Submission Details

MSN was first reported in relation to X-linked combined immunodeficiency due to moesin deficiency in 2016 (Lagresle-Peyrou et al., PMID: 27405666). This condition is characterized by T-B-NK- lymphopenia, recurrent infections, decreased circulating antibody level, and sepsis and leg ulcers in some patients. The age of onset and phenotypic presentation varied among patients reported. Four variants (missense & nonsense) that have been reported in 11 unrelated probands in 7 publications (PMIDs: 27405666, 28378256, 29556235, 32506361, 34093558, 36119109, 35754805, 34453634) are included in this curation. The variant was maternally inherited from unaffected mothers in all cases and in one case, the variant occured de novo in the proband's mother. Carrier mothers had skewed X chromosome inactivation in all hematopoietic lineages. Variants segregated with disease in 3 families. While seven probands were hemizygous for the same missense variant, p.Arg171Trp, it is likely that this variant occurs on different haplotypes, indicating that p.Arg171 may be a mutation hotspot. The mechanism of pathogenicity is known to be loss of function. This gene-disease association is also supported by mouse model, expression studies, functional alteration in non-patient cells, biochemical function, and rescue in patient cells (PMIDs: 22875842, 36119109, 34798556, 28978692, 27405666). In summary, MSN is definitively associated with X-linked combined immunodeficiency due to moesin deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.