Analysis of the androgen receptor (AR) gene in a cohort of Indonesian undermasculinized 46, XY DSD patients

Nurin Aisyiyah Listyasari,Katie L Ayers,Achmad Zulfa Juniarto,Sultana M H Faradz,Andrew H Sinclair,Gorjana Robevska

doi:10.1186/s43042-021-00134-3

Nurin Aisyiyah Listyasari, Katie L Ayers + Show 4 more

Open Access

https://doi.org/10.1186/s43042-021-00134-3

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Abstract

BackgroundPathogenic variants in the androgen receptor (AR) gene located on chromosome Xq11-12, are known to cause varying degrees of undermasculinization in 46, XY individuals. The aim of this study was to investigate the frequency of pathogenic variants in the AR gene in a cohort of 46, XY undermasculinized individuals from Indonesia who were suspected of having androgen insensitivity syndrome (AIS). All patients with 46, XY DSD referred to our center between 1994 and 2019 were collected from our clinical database. All 46, XY DSD patients without a prior molecular diagnosis with an external masculinization score (EMS) ≤ 9 were included in this study. All exons and intron–exon boundaries of AR gene were analyzed using Sanger sequencing to identify pathogenic variants of the AR gene.ResultsA cohort of 75 undermasculinized patients were selected for the study. Direct Sanger sequencing of all eight exons of the AR gene led to a genetic diagnosis in 11 patients (14.67%). All of the variants identified (p.Arg841His; p.Ile604Asn; p.Val731Met; p.Pro672Ser; p.Gln739Arg; p.Ser302Glufs*3) have been previously reported in patients with AIS.ConclusionsThis is the first study in Indonesia that highlights the significance of molecular analysis in providing a definitive diagnosis of AIS for patients with 46, XY DSD undermasculinization. This is an uncommon finding in the Indonesian population presenting with 46, XY DSD undermasculinization. A genetic diagnosis allows optimal clinical management and genetic counseling for patients and their families. As 46, XY DSD can be caused by pathogenic variants in other genes involved in gonadal development and differentiation, further genetic analysis, such as whole exome sequencing, should be carried out on those patients that did not carry an AR variant.

Highlights

Pathogenic variants in the androgen receptor (AR) gene located on chromosome Xq11-12, are known to cause varying degrees of undermasculinization in 46, XY individuals
The AR gene consists of eight exons which encode a 919 amino acid protein comprising of four major functional domains: the Nterminal domain (NTD), the central DNA-binding domain (DBD), a C-terminal ligand-binding domain (LBD), and a hinge region connecting the LBD to the DBD [10]
55 (73.33%) of the patients were being raised as males, while 19 (25.33%) of the patients were being raised as females and there was only 1 (1.33%) patient whose gender was not yet decided on

Summary

Introduction

Pathogenic variants in the androgen receptor (AR) gene located on chromosome Xq11-12, are known to cause varying degrees of undermasculinization in 46, XY individuals. The aim of this study was to investigate the frequency of pathogenic variants in the AR gene in a cohort of 46, XY undermasculinized individuals from Indonesia who were suspected of having androgen insensitivity syndrome (AIS). Individuals with disorders/differences of sex development (DSD) are often identified with atypical genitalia at birth or absence of secondary sex characteristics at adolescence [1,2,3]. This condition can result either from disorders in androgen synthesis or action, non-. Pathogenic variants of the AR gene have been identified throughout the whole coding region [14]

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