Identification of mutations that cause Congenital Insensitivity to pain in affected Palestinian families رسالة ماجستير

Abstract

Congenital insensitivity to pain (CIP) is a rare autosomal recessive disorder(Drissi et al.), characterized primarily by an inability to perceive physical pain from birth, resulting in an accumulation of bruising, inflammation and fractures that affect the patient's life expectancy(Drissi et al.). This disease is caused by mutations in many genes, the most important of these genes and the most common is the SCN9A gene, as mutations in this gene cause, in addition to CIP, the patient's sense of smell loss(Xue et al.). And the NTRK1 gene comes to be the second gene that causes CIP, as mutations in this gene lead to CIP with anhidrosis, which in turn causes additional complications for affected patients(Shatzky et al.). In this study, we tried to detect the mutations that cause CIP in five participating Palestinian families, due to the lack of studies that dealt with this disorder in our community. After performing the required clinical examination, followed by DNA extraction of a whole blood samples from the participated patients and family members, we applied sanger sequencing and Whole Exome sequencing for the PCR products in order to revel of the mutations that cause CIP. The results of this research showed the presence of two mutations that cause CIPA in the NTRK1 gene. The mutations were as follows: the first mutation is (c.1931-ins- T) in exon 15, which led to early termination in the formed amino acid sequence, and the second mutation is a missense mutation (c.2170 G>A (G724 S) in exon 16. A new mutation was VI also detected in the SCN9A gene, in exon 7(c.901A>T, K301*) which led to the replacement of the amino acid that occupies position 301 with a stop codon, leading to the loss of a large part of the protein. Additionally, we performed in silico analysis using different soft wares such as polyphen, Clinvar, and SIFT, to detect the degree of severity of the missense mutation causing CIPA, and the analysis revealed that this mutation is a pathogenic mutation. In conclusion our study revealed of three mutations that caused CIP, and CIPA in Palestinian community which would help in improving the diagnostic and genetic counseling process. And help in building a diagnostic and follow up protocol for the affected individuals, since early diagnosis and medical care interference could prevent a lot of unpleasant complication for CIP, and CIPA patients(Shorer et al.).