In summary, while Hmgcs2 shows a unique expression pattern in mouse fetal gonads, which implies it might be necessary for sex differentiation, based on our functional data in mouse and the fact that the two cases of 46,XY DSD with variants in HMGCS2 identified here were heterozygous variants, we believe that it is unlikely that HMGCS2 plays an important role in gonad development and therefore is an unlikely cause of DSDs in human. Here, HMGCS2 is linked to disorder of sexual differentiation.