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  • Test code: 04411
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Invitae Disorders of Male Sex Development Panel

Test description

The Invitae Disorders of Male Sex Development Panel analyzes up to 15 genes associated with sexual development that is inconsistent with a 46,XY chromosome complement. These disorders include 46,XY disorder of sex development (46,XY DSD) and 46,XY complete gonadal dysgenesis (46,XY CGD). Additionally, the SRY gene is present in a majority of individuals with 46,XX testicular DSD. Genetic testing of these genes may confirm a diagnosis and help guide treatment and gender assignment decisions. Identification of a disease-causing variant can guide genetic counseling and inform recurrence-risk assessment.

Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant can inform recurrence-risk assessment and genetic counseling.

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Primary panel (8 genes)

AR DHH MAP3K1 NR0B1 NR5A1 SRD5A2 SRY WT1

Add-on Kallman Syndrome Genes (4 genes)

In a 46,XY individual with ambiguous or underdeveloped genitalia (hypogonadotrophic hypogonadism) and an absence of the sense of smell, a diagnosis of Kallman syndrome may tested by including the ANOS, CHD7, FGFR1, and HESX1 genes for no additional charge. Please note, the HESX1 gene has preliminary evidence in association with Kallman syndrome. Some clinicians may wish to include a gene which does not currently have a definitive clinical association, but which may prove to be clinically significant in the future.

ANOS1 CHD7 FGFR1 HESX1

Add-on Alpha-thalassemia X-linked Intellectual Disability Gene (1 gene)

In a 46,XY individual with ambiguous genitalia, intellectual disability, characteristic dysmorphic facies, and alpha thalassemia, testing for ATRX may be indicated and can be included at no additional charge.

ATRX

Add-on Campomelic Dysplasia Gene (1 gene)

In a 46,XY individual with ambiguous genitalia and congenital bowing of long bones, a suspected diagnosis of campomelic dysplasia can be evaluated by testing the SOX9 gene. This gene can be tested at no additional charge.

SOX9

Add-on Smith-Lemli-Opitz Syndrome Gene (1 gene)

In a 46,XY individual with ambiguous genitalia and a syndromic phenotype that is consistent with Smith-Lemli-Opitz syndrome and corroborated by an abnormal biochemical profile showing elevated serum concentration of 7-dehydrocholesterol (7-DHC) reductase, a suspected diagnosis of Smith-Lemli-Opitz syndrome may be evaluated by testing the DHCR7 gene. This gene can be tested at no additional charge.

DHCR7

  • 46,XY disorder of sex development (DSD)
    • 46,XY disorder of sex development with adrenal insufficiency
    • 5-Alpha reductase deficiency
    • Meacham syndrome
  • 46,XY complete gonadal dysgenesis (CGD)
    • Swyer syndrome
  • 46,XX testicular DSD

46,XY DSD is characterized by ambiguous genitalia with penoscrotal hypospadias, incomplete closure of the labial-scrotal folds, and dysgenetic testes that produce little or no sperm. Female reproductive organs may be present in some individuals, who may achieve pregnancy with assisted reproductive technology. Affected individuals are generally identified prenatally or at birth.

46,XY complete gonadal dysgenesis (46,XY CGD) is characterized by normal female external genitalia and internal Müllerian structures, and undeveloped streak gonads with absent sperm. Affected individuals often present with primary amenorrhea. With hormone replacement therapy, affected individuals undergo normal puberty and may achieve pregnancy with assisted reproductive technology.

46,XX DSD is characterized by 46,XX chromosome complement, typical male genitalia, gynecomastia, hypergonadotropic hypogonadism secondary to testicular failure, and azoospermia, although a minority of cases present with ambiguous genitalia.

Alterations of SRY are a rare cause of 46,XY DSD but cause up to 15% of 46,XY CGD. The SRY gene is the principal gene associated with 46,XX testicular DSD and accounts for approximately 80% of affected individuals. Pathogenic changes in NR5A1 account for approximately 10-15% of 46,XY DSD but are not associated with 46,XY CGD to date. Duplications of NR0B1 are a rare cause of 46,XY DSD or 46,XY CGD. Alterations in the AR gene are thought to cause 65-95% of androgen insensitivity syndrome. The remaining genes have been reported so rarely that their individual contributions to the overall burden of these conditions are uncertain.

46,XY DSD or CGD is inherited in a Y-linked, X-linked, or autosomal dominant manner.

SRY-related disorders of sex development exhibit complete penetrance with variable expressivity. The penetrance for AR, NR5A1, and SRD5A2 is estimated at 50%–90%. The penetrance for NROB1-, MAP3K1-, DHH-, and WT1-related conditions is not yet well-established, but is expected to be high.

Prevalence of disorders of male sex development is estimated at 1 in 10,000 to 20,000.

  1. Mohnach, L, et al. Nonsyndromic Disorders of Testicular Development. 2008 May 21 [updated 2016 Jun 2]. In: Adam, MP, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301714
  2. Ostrer, H. Disorders of sex development (DSDs): an update. J. Clin. Endocrinol. Metab. 2014; 99(5):1503-9. PMID: 24758178
  3. Hiort, O, et al. Management of disorders of sex development. Nat Rev Endocrinol. 2014; 10(9):520-9. PMID: 25022812
  4. Paris, F, et al. Disorders of sex development: neonatal diagnosis and management. Endocr Dev. 2012; 22:56-71. PMID: 22846521
  5. King, TF, Conway, GS. Swyer syndrome. Curr Opin Endocrinol Diabetes Obes. 2014; 21(6):504-10. PMID: 25314337
  6. White, S, et al. Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis. PLoS ONE. 2011; 6(3):e17793. PMID: 21408189
  7. Iyer, AK, McCabe, ER. Molecular mechanisms of DAX1 action. Mol. Genet. Metab. 2004; 83(1-2):60-73. PMID: 15464421
  8. Achermann, JC, et al. Phenotypic spectrum of mutations in DAX-1 and SF-1. Mol. Cell. Endocrinol. 2001; 185(1-2):17-25. PMID: 11738790
  9. Bashamboo, A, McElreavey, K. Human sex-determination and disorders of sex-development (DSD). Semin. Cell Dev. Biol. 2015; 45:77-83. PMID: 26526145
  10. Lin, L, et al. Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function. J. Clin. Endocrinol. Metab. 2007; 92(3):991-9. PMID: 17200175
  11. Köhler, B, et al. Five novel mutations in steroidogenic factor 1 (SF1, NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency. Hum. Mutat. 2008; 29(1):59-64. PMID: 17694559
  12. Ahmed, SF, et al. Society for Endocrinology UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development (Revised 2015). Clin. Endocrinol. (Oxf). 2015. PMID: 26270788
  13. Douglas, G, et al. Guidelines for evaluating and managing children born with disorders of sexual development. Pediatr Ann. 2012; 41(4):e1-7. PMID: 22494213
  14. Pasterski, V, et al. Impact of the consensus statement and the new DSD classification system. Best Pract. Res. Clin. Endocrinol. Metab. 2010; 24(2):187-95. PMID: 20541147
  15. Délot, EC, Vilain, EJ. Nonsyndromic 46,XX Testicular Disorders of Sex Development. 2003 Oct 30. In: Adam, MP, et al, editors. GeneReviews® (Internet). University of Washington, Seattle. PMID: 20301589

Assay and technical information

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
ANOS1 NM_000216.2
AR* NM_000044.3
ATRX NM_000489.4
CHD7 NM_017780.3
DHCR7 NM_001360.2
DHH NM_021044.2
FGFR1 NM_023110.2
HESX1 NM_003865.2
MAP3K1 NM_005921.1
NR0B1 NM_000475.4
NR5A1 NM_004959.4
SOX9 NM_000346.3
SRD5A2 NM_000348.3
SRY NM_003140.2
WT1 NM_024426.4

AR: CAG repeat numbers are not determined.