Considering the predicted functional consequences of SIX1 variants, four of the seven different variants (57%) are stop-gain, representing a 2.7-fold enrichment of loss-of-function (LoF) variants in CRS compared with the spectrum previously reported in BOS/BOR/HL, which are more often caused by missense variants (73.7% of the 19 different pathogenic variants identified in 27 unrelated families reported in the literature; figure 1C, online supplemental table S3). Here, SIX1 is linked to congenital rubella syndrome.