SRY-Related Disorders of Sex Development via the SRY Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
9217 SRY 81400 81400,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9217SRY81400 81400, 81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

For Reflex to PGxome pricing click here.

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

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.

Genetics

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).

Clinical Sensitivity - Sequencing with CNV PGxome

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).

Testing Strategy

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).

Indications for Test

Candidates for this test are patients with 46,XY complete or partial gonadal dysgenesis or 46,XX sex reversal. Testing is also indicated for family members of patients who have known SRY mutations.

Gene

Official Gene Symbol OMIM ID
SRY 480000
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Berta, P, Hawkins, JR, Sinclair, AH, Taylor, A, Griffiths, BL, Goodfellow, PN, Fellous, M. 1990. Genetic evidence equating SRY and the testis-determining factor. Nature 348:448-450. PubMed ID: 2247149
  • Cotinot C, Pailhoux E, Jaubert F, Fellous M. 2002. Molecular genetics of sex determination. Semin. Reprod. Med. 20: 157–168. PubMed ID: 12428196
  • Domenice S, Yumie Nishi M, Correia Billerbeck AE, Latronico AC, Aparecida Medeiros M, Russell AJ, Vass K, Marino Carvalho F, Costa Frade EM, Prado Arnhold IJ, Bilharinho Mendonca B. 1998. A novel missense mutation (S18N) in the 5’ non-HMG box region of the SRY gene in a patient with partial gonadal dysgenesis and his normal male relatives. Hum. Genet. 102: 213–215. PubMed ID: 9521592
  • Harley, VR, Goodfellow, PN.. 1994. The biochemical role of SRY in sex determination. Mol. Reprod. Dev. 39:184-193. PubMed ID: 7826621
  • Human Gene Mutation Database (Bio-base).
  • Isidor, B, Capito, C, Paris, F, Baron, S, Corradini, N, Cabaret, B, Leclair, MD, Giraud, M, Martin-Coignard, D, David, A, Sultan, C, Le Caignec, C. 2009. Familial frameshift SRY mutation inherited from a mosaic father with testicular dysgenesis syndrome. J. Clin. Endocrinol. Metab. 94:3467-3471. PubMed ID: 19531589
  • Jäger, RJ, Anvret, M, Hall, K, Scherer, G. 1990. A human XY female with a frame shift mutation in the candidate testis-determining gene SRY. Nature 348:452-454. PubMed ID: 2247151
  • McElreavey K, Vilain E, Barbaux S, Fuqua JS, Fechner PY, Souleyreau N, Doco-Fenzy M, Gabriel R, Quereux C, Fellous M, Berkovitz GD. 1996. Loss of sequences 3’ to the testis-determining gene, SRY, including the Y pseudoautosomal boundary associated with partial testicular determination. Proc. Natl. Acad. Sci. U.S.A. 93: 8590–8594. PubMed ID: 8710915
  • Ostrer H. 1993. 46,XY Disorder of Sex Development and 46,XY Complete Gonadal Dysgenesis. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301714
  • Paliwal P, Sharma A, Birla S, Kriplani A, Khadgawat R, Sharma A. 2011. Identification of novel SRY mutations and SF1 (NR5A1) changes in patients with pure gonadal dysgenesis and 46,XY karyotype. Mol. Hum. Reprod. 17: 372–378. PubMed ID: 21242195
  • Schmitt-Ney, M, Thiele, H, Kaltwasser, P, Bardoni, B, Cisternino, M, Scherer, G. 1995. Two novel SRY missense mutations reducing DNA binding identified in XY females and their mosaic fathers. Am. J. Hum. Genet. 56:862-869. PubMed ID: 7717397

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

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Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


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