Novel pathogenic variants in the androgen receptor gene associated with androgen insensitivity syndrome identified through exome sequencing and in silico analysis.

• Novel variants in the AR cause androgen insensitivity syndrome (AIS). • A copy number variation covered a deletion of exon 2 of AR causing AIS is found. • Splicing site variant in the AR causes the loss of donor site and exon skipping. • Missense variants in the AR may affect the structure and function of AR protein. • Exome sequencing is suitable for molecular diagnosis of AIS patients. Androgen insensitivity syndrome (AIS) is a common disorder/differences of sex development with a 46, XY karyotype, but diverse genital phenotypes. Various pathogenic variants within the androgen receptor (AR) gene on the X chromosome are the primary pathogenesis of AIS. However, some patients with AIS still lack a definitive molecular diagnosis. Here, molecular diagnosis of eight patients with the clinical phenotype of AIS was performed using exome sequencing. We found eight variants of the AR gene, including p.(C131*), p.(W435*), p.(T653Lfs*8), c.2318+1G>T, p.(S397R), p.(Y572C), p.(S648G), and p.(D691G), and a pathogenic copy number variation covering a deletion of exon 2 of AR gene. Patient pedigree validation confirmed that the discovered variants conformed to the X-linked recessive inheritance patterns of AIS. In silico analysis indicated that the splice site variant (c.2318+1G>T) could lead to loss of the original 5′ splice donor site and exon skipping. Missense variants, including p.(S397R), p.(S648G), and p.(D691G), may affect the structure and function of the AR protein. Our results highlight the applicability of exome sequencing for molecular diagnosis of AIS. The novel variants found in this study enrich the pathogenic variant spectrum of the AR gene and provide a basis for the diagnosis and management of patients with AIS. A definite molecular diagnosis will provide accurate guidance for genetic counseling of proband's family members. [ABSTRACT FROM AUTHOR]