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.
Highlights
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 [1]
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
Results from an analysis using a targeted DSD gene panel described a total of 13 46,XY DSD patients who had more than one curated variant in diagnostic DSD genes [5]
Summary
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 [1]. The genetic cause of less than 50% of DSD individuals has been solved [2,3]. Oligogenic inheritance is currently discovered for several other disorders of the endocrine systems. In congenital hypogonadotropic hypogonadism (CHH) more than 25 causative genes are considered to explain around 50% of the cases, and in at least 20% of cases disease-causing variants in two or more genes have been identified [15,16,17,18,19,20,21]. In congenital hypothyroidism digenic [22,23] and polygenic [24] candidate-gene variants have been associated with the phenotypes [25]
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