A deep intronic mutation in AR gene causing androgen insensitivity syndrome: difficulties of diagnostics

Abstract

Partial androgen resistance syndrome (PAIS) is the most difficult form of disorders/differences of sex development 46,XY (DSD 46,XY) for choosing of patient management. To date, there are no clear biochemical criteria, especially before puberty, that allow differentiating PAIS from other PAIS-like forms of DSD 46, XY, and genetic verification of the partial form of AIS plays an important role. Meanwhile, according to the literature, mutations in the coding region of AR gene have not been identified in more than 50% of patients with suspected AIS. We performed an extensive analysis of the AR gene in a patient with clinical and laboratory signs of AIS and found a deep intron mutation in the AR gene (p. 2450–42G>A). This variant creates an alternative splice acceptor site resulted a disturbance of the AR function. These findings indicate the need for extensive genetic analysis in a cohort of patients with suspected CPA in the absence of mutations in the AR gene using standard methods of genetic diagnosis.

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

“…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 long-read sequencing which also preserves epigenetic information [ 28 , 29 ], could better clarify the role of noncoding variation in AIS.…”