LHCGR-related Disorders via the LHCGR Gene

The LHCGR gene encodes the receptor for both luteinizing hormone (LH) and choriogonadotropin (CG). Activating LHCGR pathogenic variants cause familial male precocious puberty while inactivating LHCGR pathogenic variants cause Leydig cell hypoplasia (LCH) in both males and females.

Familial male precocious puberty is a gonadotropin-independent disorder. Affected males generally exhibit signs of puberty by 4 years old (Shenker et al. 1993). This disease is inherited in an autosomal dominant manner, but is limited to males.

Leydig cell hypoplasia in 46, XY males has been classified into two types. Type I is characterized by complete 46,XY male pseudohermaphroditism, absent development of secondary male sex characteristics, low testosterone and high LH levels, total lack of responsiveness to LH/CG challenge, and lack of breast development due to complete inactivation of LHCGR. Type II presents a wide phenotypic range from micropenis to severe hypospadias due to partial inactivation of LHCGR (Themmen and Huhtaniemi 2000).

Leydig cell hypoplasia in 46, XX females leads to milder features characterized by amenorrhea, defective follicular development and ovulation, and infertility (Themmen and Huhtaniemi 2000).

Familial male precocious puberty is an autosomal dominant disorder caused by activating pathogenic variants in the LHCGR gene (Shenker et al. 1993) while Leydig cell hypoplasia in both males and females is an autosomal recessive disorder caused by inactivating pathogenic variants in the LHCGR gene (Kremer et al. 1995; Latronico et al. 1996).

The LHCGR gene has 11 coding exons that encode the receptor for both luteinizing hormone and choriogonadotropin, which belongs to the G-protein coupled receptor family. While only missense LHCGR (activating) pathogenic variants have been found in familial male precocious puberty, genetic defects of LHCGR found to date in the spectrum of Leydig cell hypoplasia include missense, nonsense, splicing, small deletions and large deletions (Human Gene Mutation Database). A mutation hot spot has been found in exon 11, which contains the common mutation p.Asp578Gly (Laue et al. 1995).

In a study of 32 unrelated families affected by familial male precocious puberty, all families were found through sequencing to have a LHCGR pathogenic variant (Laue et al. 1995), which indicated a high clinical sensitivity in sequencing for this disease. Detection rate of pathogenic variants in the LHCGR gene in a large cohort of patients with Leydig cell hypoplasia is unknown in the literature because only a limited number of cases have been reported.

This test provides full coverage of all coding exons of the LHCGR gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.