Identification of novel gene(s) associated with Crisponi/Cold Induced Sweating syndrome-like phenotypes by whole-exome sequencing

Crisponi/Cold Induced Sweating syndrome type 1 (CS/CISS1; MIM#272430) is a rare autosomal recessive disorder characterized mainly by four distinct features; hyperthermia and feeding difficulties in the neonatal period, scoliosis and cold-induced sweating in the evolutive period. It is caused by defects (35 those identified so far in 56 patients) in the CRLF1 gene. The highest prevalence has been detected in Sardinia, Turkey and Spain. At the moment there is no clear correlation between the clinical phenotype and the type/localization of defect in the gene. A functional study on the changed forms of CRLF1 protein associated with CS/CISS1, showed that the phenotypic severity of the disorder depends on its defective/altered secretion. However, the disease mechanism is still poorly understood as well as the physiological role of CRLF1. The syndrome is often not correctly diagnosed due to the extremely complex phenotype, mostly still unknown, with a high neonatal mortality rate. Although the identification of defects in the CRLF1 gene provides a definite diagnosis in patients with suspected clinical diagnosis of CS/CISS1 syndrome, a fraction of such cases remain yet genetically unexplained after sequencing of the CRLF1 gene. In these CS/CISS1 syndrome-like phenotypes cases, whole-exome sequencing, which focuses only on DNA portions containing genes, represents the best approach to discover new disease-causing gene(s). The success in such discovery will help in better understanding the pathogenesis of the disease, in better dissecting pathways and networks where CRLF1 is involved and function, and hopefully in identifying novel therapeutic targets to achieve optimal management and treatment of the disease.