Further delineation of bone marrow failure syndrome caused by novel compound heterozygous variants of MYSM1.

Myb-like SWIRM and MPN domains (MYSM1) is a chromatin-binding transcriptional regulator that mediates histone 2A deubiquitination, which plays a vital role in hematopoiesis and lymphocyte differentiation. Biallelic variants in MYSM1 cause a rare bone marrow failure syndrome (OMIM #618116). To date, only three pathogenic variants (E390*, R478*, and H656R) of MYSM1 have been reported in nine patients, and all variants are homozygous. Here, we describe a Chinese female patient who mainly presented with leukopenia, granulocytopenia, thrombocytopenia, severe anemia, and B-cell and natural killer cell deficiency in the peripheral blood, and was diagnosed with bone marrow failure. Trio whole-exome sequencing revealed a novel compound heterozygous variant in MYSM1 (c.399G>A, p.L133L, and c.1467C>G, p.Y489*). The c.399G>A synonymous variant is located at the 3'-end of exon 6, which is predicted to affect MYSM1 mRNA splicing. Analysis of the products obtained from the reverse transcription-polymerase chain reaction revealed that the c.399G>A variant leads to exon 6 skipping, resulting in a premature termination codon (c.321_399 del, p.V108Lfs*13). cDNA sequencing suggested that the c.1467C>G variant triggered nonsense-mediated mRNA degradation. Moreover, we identified a novel transcript of MYSM1 mRNA (missing exons 5 and 6) in human blood cells. Our results expand the mutation spectrum of MYSM1; additionally, this is the first report of a synonymous splicing variant that induces post-transcriptional skipping of exon 6 leading to a bone marrow failure syndrome phenotype.