We report a 21-year-old patient who has no history of consanguinity, immunodeficiency, miscarriages or infant deaths in the family. At the age of five, he was diagnosed with combined immunodeficiency, and since then he has suffered from multiple conditions including recurrent and chronic severe respiratory and GIT infections, vitiligo, autoimmune polyendocrinopathy, and surrenalian failure. IgG, IgA and IgM hypogammaglobulinemia and CD3+, CD19+ and CD16+CD56+ lymphopenia have been detected in the patient. Patient shows signs of severe malnutrition (27 kg, 1.45 m) caused by chronic recurrent Campylobacter diarrhoea which relapses despite antibiotic therapy and gut microbiota transplantation.
NGS panel targeted at primary immunodeficiency related genes was used to examine the patient DNA sample
We detected two missense variants in RAG1 gene in trans configuration. Variant p.His612Arg has been previously reported in milder phenotypes of combined immunodeficiency and it shows only reduced amount of the protein RAG1 with at least partially retained VDJ recombination. The second variant p.Arg897Gln has not been described yet, however, it has not been found in population databases, and computation prediction tools evaluated the variant as pathogenic. As a nonsense variant in the same amino acid position has been described in cases of SCID, we suggested this missense variant might be connected with a milder phenotype that we observed in our patient.
In conclusion, we detected two hypomorphic missense mutations in RAG1 in a patient suffering from CID, severe recurrent diarrhoea and failure to thrive.
H.G. and A.C. contributed equally.
Supported by: AZV NV16-34414A