Balkan Journal of Medical Genetics

ANDROGEN INSENSITIVITY SYNDROME DUE TO NON-CODING VARIATION IN THE ANDROGEN RECEPTOR GENE: REVIEW OF THE LITERATURE AND CASE REPORT OF A PATIENT WITH MOSAIC C.-547C>T VARIANT
Noveski P, Plaseski T, Dimitrovska M, Plaseska-Karanfilska D
*Corresponding Author: Dijana Plaseska-Karanfilska, MD, PhD, Research Centre for Genetic Engineering and Biotechnology ‘Georgi D. Efremov’, Macedonian Academy of Sciences and Arts, Krste Misirkov 2, 1000 Skopje, Republic of Macedonia, Tel. +389 2 3235 410, E-mail: dijana@manu.edu.mk
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INTRODUCTION

Disorders of Sexual Development (DSD) represent a group of conditions that affect the development of the reproductive system, classified as 46,XY DSD, 46,XX DSD and sex chromosomal DSD. The etiology of DSDs can be complex with many different genetic and environmental factors contributing to their development. In congenital DSD, the severity and age of onset are highly variable and depend on the biological function of the affected gene, but the variability could also be associated with specific mutations in the affected gene, and even a variable phenotype could be observed in patients with the same mutation. Studies using genetic testing with sequencing and deletion/ duplication analysis of the AR gene identified causality in approximately 50% of the 46,XY DSD cases [1]. Next generation sequencing (NGS) analysis, using a targeted gene panel, showed a 60% diagnostic rate in patients with 46,XY DSD disorders of androgen synthesis and action, but only a 19% detection rate in the patients with 46,XX DSD [2]. Androgen insensitivity syndrome (AIS) represents a frequent form of 46,XY DSD where pathogenic mutations in the androgen receptor (AR) gene are responsible for a spectrum of defects in androgen action: complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS) and mild androgen insensitivity syndrome (MAIS) [3]. So far, pathogenic mutations in affected patients were identified primarily in the coding regions and conserved splice sites of the AR, and rarely, single exon deletions/duplications or whole gene deletions were also reported [3]. Genotype-phenotype correlation exists for certain AR mutations in CAIS patients [4], but also, different AIS phenotypes for identical mutations were observed [5]. This variable expressivity is associated with several mutations and is often attributed to the oligogenic factors [6, 7], sometimes, however, also to mosaicism [8]. Recently, the recurrent germline pathogenic variant c.-547C>T in the 5’ untranslated region (5’-UTR) of the AR gene was described in two unrelated patients with CAIS [9]. Here, we report on a mosaic form of the same pathogenic variant in a patient with PAIS. The current understanding of the involvement of the 5’UTR variation in highly penetrant diseases is discussed and an overview of the known AR non-coding pathogenic variants is given.

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