Inborn errors of immunity (IEIs) are a group of genetic disorders in which parts of the human immune system are missing, dysfunctional, or poorly regulated. MSN encodes moesin, a cytoskeletal adaptor protein that plays a critical role in maintaining cell rigidity and is primarily expressed in lymphocytes and endothelial cells. Missense and premature stop variants in the MSN gene are known to cause X-linked moesin-associated immunodeficiency (X-MAID), a rare, sex-linked disease.
Clinical assessments and an IEI gene panel were performed. The identified MSN variant was segregated through the family. RNA was isolated from blood samples collected from the brothers, their mother, and healthy controls and then sequenced. RNA-sequencing results were validated using quantitative PCR.
We identified two brothers with a hemizygous, synonymous variant in MSN (NM_002444.3: c.795G>A, p.Pro265=) that was predicted by in silico prediction tools to be damaging (CADD score of 25) and likely to alter mRNA splicing (SpliceAI delta score for donor loss was 0.82). The brothers inherited the variant from their healthy, carrier mother. The brothers presented with a very similar phenotype of severe lower leg dermatitis, chronic nonhealing ulcers (clinically diagnosed as pyoderma gangrenosum but with histology more consistent with reactive angiomatosis), clinical features of venous insufficiency, hypogammaglobulinemia, and mild lymphopenia. RNA sequencing revealed aberrant splicing of the MSN transcript in the brothers, consisting of either a complete skip of exon 7 or the retention of intronic sequences that result in a premature stop codon. These aberrant splicing events were observed at low levels in the carrier mother and were absent in the healthy controls. Quantitative PCR validated the splicing events, revealing minimal MSN transcript levels in the brothers, consistent with transcript degradation. Investigations into moesin expression in the brothers’ lymphocytes are currently underway.
This study is the first to report X-MAID caused by an MSN splicing variant and further emphasizes the possibility that synonymous variants can be disease causing.
