Molecular and genetic characterization, clinical evaluation and pilot study to assess the feasibility of a carrier screening for Crisponi syndrome in Sardinia

Crisponi syndrome (CS) and cold-induced sweating syndrome type 1 (CISS1) share clinical characteristics, such as dysmorphic features, muscle contractions, scoliosis and cold-induced sweating, with CS patients showing a severe clinical course in infancy involving hyperthermia, associated with death in most cases in the first years of life. Functional and clinical studies supported the fact that they represent manifestations of the same autosomal recessive disorder caused by mutations in the CRLF1 gene with different degrees of severity. Anyway the debate about what term is more appropriate to indicate the syndrome is still open. During my project we expanded the mutational spectrum of CRLF1 in the syndrome and carried out a meta-analysis of the literature for all the mutations described so far. To date, overall 42 distinct CRLF1 mutations found either in homozygosity or in compound heterozygosity have been found in CS/CISS1 patients. In particular we are describing 11 new mutations in addition to the 31 already reported in literature along with a detailed clinical phenotype and genotype/phenotype correlation. The highest prevalence is registered in Sardinia, Turkey and Spain. In Sardinia the evaluation of the allele frequency for two out of the three founder mutations estimated a carrier frequency of 1,4% with an incidence of about 1 case per 20,700 newborns.