46,XX Differences of Sex Development (DSD) via the WNT4 Gene

Disorders of Sex Development (DSD) is a congenital condition in which the development of chromosomal, gonadal, or anatomical sex is atypical (Hughes et al. Arch Dis Child 91(7): 554-563, 2006). Three subtypes of DSD are generally recognized: Sex Chromosome DSD, 46,XX DSD and 46,XY DSD. 46,XX DSD is defined by a normal 46,XX karyotype in conjunction with virilization. Mullerian aplasia and hyperandrogenism are characterized by regression or absence of the mullerian duct derivates (uterus, fallopian tubes and upper part of the vagina), primary amenorrhea and elevated androgen levels. Often the first noticeable sign of mullerian aplasia and hyperandrogenism is the absence of menstruation in adolescent girls. Mullerian aplasia and hyperandrogenism features overlap with Rokitansky-Kuster-Hauser syndrome. SERKAL syndrome is characterized by female sex reversal, and kidney, adrenal and lung dysgenesis (Mandel et al. Am J Hum Genet 82(1):39-47, 2008). SERKAL syndrome has only been reported in one consanguineous family from the Middle East. All affected fetuses had renal agenesis.

WNT4 encodes for a signaling peptide that promotes female fate and prevents testis formation. Mullerian aplasia and hyperandrogenism is inherited in an autosomal dominant manner while SERKAL syndrome is inherited in an autosomal recessive manner due to mutations in WNT4 (Biason-Lauber et al. New Eng J Med 351(8):792-798, 2004; Mandel et al., 2008). All pathogenic variants reported to date are missense mutations.

Analytical sensitivity may be high because all WNT4 mutations reported to date are expected to be detected by direct sequencing of genomic DNA. Clinical sensitivity is problematic to predict due to the lack of documented cases.

No gross deletion or duplication mutations in WNT4 have been reported in patients with SERKAL syndrome or mullerian duct abnormalities.

This test provides full coverage of all coding exons of the WNT4 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. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).