HESX1-Related Disorders via the HESX1 Gene

The HESX1 gene encodes a conserved homeobox protein that is a transcriptional repressor in the developing forebrain and pituitary gland. Genetic defects in this gene have been associated with a wide spectrum of diseases including septooptic dysplasia (Webb et al. 2010; Dattani et al. 1998), combined pituitary hormone deficiency (Carvalho et al. 2003), and isolated growth hormone deficiency (Vivenza et al. 2011; McNay et al. 2007).

Septooptic dysplasia (SOD) is a clinically heterogeneous disorder of early brain development with three characteristic features: hypoplasia of the optic nerves, midline abnormalities of the brain, and pituitary hypoplasia. Signs and symptoms vary significantly. Only about 30% of patients diagnosed with septooptic dysplasia have all three major features; most affected individuals have two of the major features.

HESX1 defects can cause combined pituitary hormone deficiency (CPHD) without associated hypoplasia of the optic nerves or midline abnormalities of the brain. CPHD is a multi-system developmental condition due to a deficiency of hormones produced by the pituitary gland. A failure to grow at the expected rate and short stature usually start to appear in early childhood. Other features include hypothyroidism, delayed or absent puberty, and infertility. Rarer features include deficiency of the hormone cortisol, intellectual disability, and hypoplasia of optic nerves.

HESX1-related disorders can be inherited in both autosomal dominant and recessive modes. The mutation type has not been well correlated with the mode of disease inheritance (Webb et al. 2010). Incomplete penetrance may occur in patients with heterozygous HESX1 pathogenic variants (Thomas et al. 2001). HESX1 pathogenic variants are an uncommon cause of septooptic dysplasia and hypopituitarism, accounting for less than 1% of cases (McNay et al. 2007).

Genetic defects of HESX1 found to date include missense, nonsense, splicing mutations, and small indels (Human Gene Mutation Database). No large deletions and duplications have been reported. The HESX1 gene (4 coding exons) encodes a conserved homeobox protein that is a transcriptional repressor in the developing forebrain and pituitary gland.

In a study of 228 patients with a broad spectrum of congenital pituitary defects, ranging in severity from isolated growth hormone deficiency to SOD with panhypopituitarism, only three heterozygous missense HESX1 pathogenic variants (1.3%) were found (Thomas et al. 2001).

In a study of nonfamilial patients (724) with either SOD (n = 314) or isolated pituitary dysfunction, optic nerve hypoplasia, or midline neurological abnormalities (n = 410), and 126 patients with familial hypopituitarism from 66 unrelated families and in 11 patients born to consanguineous parents, the overall incidence of coding region HESX1 pathogenic variants was less than 1% (McNay et al. 2007).

This test provides full coverage of all coding exons of the HESX1 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).