Mechanism of Sex Determination in Humans: Insights from Disorders of Sex Development

Abstract

In this review we will consider the gene mutations responsible for the non-syndromic forms of disorders of sex development (DSD) and how recent genetic findings are providing insights into the mechanism of sex determination. High-throughput sequencing technologies are having a major impact on our understanding of the genetic basis of rare human disorders, including DSD. The study of human DSD is progressively revealing subtle differences in the genetics of the sex-determining system between the mouse and the human. This plasticity of the sex-determining pathway is apparent in (a) the difference in phenotypes in human and mouse associated with the same gene, (b) the different gene regulatory mechanisms between human and mouse, and finally (c) the different and unexpected reproductive phenotypes seen in association with mutations in well-studied sex-determining genes.

Novel Familial Variant of the Desert Hedgehog Gene: Clinical Findings in Two Sisters with 46,XY Gonadal Dysgenesis or 46,XX Karyotype and Literature Review

“…The new next-generation sequencing will permit more precocious diagnosis in comparison with classic single gene sequencing [14, 35, 36] and avoid a high rate of missed diagnoses still present in females with 46,XY GD [24]. In addition, the two 46,XX women with homozygous DHH mutation reported in this paper and by Sato e al.…”

“…46,XY GD with female phenotype is a rare disorder of sex development (estimated incidence around 1: 100,000 births) [23, 24]. It is usually described as complete, characterized by the presence of female external genitalia, bilateral streak gonads and uterus, and partially characterized by a streak gonad, a contralateral dysgenetic testis and absent or rudimentary müllerian (due to antimüllerian hormone production in the fetus) or wolffian structures [12, 23, 24].…”

“…It is usually described as complete, characterized by the presence of female external genitalia, bilateral streak gonads and uterus, and partially characterized by a streak gonad, a contralateral dysgenetic testis and absent or rudimentary müllerian (due to antimüllerian hormone production in the fetus) or wolffian structures [12, 23, 24]. In about 15–20%, the cause of 46,XY GD is a mutation in the SRY gene [23, 24], which is the master regulator starting the male sex-determining cascade in utero [4]. Other autosomal genes involved in gonadal development – such as SOX9, NR5A1, GATA4, FOG2, CBX2 MKAP3K1, DMRT1 – may determine this condition [24].…”

“…In about 15–20%, the cause of 46,XY GD is a mutation in the SRY gene [23, 24], which is the master regulator starting the male sex-determining cascade in utero [4]. Other autosomal genes involved in gonadal development – such as SOX9, NR5A1, GATA4, FOG2, CBX2 MKAP3K1, DMRT1 – may determine this condition [24]. Recently, analysis of copy number variants by genome-wide human array suggested that dysfunctional pathways of human gonad development may also be related to rearrangements of noncoding sequences disturbing gene regulation [25].…”

“…Recently, analysis of copy number variants by genome-wide human array suggested that dysfunctional pathways of human gonad development may also be related to rearrangements of noncoding sequences disturbing gene regulation [25]. However, the cause of 46,XY GD remains unknown in several subjects [24]. …”