreign body or developmental abnormality, and systemic conditions which include genetic (such as cystic fibrosis), immunodeficient (principally antibody deficiency) and systemic inflammatory states (such as rheumatoid arthritis). Because of this complexity, even with intensive investigation, in many cases there is no known identifiable cause
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