To date all eight known individuals with ZSWIM6-related ID carry a de novo recurrent single-nucleotide variant that introduces a premature termination codon (PTC) in exon 13 (chr5[GRCh37]: g60837744C>T; GenBank: NM_020928.1; c.2737C>T [p.Arg913Ter]).
We demonstrated that the c.2737C>T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the variant resulting in a truncated ZSWIM6 protein lacking the terminal Sin3-like domain, which could have a dominant-negative effect. There are several lines of evidence, including developmental studies, animal experiments and genome wide association studies in human populations, that supports ZSWIM6 having an important role in the development and function of nerve cells, although more studies are required to fully understand the basic functions of ZSWIM6 and the effect at a cellular level, of a shortened ZSWIM6 protein due to this recurrent mutation.
Diagram showing predicted ZSWIM6 protein domains (lower) relative to exonic structure (upper) and positions of the p.Arg913Ter and p.Gln874Ter variants reported here (in red and black, respectively) and the previously reported p.Arg1163Trp recurrent missense variant located within the C-terminal Sin3-like domain (from Palmer et al., 2017).