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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DISCUSSION

Sexual development is a complex process starting at the beginning of the embryonic development and lasting through puberty, involving a large number of genes with specific temporal and spatial regulation of their expression. For the genetic diagnosis of rare disorders, a single-gene testing is still useful in the cases with a clear etiology, although the use of a panel of associated genes, analyzed with short reads massively parallel sequencing, is already an established practice. Despite this advancement in the genetic diagnosis, there is still a large proportion of undiagnosed DSD patients, with diagnostic rate being ∼50% [15]. There is emerging evidence that 5′UTR variants could be a cause of penetrant human diseases. Approximately half of the human transcripts naturally contain upstream open reading frames (uORF) in their 5′UTR which modulate the production of the main protein by disturbing the protein translation [16, 17]. Variants that introduce or disrupt uORF are rare and are subjected to strong negative selection because of their ability to cause a disease [17-19]. A recent study based on a large cohort of human whole genome sequences identified a subset of genes, among which was AR gene, where high-impact uORF-perturbing variants would have a deleterious effect on gene function [17]. Previous functional analysis of the c.-547C>T pathogenic variant confirmed the mutation’s deleterious effect on AR function and association with CAIS phenotype [9]. This was in line with the predicted functional consequence given by the UTRannotator tool. A variant was also not identified in the Genome Aggregation Database (gnomAD), a large-scale population database for variant frequencies [20]. The presence of PAIS in our patient, compared to CAIS in patients described by Hornig et al., is in line with the previous findings that variable expressivity in AIS could be attributed to mosaicism [8, 21]. Specifically, there is a phenotypic overlap consisting of the absence of a uterus, blind ending vagina and positive hCG test as well as a phenotypic difference consisting of the presence of ambiguous genitalia in our patient. This stands in contrast to the presence of female genitalia in the patients described by Hornig et al. In individuals with PAIS and ambiguous genitalia, the tendency is to assign sex of rearing after an expert evaluation has been completed [22]. This was the procedure that was followed in our case, and we are unaware for the reasons behind parents’ decision. Although preferable for studies of androgen action, we have not tested patient’s gonadal tissue or genital skin fibroblasts for mosaicism, but the presence of the same rate of the mutation in two different cell types is suggestive that the mutation is present in the entire body, in approximately the same rate. In general, regions outside the AR coding sequences and conserved splice sites have been less extensively studied in AIS patients. The non-coding AR pathogenic variants reported on so far are presented in Table 1. Recently, there was a report of a large family pedigree of PAIS patients with disease causing LINE-1 retrotransposon insertion in the 5′UTR region of the AR gene [23]. Another study identified deep intronic mutation in intron 6, creating an alternative splice acceptor site of the AR gene, in a family with PAIS patients [24]. The same mutation was found in an unrelated patient, also with PAIS [25]. Deep intronic mutations were observed in CAIS patients [24, 26, 27]. Studying the noncoding region of the AR gene is highly challenging due to its genomic size of 186,500 nucleotides, as compared of only 2763 nucleotides of the coding sequence. However, the probability of identifying pathogenic variants outside of the AR coding regions in AIS patients is high [25]. Further advancements in genetic diagnostics with the introduction of targeted sequencing of the whole genomic locus of AR gene, using targeted longread sequencing which also preserves epigenetic information [28, 29], could better clarify the role of noncoding variation in AIS. In conclusion, comprehensive genetic testing by targeting the entire AR gene locus, together with the development of appropriate annotation tools, would contribute to the identification of the missing heritability of AIS.

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