XY females (n = 17) were analysed for mutations in SRY (sex-determining region Y gene), a gene that has recently been equated with the testis determining factor (TDF). SRY sequences were amplified by the polymerase chain reaction (PCR) and analysed by both the single strand conformational polymorphism assay (SSCP) and DNA sequencing. The DNA from two individuals gave altered SSCP patterns; only these two individuals showed any DNA sequence variation. In both cases, a single base change was found, one altering a tryptophan codon to a stop codon, the other causing a glycine to arginine amino acid substitution. These substitutions lie in the high mobility group (HMG)-related box of the SRY protein, a potential DNA-binding domain. The corresponding regions of DNA from the father of one individual and the paternal uncle of the other, were sequenced and found to be normal. Thus, in both cases, sex reversal is associated with de novo mutations in SRY. Combining this data with two previously published reports, a total of 40 XY females have now been analysed for mutations in SRY. The number of de novo mutations in SRY is now doubled to four, adding further strength to the argument that SRY is TDF.

The use of DNA variants in the mapping of the human genome and in the positional cloning of monogenic disease genes is well established. Determining the genetic bases of the more common "multifactorial" diseases, however, presents a major challenge. The genetics of these diseases are complicated by the interplay between many genes and the environment. These investigations will require large numbers of DNA markers and the technology to screen large populations with these markers. The systematic identification of the common DNA polymorphisms in the human genome coupled with the development of high throughput screening methods should allow ultimately the elucidation of the genetic component of most clinical and nonclinical phenotypes.

We report a case of a female infant with a de novo deletion of the short arm of chromosome 9, sex reversal, and an apparently intact SRY gene. Sex reversal has been reported in a number of subjects with a normal Y chromosome and a deletion of the terminal segment of the short arm of chromosome 9. The factors controlling early development of the male testes are unknown. There are likely to be many genes involved and we present additional evidence that one of these is situated on the end of the short arm of chromosome 9. (J Med Genet 1993;30:518-20) The primary event in the determination of male and female sex is dependent on the presence or absence of the sex determining region of the Y chromosome (SRY).1 Sex reversal has been reported in a number of subjects with a Y chromosome and a terminal deletion of the short arm of chromosome 9.2-6 These cases involved translocation of chromosome 9 with other chromosomes and therefore they were trisomic for part of another chromosome in addition to being monosomic for terminal 9p. We report a case of a sex reversed female infant with a de novo deletion of the distal short arm of chromosome 9, sex reversal, and an apparently intact SRY gene. Figure 1 Partial G banded metaphase to show deleted chromosome 9 with apparently terminal deletion of the short arm del (9) (p2305). Frozen fibroblasts from the proband are banked at Guy's Hospital, reference 90/3077.The SRY gene was amplified by the polymerase chain reaction, cloned, and sequenced and no mutations found.' Endocrine investigations Endocrine investigation was consistent with gonadal failure with a raised FSH of > 40 mU/l (normal range < 2 mU/l). The LH rose markedly after LHRH stimulation from 11 IU/l to > 50 IU/l (resting normal range 1-6 IU/1). The testosterone rose only minimally from 0*9 to 1-5 nmol/l (resting normal range A1Onmol/l) after three injections of HCG (1000 units x 3).~~- Docherty, Robb, Ramani, Hawkins, Grant Summary of patients with sex reversal and deletions of the distal short arm of chromosome 9.

The androgen receptor (AR) is essential to the normal development of the male internal and external genitalia. Consequently, impairment of AR function can result in undermasculinized genitalia that vary from a completely female appearance to isolated hypospadias. Since in vitro studies demonstrate that AR function is reduced by expansion of the polyglutamine tract within the receptor [AR(Gln)(n)]; this study examined whether longer AR(Gln)(n) repeats are associated with moderate to severe undermasculinization. The average AR(Gln)(n) length of the undermasculinized group (n = 78, median 25, interquartile range 23-26) was significantly greater than that of the control population (n = 850, median 23, inter-quartile range 22-26, P = 0.002). The odds ratio of having >/=23 repeats (as opposed to