In summary, whereas the classic BOS/BOR/HL-associated variants are usually missense substitutions that may have dominant-negative activity (figure 1C),4 14 we propose that heterozygous SIX1 LoF variants are associated with a haploinsufficiency phenotype that overlaps with BOS/BOR/HL, but includes a propensity to CRS in some individuals and non-penetrance in others. The gene discussed is SIX1; the disease is congenital rubella syndrome.