SRY-Related Disorders of Sex Development via the SRY Gene

The sex-determining region Y (SRY) gene on the Y chromosome plays a pivotal role in testis determination (Berta et al., 1990). Loss-of-function mutations in the SRY gene can cause 46,XY complete or partial gonadal dysgenesis.

The major clinical phenotype caused by SRY mutations is SRY-related 46,XY complete gonadal dysgenesis (OMIM# 400044). 46,XY complete gonadal dysgenesis is also termed Swyer syndrome or 46,XY pure gonadal dysgenesis (Cotinot et al., 2002; Ostrer, 2008). While having a 46,XY karyotype at a chromosomal level as males normally do, patients affected by 46,XY complete gonadal dysgenesis are phenotypically female with functional female genitalia and structures including a vagina, uterus and fallopian tubes. The key feature of these affected women is the replacement of the ovaries by functionless scar tissue due to the lack of proper ovarian development. Lacking sex glands, affected women do not produce sex hormones (estrogen or progesterone), will not undergo puberty and thus are infertile. Most patients are diagnosed during adolescence when primary amenorrhea is revealed. Notably, patients with 46,XY complete gonadal dysgenesis have an increased risk of developing cancer in the underdeveloped gonadal tissue. Gonadal tumors can develop at any age even before a diagnosis of 46,XY complete gonadal dysgenesis during childhood.

46,XY partial gonadal dysgenesis (also termed 46,XY partial testicular dysgenesis) is characterized by ambiguous external genitalia with a wide spectrum of genital ambiguity, dysgenetic testis and a mixture of both Wolffian and Mullerian ducts (McElreavey et al., 1996; Domenice et al., 1998; Cotinot et al., 2002).

The third, but much less frequent, SRY-related DSD is 46,XX sex reversal (OMIM# 400045) caused by translocation of a segment of the Y chromosome containing the SRY gene to the X chromosome. In this condition, patients with a 46, XX karyotype are phenotypically male (Ostrer, 2008). True hermaphroditism is common in patients with this translocation.

46,XY complete or partial gonadal dysgenesis can be caused by mutations in different genes with different inheritance patterns including autosomal dominant (the WNT4 and NR5A1 genes), autosomal recessive (the DHH gene), X-linked (the NR0B1 gene) or Y-linked (the SRY gene) (Paliwal et al., 2011; Ostrer et al. GeneReviews, 2008). In approximately 10-15% of cases, 46,XY complete or partial gonadal dysgenesis is caused by mutations in the sex-determining region Y (SRY) gene on the Y chromosome. The SRY gene plays a pivotal role in testis determination (Berta et al., 1990; Jäger et al., 1990). Genetic aberrations throughout this single exon gene include missense, nonsense, regulatory mutations and small deletion/insertions. Most of these causative mutations are clustered in the region (codons 13 through 82) coding the high-mobility-group (HMG) box, which is responsible for DNA binding and bending (Harley et al., 1994). Deletions or duplications of the segment of the Y chromosome involving the SRY gene have also been reported but are relatively uncommon (Human Gene Mutation Database). Most of the documented SRY causative mutations are de novo, but familial mutations transmitted from mosaic fathers have also been reported (Schmitt-Ney et al., 1995; Isidor et al., 2009).

SRY mutations have been found via DNA sequencing in approximately 10-15% of patients with 46,XY complete or partial gonadal dysgenesis (Paliwal et al., 2011).

The detection rate of copy number changes involving the SRY gene in a large cohort of patients is unavailable in the literature because these have been only reported in limited individual cases and are relatively uncommon (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the SRY gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing.

It also includes targeted testing of two regulatory mutations c. -75G>A and c.-130G>C (Human Gene Mutation Database).

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).