The Invitae Androgen Insensitivity Panel analyzes AR and SRD5A2, two genes that are associated with ambiguous or feminized external sexual development in an individual with a 46,XY chromosome complement. Pathogenic changes in the AR gene cause androgen insensitivity; changes in SRD5A2 disrupt the conversion of testosterone into active dihydrotestosterone.
Genetic testing of these genes may confirm a diagnosis and help guide treatment and gender-assignment decisions. Identification of a disease-causing variant can also guide genetic counseling and inform risk assessment for other relatives. This test is not intended to test for Kennedy’s disease-related polyglutamine repeat expansions within the androgen receptor (AR) gene.
Androgen insensitivity syndrome (AIS) due to defective function or absence of the androgen receptor is characterized by variable levels of virilization and infertility in all affected individuals and by female or ambiguous external genitalia in a 46,XY individual. Response to testosterone may be partial or absent and results in partial AIS (PAIS) or complete AIS (CAIS), respectively. Individuals with PAIS present with hypospadias, micropenis, and bifid scrotum with undescended testes. When presenting as a mild phenotype, these individuals appear as males with gynecomastia. In contrast, severe forms result in female external genitalia with clitoromegaly and partial labial fusion with internal testes. PAIS results from missense changes in the AR gene. CAIS manifests as normal female external genitalia with fully formed but undescended testes, normal breast development, and primary amenorrhea. Internal female reproductive organs as well as male Wolffian duct derivatives are absent. Biochemical analysis shows increased luteinizing hormone and testosterone in adults. CAIS results from severe changes in the AR gene that eliminate the gene’s presence or function.
Sex development inconsistent with a 46,XY chromosome complement due to steroid 5-alpha reductase deficiency arises from a defect in testosterone metabolism into active dihydrotestosterone, which is essential for the development of male secondary sexual characteristics. Individuals with homozygous or compound heterozygous pathogenic changes in the SRD5A2 gene exhibit ambiguous or complete female external sex development but do not develop breasts or internal female reproductive organs. The clinical spectrum varies, ranging from a female with a blind vaginal pouch to a male with hypospadias, undescended testes, and micropenis (pseudovaginal perineoscrotal hypospadias). Wolffian duct derivatives are normal but fertility is impaired due to poor spermatogenesis. Prevalence of SRD5A2 deficiency is increased in some populations in the Mediterranean and Latin America.
Absence or disruption of the androgen receptor due to pathogenic changes in the AR gene is responsible for 50%–95% of androgen insensitivity. Steroid 5-alpha reductase deficiency is caused entirely by homozygous or compound heterozygous pathogenic changes in the SRD5A2 gene.
Androgen insensitivity is X-linked and steroid 5-alpha reductase deficiency shows male-limited autosomal recessive inheritance.
Pathogenic variants in AR and SRD5A2 have complete penetrance with variable expressivity.
The prevalence of androgen insensitivity or steroid 5-alpha reductase deficiency is not known. Incidence of androgen insensitivity is thought to be 1 in 20,000 to 100,000 individuals with a 46,XY chromosome complement.
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Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|
AR: CAG repeat numbers are not determined.