Short Stature with or without Partial Isolated Growth Hormone Deficiency via the GHSR Gene

Short stature is a multifactorial developmental disorder. Short stature with or without partial isolated growth hormone deficiency (OMIM 604271) is a genetic disorder of growth failure due to defective growth hormone secretagogue receptor (GHSR) (Howard et al. Science 273:974-977, 1996; Pantel et al. J Clin Invest 116:760-768, 2006). It has been reported that a patient with recessive partial isolated growth hormone deficiency due to GHSR variants had growth delay associated with recurrent abdominal pain, vomiting, ketosis, hypoglycemia, and low body mass index (Pantel et al. J Clin Endocrinol Metab 94:4334-4341, 2009). On the other hand, a semidominant transmission with incomplete penetrance of short stature with or without partial isolated growth hormone deficiency has been reported in patients of two unrelated families from Morocco (Pantel et al. 2006).

Short stature with or without partial isolated growth hormone deficiency is caused by variants in the GHSR gene (Pantel et al. J Clin Invest 116:760-768, 2006). The GHSR gene encodes a growth hormone secretagogue receptor (GHSR), an orphan 7-transmembrane G-protein coupled receptor that acts on the pituitary gland and the hypothalamus to stimulate growth hormone release (Howard et al. Science 273:974-977, 1996; Smith et al. Endocr Rev 18:621-645, 1997). The GHSR receptor has a constitutive activity, defined as ligand-independent signaling activity, of unknown clinical significance and an endogenous ligand known as ghrelin, a hormone predominantly produced by the stomach to stimulate growth hormone secretion (Holst et al. Mol Endocrinol 17:2201-2210, 2003; Kojima et al. Nature 402:656-660, 1999; Pantel et al. 2006). A mix of missense and nonsense variants within the GHSR gene and variants in its promoter region have been reported (Wang et al. J Clin Endocrinol Metab 89:157-162, 2004; Pantel et al. 2006; Liu et al. J Pharmacol Exp Ther 322:1036-1043, 2007; Mager et al. PLoS One 3:e2941, 2008; Pantel et al. J Clin Endocrinol Metab 94:4334-4341, 2009). The missense variant c.611C>A (p.Ala204Glu), which results in a semidominant transmission with incomplete penetrance of short stature, has been demonstrated to affect the constitutive activity and the cell surface expression of the GHSR receptor but does not affect the specific binding to ghrelin (Pantel et al. 2006; Liu et al. 2007).

Sensitivity of this test is currently unknown.

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