DHH-related Differences of Sex Development via the DHH Gene

Mutations in the desert hedgehog (DHH) gene can cause 46,XY complete gonadal dysgenesis or 46,XY partial gonadal dysgenesis with minifascicular neuropathy.

The major clinical phenotype caused by DHH mutations is DHH-related 46,XY complete gonadal dysgenesis (OMIM# 233420). 46,XY complete gonadal dysgenesis is also termed Swyer syndrome or 46,XY pure gonadal dysgenesis (Cotinot et al., 2002; Ostrer et al., 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 ovary by functionless scar tissue due to lacking 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). Mutations in the DHH gene also cause 46,XY partial gonadal dysgenesis with minifascicular neuropathy (OMIM# 607080), which is characterized by extensive minifascicular formation within the endoneurium of the sural nerve and decreased density of myelinated fibers (Umehara et al., 2000).

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., 2008). The desert hedgehog (DHH) gene encodes a member of the hedgehog family of signaling proteins, which is a key molecule in both male gonadal differentiation and perineurial formation in peripheral nerves. To date, only a limited number of pathogenic DHH mutations have been documented throughout this three-exon gene, including missense mutations and small deletion/insertions (Human Gene Mutation Database).

The DHH mutation detection rate in a large cohort of patients affected by 46,XY complete gonadal dysgenesis or 46,XY partial gonadal dysgenesis with minifascicular neuropathy is unavailable in the literature because these DHH mutations have only been reported in limited individual cases.

Thus far, no gross deletions or duplications have been reported in DHH (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the DHH 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).