W179 - X-MAID Disease Caused by a Novel Synonymous MSN Variant That Disrupts mRNA Splicing

Abstract Text:

Introduction: 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.

Methods: Clinical assessments and a targeted gene panel were performed. The identified MSN variant was segregated through the family. RNA was isolated from blood samples and then sequenced. RNA-sequencing results were validated using quantitative PCR.

Results: 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 non-healing ulcers, 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, and were validated using quantitative PCR.

Conclusion: 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.