Hypospadias Panel

Hypospadias is one of the most common congenital malformations of the male external genitalia, affecting one in 200-300 boys (Blaschko et al. 2012. PubMed ID: 22790208). It is defined as a defect in the development of the ventral aspect of the penis along with an ectopic opening of the urethral meatus (Kalfa et al. 2011. PubMed ID: 21256920). Hypospadias is considered to be a mild form of the 46,XY disorder of sex development (DSD) (Hughes et al. 2006. PubMed ID: 18947601). Hypospadias can present as an isolated condition or can be accompanied by additional abnormalities, most commonly other genitourinary abnormalities including cryptorchidism, bifid scrotum, vesicoureteral reflux, and inguinal hernia (Holmes. 2012). In addition, Hypospadias can be associated with various syndromic disorders, including the androgen insensitivity syndrome, Denys-Drash syndrome, Opitz syndrome, Smith-Lemli-Opitz syndrome, and WAGR syndrome (van der Zanden et al. 2012. PubMed ID: 22371315; Shih et al. 2014. PubMed ID: 24657417; Bouty et al. 2015. PubMed ID:26613581).

Hypospadias is a multifactorial complex condition with both genetic and environmental factors involved in the pathogenesis. Genetic abnormalities, including both chromosomal and single-gene alterations, have been reported to account for about 30% of hypospadias cases (Ságodi et al. 2014. PubMed ID: 24936573). They can be inherited in an autosomal dominant, autosomal recessive, X-linked, or Y-linked manner depending on the gene involved. Genes and genomic regulation involved in the development of the male external genitalia (WT1 and SF1), patterning of genital tubercle (BMP4, BMP7, HOXA4, HOXB6, FGF8, FGFR2), and masculinization (SRY, SOX9, AR, SRD5A, HSD3B2) have all been associated with hypospadias (van der Zanden et al. 2012. PubMed ID: 22371315; Shih et al. 2014. PubMed ID: 24657417; Bouty et al. 2015. PubMed ID: 26613581). See individual gene test descriptions for information on molecular biology of gene products and mutation spectra.

Copy number variants (CNVs) are a common genetic cause of hypospadias. Clinically significant CNVs were detected in 17.2% of patients with hypospadias (Tannour-Louet et al. 2010. PubMed ID: 21048976). For this reason, genetic testing to detect large cytogenetic events and CNVs is recommended in the case of a patient with hypospadias. Our CNV analysis enables these large cytogenetic abnormalities as well as some exon level CNVs to be identified from NGS data.

This multi-gene panel analyzes genes involved in both syndromic and non-syndromic hypospadias. Genes in this panel account for approximately 20-30% of cases of 46,XY DSD (Baxter et al. 2015. PubMed ID: 25383892). In one cohort, clinically significant deletions and duplications were detected in 17.2% of patients with hypospadias (Tannour-Louet et al. 2010. PubMed ID: 21048976).

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

This panel typically provides 99.7% 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).