Mar elements are rare in the general population (estimated to occur in 0.044% of newborn infants) (Liehr et al., 2004), but >30% mar element carriers are clinically abnormal (Liehr et al., 2006) and mar elements are enriched approximately 7-fold in patients with developmental delay (0.288% of cases) (Liehr and Weise, 2007). The size, genetic content, and extent of somatic mosaicism contribute to the clinical impact of a mar carrier case (Liehr et al., 2013). Somatic mosaicism is present in slightly more than 50% of mar carriers, and the extent of mosaicism can range from very low (<0.5%) to very high (>95%); nonetheless, it is difficult to directly correlate the extent of mosaicism to the magnitude of the clinical phenotype, likely because only one tissue is typically evaluated (Liehr et al., 2013). The mitotic stability of mar elements in vitro is dependent on their shape and telomeres (Hussein et al., 2014). Whether the 9p24.1 mar element described here affects the clinical phenotypes in these two carriers is unknown; the mosaicism in presumably clonal hiPSCs has made it difficult to functionally evaluate the causal impact of this mar element.
