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

Idoia Martínez De Lapiscina,Idoia Martínez De Lapiscina,Idoia Martínez De Lapiscina,Ines Costa,Amaia Rodríguez-Estévez,Amaia Vela,Amaia Rodríguez-Estévez,Amaia Vela,Amaia Vela,Rana Aa Mahmoud,Christa E Flück,Jose Manuel Rial-Rodriguez,Isabel Esteva,Milagros Alonso,Kay-Sara Sauter,Kay-Sara Sauter,Christa E Flück,Luis Castano,Amaia Rodríguez-Estévez

doi:10.3390/ijms21228554

Abstract

Variants of NR5A1 are often found in individuals with 46,XY disorders of sex development (DSD) and manifest with a very broad spectrum of clinical characteristics and variable sex hormone levels. Such complex phenotypic expression can be due to the inheritance of additional genetic hits in DSD-associated genes that modify sex determination, differentiation and organ function in patients with heterozygous NR5A1 variants. Here we describe the clinical, biochemical and genetic features of a series of seven patients harboring monoallelic variants in the NR5A1 gene. We tested the transactivation activity of novel NR5A1 variants. We additionally included six of these patients in a targeted diagnostic gene panel for DSD and identified a second genetic hit in known DSD-causing genes STAR, AMH and ZFPM2/FOG2 in three individuals. Our study increases the number of NR5A1 variants related to 46,XY DSD and supports the hypothesis that a digenic mode of inheritance may contribute towards the broad spectrum of phenotypes observed in individuals with a heterozygous NR5A1 variation.

Highlights

Sex development depends on a tightly controlled network of transcription factors and signaling pathways working in concert to produce functional gonads and typical sex organs
Our study increases the number of NR5A1 variants related to 46,XY disorders of sex development (DSD) and supports the hypothesis that a digenic mode of inheritance may contribute towards the broad spectrum of phenotypes observed in individuals with a heterozygous NR5A1 variation
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Summary

Introduction

Sex development depends on a tightly controlled network of transcription factors and signaling pathways working in concert to produce functional gonads and typical sex organs. Variations in this complex development lead to disorders/differences of sex development (DSD), which may manifest with a broad spectrum of clinical conditions [1]. Later studies revealed that an adrenal phenotype is rarely found in patients with NR5A1 variants [5], and that the gonadal and reproductive phenotype may be very broad including 46,XY and 46,XX cases [6]. Sex hormones and anti-Müllerian hormone (AMH) levels are found in patients with NR5A1 variants, as well as inconsistent findings regarding gonadal histology [2]

Methods

Results

Conclusion