Differences of Sex Development (DSD) Panel

Disorders of sex development (DSD) are congenital conditions with atypical development of chromosomal, gonadal, or anatomic sex (Hughes et al. 2006. PubMed ID: 18947601). This group of disorders are highly heterogeneous and range in severity from hypospadias (1 in 250 boys), ambiguous genitalia (1 in 4,500 live births), to complete XX or XY sex reversal (1 in 20,000 births) (Park et al. 2006; Ohnesorg et al. 2014. PubMed ID: 24504012).

Three subtypes of DSD are generally recognized: Sex Chromosome DSD, 46,XY DSD, and 46,XX DSD. Sex chromosome DSDs include Turner syndrome (45,X), Klinefelter syndrome (47,XXY), mosaic 45,X/46,XY mixed gonadal dysgenesis, and 46,XX/46/XY ovotesticular DSD.

46,XY DSD include complete and partial gonadal dysgenesis (CGD) and result from incomplete intrauterine virilization. It is characterized by a 46,XY karyotype, ambiguous or ‘female’ external genitalia, variable gonadal dysgenesis, hypospadias, azoospermia, and müllerian structures that range from absence to presence of a uterus and fallopian tubes (Mohnach et al. 2016. PubMed ID: 20301714). The main cause is pathogenic variants or deletions of SRY, which have been identified in 15% of individuals with 46,XY CGD.

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). These include 46,XX testicular and ovotesticular DSD, as well as 46,XX gonadal dysgenesis. Known etiologies include SRY translocation, and SOX9 or SOX3 gene CNVs.

Clinical management of DSD is often difficult and currently only 13% patients receive an accurate clinical genetic diagnosis (Arboleda et al. 2013. PubMed ID: 22435390). An accurate diagnosis is critical to predict the occurrence of life-threatening crises, response to hormone replacement therapy, eventual gender, fertility, and recurrence risk.

DSD are complex conditions caused by a wide range of genetic anomalies. They can be inherited in an autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), and Y-linked (YL) manner, or arise de novo 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; Eggers et al. 2016. PubMed ID: 27899157). These genes are implicated in sex determination, sex differentiation and hypogonadism.

Androgen insensitivity is the most common form of DSD and is caused by a mix of missense, protein truncating variants, and deletions in the AR gene. Pathogenic variants in the AR gene have been reported in 9.4% (26/278) of 46,XY DSD patients. Beyond the AR gene, pathogenic variants in NR5A1, SRD5A2, ZFPM2, HSD17B3, DHH, MAP3K1, SRY, CYP21A2, SOX9, duplication of NR0B1 and deletion of DMRT1 have also been frequently detected in DSD patients (Baxter et al. 2015. PubMed ID: 25383892; Eggers. et al. 2016. PubMed ID: 27899157).

Sex chromosome aneuploidy, structural abnormality and copy number variants (CNVs) are common genetic causes of DSD. Deletions or duplications have been reported in SOX3, LHCGR, SRY, NR0B1, DMRT1, NR5A1, GATA4, WT1, WNT4, and FGFR2 genes in DSD patients. For this reason, genetic testing to detect large cytogenetic events and CNVs is recommended in the case of a patient with ambiguous genitalia or other suspected disorder of sex development. Our CNV analysis enables these large cytogenetic abnormalities as well as exon level CNVs to be identified from NGS data.

See individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants.

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 panel analyzes genes involved in both syndromic and non-syndromic Disorders of Sex Development (DSD). 64 genes in this panel have provided genetic diagnosis in 35%-43% of patients with 46,XY DSD and in 17% of patients with 46,XX DSD (Baxter et al. 2015. PubMed ID: 25383892; Eggers. et al. 2016. PubMed ID: 27899157).

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

This panel typically provides 99.2% 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).