Table 3 Genes predisposing to nonsyndromic sex reversal and pubertal delay

GNRHR (gonadotropin-releasing hormone receptor)

4q13.2

This gene encodes the receptor for type 1 gonadotropin-releasing hormone, a receptor that is expressed on the surface of pituitary gonadotrope cells, lymphocytes, breast, ovary, and prostate. GNRHR becomes activated after binding with gonadotropin-releasing hormone, and the complex formed causes the release of gonadotropic luteinizing hormones (LH) and follicle-stimulating hormones (FSH) [123].

At least 19 different mutations have been identified, including heterozygous mutations named Gln106Arg/Arg262Gln and Arg262Gln/Tyr28Cys [17] as well as homozygous missense mutation named g. G7167A; p. Arg139His [124].

Causes low levels of circulating gonadotropins and testosterone, resulting in hypogonadotropic hypogonadism 7 (HH7), a disorder characterized by absent or incomplete sexual maturation by the age of 18 years [125].

PROP1 (PROP paired-like homeobox 1)

5q35.3

The gene produces a transcription factor embedded only in the pituitary gland and releases hormones for growth, reproduction, and cell differentiation in the pituitary gland [126].

At least 25 mutations had been reported, the most common of which deletes two amino acids, written as 301-302delAG [126].

Reduces pituitary cell differentiation and prevents the release of hormones from the pituitary gland, causing a condition called combined pituitary hormone deficiency, with features like short stature and delayed or absent puberty [126].

DMRT1 (doublesex- and MAB3-related transcription factor 1)

9p24.3

The gene encodes a transcription factor expressed in the testis and involved in male sex determination and differentiation before and after birth by promoting male-specific genes and repressing female-specific genes. May also play a minor role in oogenesis [127].

Deletions in the gene had been reported [127].

Predisposes to male-to-female sex reversal in the presence of a normal 46, XY karyotype, referred to as 46, XY sex reversal 4 (SRXY4), characterized by complete or partial gonadal dysgenesis. The mutation may also cause testicular germ cell tumors [127].

SOX3 (SRY-box transcription factor 3)

Xq27.1

The gene codes for a transcription factor embedded in the hypothalamus and pituitary gland where it regulates neuronal development and differentiation, and as well promote male sex development [128].

Copy number variations including two duplications of about 123 kb and 85 kb, a 343 kb deletion immediately upstream of SOX3, and a large duplication of approximately 6 Mb that encompasses SOX3 have been reported [128].

Causes 46, XX sex reversal 3 (SRXX3), characterized by XX male reversal and a complex phenotype that includes scrotal hypoplasia, microcephaly, developmental delay, and growth retardation [128]. Also causes 46, XX testicular disorder of sex development [128].

RSPO1 (R-spondin 1)

1p34.3

Produces a protein that is essential in ovary determination through regulation of Wnt signaling [129].

c.286+1G>A [130].

Causes oocytes depletion and masculinized ovaries, resulting in XX true hermaphroditism, also known as an ovotesticular disorder of sexual development, a disorder of gonadal development characterized by the presence of both ovarian and testicular tissue in 46, XX individuals [130].