<abstract xmlns="http://www.w3.org/1999/xhtml">

<p>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 <italic>de novo</italic> c.-547C>T pathogenic variant in the 5′UTR of androgen receptor (<italic>AR</italic>) 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 <italic>AR</italic> 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 <italic>AR</italic> gene and our case emphasizes the importance of molecular testing of the entire <italic>AR</italic> 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.</p>
</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.

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&gt;T Variant

Diabetes and Metabolic Disorders, Clinical Centre “Mother Teresa“

Balkan Journal of Medical Genetics

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

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

Sexual development (SD) is a complex process with strict spatiotemporal regulation of gene expression. Despite advancements in molecular diagnostics, disorders...

AR Mutation	Mutation type and location within non-coding AR sequence	Phenotype (number of affected individuals and family history)	Inheritance	Reported by [ref]
c.-547C>T	SNV in 5′UTR	CAIS (n=2, unrelated cases)	Inherited	Hornig et al. [9]
c.-547C>T	SNV in 5′UTR	PAIS (n=1, no family history)	De novo, mosaic	This study
LINE-1 insertion at c.-268	Insertion of >800 nucleotides in 5′UTR	PAIS (n=9; one family, 4 generations)	Inherited	Batista et al. [23]
с.2450–42G>A	Deep intronic SNV in intron 6	PAIS (n=3; one family, 3 generations)	Inherited	Ono et al. [24]
с.2450–42G>A	Deep intronic SNV in intron 6	PAIS (n=1, uncle with similar symptoms but without genetic test)	Not reported, presumable inherited	Kalinchenko et al. [25]
c.1769–11T>A	Deep intronic SNV in intron 2	CAIS (n=3; one family, 3 generations, reported as PAIS but phenotype is more suggestive of CAIS, as described in [23])	Inherited	Brüggenwirth et al. [26]
c.2450-118A>G	Deep intronic SNV in intron 6	CAIS (n=2; one family, 2 generations)	Inherited	Känsäkoski et al. [27]

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

Article Category: Case Report

Published Online: Jul 31, 2023

Page range: 51 - 56

DOI: https://doi.org/10.2478/bjmg-2023-0012

Keywords
Androgen insensitivity syndrome (AIS), 5′UTR variant, upstream open reading frames (uORFs), non-coding variation, mosaicism

© 2023 P Noveski et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Figure 1.

Non-coding disease causing mutations in AR gene reported in AIS patients.

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

Article Category: Case Report

Published Online: Jul 31, 2023

Page range: 51 - 56

DOI: https://doi.org/10.2478/bjmg-2023-0012

KeywordsAndrogen insensitivity syndrome (AIS), 5′UTR variant, upstream open reading frames (uORFs), non-coding variation, mosaicism

© 2023 P Noveski et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Figure 1.

Non-coding disease causing mutations in AR gene reported in AIS patients.

Keywords
Androgen insensitivity syndrome (AIS), 5′UTR variant, upstream open reading frames (uORFs), non-coding variation, mosaicism