Whole exome sequencing identified a novel splice donor site variant in interleukin 2 receptor alpha chain

Interleukin 2 receptor alpha chain (IL-2R alpha or CD25) deficiency (OMIM #606367) is an immune dysregulation disorder segregating in autosomal recessive form. The disease is caused by biallelic variants in the IL-2R alpha gene encoding IL-2R alpha also known as CD25 protein. IL-2R alpha combines with gamma and beta chains of interleukin 2 receptor to form a functional interleukin 2 receptor (IL-2R). In the present study, we identified a Pakistani family presenting a unique presentation of IL-2R alpha deficiency. Clinical whole exome sequencing revealed a novel splice donor site variant (NM_001378789.1 (NP_001365718); c.64 + 1G > A) in the IL-2R alpha gene. American College of Medical Genetics (ACMG) guidelines interpreted the identified variant as likely pathogenic. The IL-2R alpha gene mutation usually presents with autoimmunity and immunodeficiency but in our patient, it presents with congenital diarrhea, metabolic crisis, and strong family history of death in infancy due to the similar complications. Her congenital diarrhea is attributed to autoimmunity in the form of autoimmune enteropathy and eczema. The laboratory findings revealed severe metabolic acidosis hypokalemia and elevated lactate and ammonia levels. This is a new presentation of IL-2R alpha gene mutation. The present study highlights the importance of clinical whole exome sequencing in the correct diagnosis of congenital disorders. The study will also help clinical geneticists for genetic counseling and prevention of the disease in the affected family.

Automated summary

This study reports a unique case of IL-2R alpha deficiency caused by a novel mutation in a Pakistani family. Clinical whole exome sequencing revealed a new variant, which was interpreted as likely pathogenic. The patient presented with congenital diarrhea, metabolic crisis, and a strong family history of death in infancy due to similar complications.