Ambiguous Genitalia Panel

Ambiguous genitalia is a rare condition in which external genitalia do not appear to have the typical appearance of either male or female. Ambiguous genitalia is a subset of disorder of sex development (DSD). Sex development is a complex process under genetic control directing the initially bi-potential gonad to develop into either a testis or an ovary (sex determination), and the consequent differentiation of internal ducts and external genitalia (sex differentiation) (Laino et al. 2014. PubMed ID: 25248670). Disruption of either determination or differentiation can lead to DSD which are congenital conditions with atypical development of chromosomal, gonadal, or anatomic sex (Hughes et al. 2006. PubMed ID: 18947601). DSD, ranging in severity from genital abnormalities to complete sex reversal, includes congenital development of ambiguous genitalia, disjunction between the internal and external sex anatomy, incomplete development of sex anatomy, sex chromosome anomalies (Turner Syndrome; Klinefelter Syndrome) and disorders of gonadal development (Park et al. 2006).

Three subtypes of DSD are generally recognized: Sex Chromosome DSD, 46,XX DSD and 46,XY DSD. 46,XY DSD result from incomplete intrauterine virilization and are characterized by ambiguous or ‘female’ external genitalia, variable gonadal dysgenesis, hypospadias, oligospermia, azoospermia, and müllerian structures that range from absence to presence of a uterus and fallopian tubes (Mohnach et al. 2016. PubMed ID: 20301714). 46,XX DSD relate to excess androgen and are characterized by ambiguous or ‘male’ external genitalia, müllerian aplasia, hyperandrogenism and primary amenorrhea (Knarston et al. 2016. PubMed ID: 26846580).

DSD are complex conditions caused by a wide range of genetic anomalies. They can be inherited in an autosomal dominant, autosomal recessive, X-linked, or Y-linked manner depending on the gene involved. To date, more than 60 genes have been showed to be involved in DSD (Baxter et al. 2015. PubMed ID: 25383892). These genes are implicated in sex determination, sex differentiation and causes of hypogonadism. The most commonly involved genes in DSD include SRY, NR5A1, MAP3K1, DHH, NR0B1 (DAX1), WNT4, CYP21A2, and SOX9. See individual gene test descriptions for information on molecular biology of gene products and mutation spectra.

Copy number variants (CNVs) are also a common genetic cause of ambiguous genitalia. Clinically significant CNVs were detected in 25% of patients with ambiguous genitalia (Tannour-Louet et al. 2010. PubMed ID: 21048976). For this reason, genetic testing to detect large cytogenetic events and CNVs is recommended for patients with ambiguous genitalia. Our CNV analysis enables these large cytogenetic abnormalities as well as some exon level CNVs to be identified from NGS data.

Due to low mappability of reads for CYP21A2 caused by the presence of pseudogenes with very high sequence similarity, we cannot confidently call variants in this gene via NGS sequencing, and this gene is not included in this panel. Please see our individual gene summary if CYP21A2 testing is desired.

This multi-gene panel analyzes genes involved in both syndromic and non-syndromic Disorders of Sex Development (DSD). 64 genes in this panel account for approximately 35% of cases of 46,XY DSD (Baxter et al. 2015. PubMed ID: 25383892). In one cohort, clinically significant CNVs were detected in 25% of patients with ambiguous genitalia (Tannour-Louet et al. 2010. PubMed ID: 21048976). So far, gross deletions or duplications have been reported in SOX3, LHCGR, SRY, NR0B1, DMRT1, NR5A1, GATA4, WT1, and WNT4.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.6% coverage of all coding exons of the genes 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 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).