CHD7 missense variants and clinical characteristics of Chinese males with infertility

Background: Isolated hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS) are rare genetic diseases that cause male infertility. The chromodomain helicase DNA-binding protein 7 (CHD7) gene is commonly associated with KS and IHH. We speculated that CHD7 variants may be associated with male infertility.

Methods: Two hundred males with azoospermia and 120 with oligozoospermia were recruited. The patients underwent clinical examination and reproductive hormone testing. A panel of genes including CHD7 and others related to spermatogenic failure was sequenced by targeted-gene exome sequencing.

Results: Three patients with severe oligozoospermia had CHD7 variants (a detection rate of 0.94% (3/320)). After prediction software analysis, two of the variants c.3464G>A (p.R1155H) and c.4516G>A (p.G1506S) were predicted to be likely pathogenic. Although predicted to be benign, the variants of c.2824A>G (p.T942A) located in the chromodomain 2 could not be excluded as disease causing. The patients with variants had small testicular volumes. In particular, the testes of the patient with a p.G1506S variant varied in size (left, 8 ml; right, 4.5 ml). Two patients (patients 31 and 120) had low E2 levels and two (patients 83 and 120) had low T levels. Ultimately, these variants were classified as "variants of unknown significant" that may be associated with male infertility.

Conclusions: There may be a relationship between the CHD7 gene missense variants and male infertility. These variants are easier to find in patients with azoospermia and severe oligospermia whose testosterone levels are decreased.