Abstract
Reported synonymous substitutions are generally non-pathogenic, and rare pathogenic synonymous variants may be disregarded unless there is a high index of suspicion. In a case of IL7 receptor deficiency severe combined immunodeficiency (SCID), the relevance of a non-reported synonymous variant was only suspected through the use of additional in silico computational tools, which focused on the impact of mutations on gene splicing. The pathogenic nature of the variant was confirmed using experimental validation of the effect on mRNA splicing and IL7 pathway function. This case reinforces the need to use additional experimental methods to establish the functional impact of specific mutations, in particular for cases such as SCID where prompt diagnosis can greatly impact on diagnosis, treatment, and survival.
Highlights
We report a 5-month-old male born to non-consanguineous parents who fulfilled clinical and immunological parameters for severe combined immunodeficiency (SCID)
It is clear that impact on splicing of this exon can lead to severe phenotypes, as illustrated in this study, which supports splicing as one of the evolutionary forces that maintains the conservation of this site
We report the first case of an IL7R causal synonymous mutation in a male patient with T−B+NK+ SCID phenotype
Summary
We report a 5-month-old male born to non-consanguineous parents who fulfilled clinical and immunological parameters for severe combined immunodeficiency (SCID). He was admitted with a history of high fever, diarrhea, and oral thrush (Figure 1A). Sanger sequencing of the IL7R gene revealed a heterozygous non-synonymous mutation (c.353G>A, p.C118Y) in exon 3. Patients suffer severe and opportunistic infections, protracted diarrhea, and failure to thrive, leading to a fatal outcome in their first year of life (4). SCID is a genetically heterogeneous disorder caused by mutations in more than 20 different genes and is classified according to the immunological phenotype and the corresponding underlying molecular defect. A rapid molecular screen is essential to distinguish among SCID patients, so they undergo early HSCT (6)
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