Additional deletion in sex-determining region of human Y chromosome resolves paradox of X,t(Y;22) female

Abstract

WHETHER a human embryo develops as a male or a female is determined by the presence of the Y chromosome1,2. The sex-determining function lies entirely in interval 1A, inasmuch as most XX individuals with descended testes and normal male external genitalia carry this small region of the Y chromosome3. We have localized an essential part of the sex-determining function to a portion of interval 1A, on the basis of the discovery of a female with a reciprocal Y;22 translocation and part of 1A deleted at the translocation breakpoint3. Recently, a paradox has arisen with the report4 of four partially masculinized XX individuals who carry only a portion of interval 1A—a portion that does not overlap the deletion in the X,t(Y;22) female. These recent findings imply that the sex-determining function lies in the portion of 1A present in the four XX intersexes and not in the portion deleted in the X,t(Y;22) female. To explain the X,t(Y;22) individual, it was proposed that she was female because of a chromosomal position effect4 or delayed development of the gonadal soma5. Here we report that the X,t(Y;22) female has a deletion of a second portion of interval 1A—a portion corresponding closely to that present4 in the XX intersexes. This resolves the apparent contradiction. Nonetheless, phenotype-genotype correlations suggest that two or more genetic elements in interval 1A may contribute to the sex-determining function of the Y chromosome. The X,t(Y;22) female lacks the ZFY gene but does not exhibit the complex phenotype known as Turner's syndrome, arguing against the hypothesis5 that ZFY is the Turner's syndrome gene on the Y chromosome.