Oligogenic Origin of Differences of Sex Development in Humans

Abstract

Sex development is a very complex biological event that requires the concerted collaboration of a large network of genes in a spatial and temporal correct fashion. In the past, much has been learned about human sex development from monogenic disorders/differences of sex development (DSD), but the broad spectrum of phenotypes in numerous DSD individuals remains a conundrum. Currently, the genetic cause of less than 50% of DSD individuals has been solved and oligogenic disease has been proposed. In recent years, multiple genetic hits have been found in individuals with DSD thanks to high throughput sequencing. Our group has been searching for additional genetic hits explaining the phenotypic variability over the past years in two cohorts of patients: 46,XY DSD patients carriers of NR5A1 variants and 46,XY DSD and 46,XX DSD with MAMLD1 variants. In both cohorts, our results suggest that the broad phenotypes may be explained by oligogenic origin, in which multiple hits may contribute to a DSD phenotype, unique to each individual. A search for an underlying network of the identified genes also revealed that a considerable number of these genes showed interactions, suggesting that genetic variations in these genes may affect sex development in concert.

Disorders of Sex Development: Classification, Review, and Impact on Fertility

“…However, there have been and are many controversies around DSDs, both because of the negative connotations perceived by organizations and professionals when using terms such as "disorders," and because some health professionals consider as inaccurate, non-descript, and confusing certain terms such as "intersex," "pseudohermaphroditism," "hermaphroditism," and "sex reversal" [3][4][5]. Other authors [6,7] prefer the term "differences" and use the same acronym-DSD-to refer to differences of sex development; meanwhile, others, as well as ourselves, do not consider the nomenclature and classification proposed in the Chicago consensus as the most appropriate. We believe that it is preferable to analyze normal or physiological sex determination and subsequent sex differentiation to expose any anomalies, as they would be included in a pathophysiological and clinical classification of anomalies in sex development (ASDs) [8,9], and then to continue with their orderly exposure and with the related fertility problems.…”

Pathophysiological Bases for the Classification of the Human Sex Development Anomalies

“…However, there have been and there are many controversies, both due to the negative connotations perceived by organizations and professionals when terms such as "disorders" are used (perhaps due to the perceived implications that "sex" involves sexual behavior), and because some health professionals have considered inaccurate, not very descriptive and confusing certain terms such as "intersex", "pseudohermaphroditism", "hermaphroditism", "sex reversal", etc., or they were felt pejorative among families and patient support groups. Other authors [35,36] prefer the term "differences" and use the same acronym DSD (differences of sex development). However, many authors [37,38] do not consider the nomenclature proposed in the Chicago consensus as the most appropriate.…”

Variants of STAR, AMH and ZFPM2/FOG2 May Contribute towards the Broad Phenotype Observed in 46,XY DSD Patients with Heterozygous Variants of NR5A1

“…Possible digenic or oligogenic inheritance of genetic disorders of sex development with a broad phenotype has been discussed by us [ 8 , 14 , 36 ] and others [ 2 , 10 , 11 , 12 , 13 , 37 , 38 ]. We therefore searched for additional gene variants in the studied cases and found a second genetic variant in a gene previously reported to be involved in male sex development [ 6 ] in three individuals ( Table 2 ).…”

“…The advantage of next generation sequencing (NGS) for elucidating the possibility of an oligogenic inheritance for DSD and other endocrine pathologies has been highlighted [ 14 ]. In the present work, we describe the clinical features of seven 46,XY DSD patients harboring a heterozygous NR5A1 variation.…”