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
page: 51
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Abstract
Sexual development (SD) is a complex process with
strict spatiotemporal regulation of gene expression. Despite
advancements in molecular diagnostics, disorders
of sexual development (DSD) have a diagnostic rate of
∼50%. Androgen insensitivity syndrome (AIS) represents
the most common form of 46,XY DSD, with a spectrum of
defects in androgen action. Considering the importance of
very strict regulation of the SD, it is reasonable to assume
that the genetic cause for proportion of the DSD lies in the
non-coding part of the genome that regulates proper gene
functioning. Here we present a patient with partial AIS
(PAIS) due to a mosaic de novo c.-547C>T pathogenic
variant in the 5’UTR of androgen receptor (AR) gene.
The same mutation was previously described as inherited,
in two unrelated patients with complete AIS (CAIS).
Thus, our case further confirms the previous findings that
variable gene expressivity could be attributed to mosaicism.
Mutations in 5’UTR could create new upstream
open reading frames (uORFs) or could disrupt the existing
one. A recent systematic genome-wide study identified
AR as a member of a subset of genes where modifications
of uORFs represents an important disease mechanism.
Only a small number of studies are reporting non-coding
mutations in the AR gene and our case emphasizes the
importance of molecular testing of the entire AR locus in
AIS patients. The introduction of new methods for comprehensive
molecular testing in routine genetic diagnosis,
accompanied with new tools for in sillico analysis could
improve the genetic diagnosis of AIS, and DSD in general.
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