Distribution of Disease-Causing Mutations through Different Protein Domains in Patients with Severe Combined Immunodeficiency

Severe combined immunodeficiency (SCID) has been described as the most severe form of primary immunodeficiency disorders (PID). The disease can be caused by mutations in more than 20 different genes with prevalence of 1 in 50000 to 100000 live births. In the present study, we described the protein domain position of variants in 14 main genes in patients with SCID. We also aimed to investigate the correlation between the variant distribution of protein domains and its pathogenicity and clinical outcome of the variant.

Molecular genetic analysis including Sanger sequencing, targeted gene panel and whole exome sequencing were performed on 50 patients with SCID. Moreover, protein domains characteristics were extracted from different databases such as Uniprot and PDB and the reported mutations were obtained from HGMD and ENSEMBL databases.

Our results showed that the mortality rate had a significant correlation with severity of clinical manifestations in the patients (p-value=0.000). There was also a significant relationship between the protein type and mutation severity (p-value=0.001) and severity of clinical manifestations (p-value=0.025). However, there was no significant relationship between the mortality rate and occurrence of mutations in different domains of proteins (p-value=0.304) and the severity of mutations (p-value= 0.586).

In severe genetic diseases such as SCID, mutations in related genes have affected the structure of the protein enough to cause severe symptoms. However, there are differences in the pathogenicity of the mutations based on their location on the protein domains. In order to determine these variations and predict the outcome of mutations, it is necessary to use in silico and laboratory methods along with statistical and data mining tools to track these minor differences