NR5A1-Related Disorders via the NR5A1 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
903 NR5A1$650.00 81479 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity
NR5A1 mutations have been found in 10-15% of patients with 46,XY complete or partial gonadal dysgenesis (El-Khairi et al., 2012).

In a cohort of 315 men with idiopathic spermatogenic failure, NR5A1 mutations were found in 4% of cases (Bashamboo et al., 2010).

In a limited number of sporadic patients with premature ovarian failure, 8% (2 out of 25) had de novo NR5A1 mutations (Lourenço et al., 2009).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 NR5A1$990.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Sensitivity
In a limited number of patients with 46,XY gonadal dysgenesis in whom sequencing analyses failed to identify a genetic cause, 5% (1 out of 20) had a partial deletion within NR5A1 (Barbaro et al., 2011). Other large NR5A1 deletions have only been reported in limited individual cases.

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Clinical Features
Mutations in the NR5A1 gene, which encodes steroidogenic factor 1 (SF1), can cause a wide range of phenotypes, including 46,XY partial or complete gonadal dysgenesis, spermatogenic failure, and 46,XX primary ovarian insufficiency (El-Khairi et al., 2012).

NR5A1-related 46,XY gonadal dysgenesis (OMIM# 612965) can be partial or complete (El-Khairi et al., 2012; Cotinot et al., 2002; Ostrer et al., 2008). 46,XY partial gonadal dysgenesis (also termed 46,XY partial testicular dysgenesis) is the more common condition and is characterized by ambiguous external genitalia with a wide spectrum of genital ambiguity, dysgenetic testis and a mixture of both Wolffian and Mullerian ducts (McElreavey et al., 1996; Domenice et al., 1998; Cotinot et al., 2002).

46,XY complete gonadal dysgenesis (also termed Swyer syndrome or 46,XY pure gonadal dysgenesis) represents the more severe (and rarer) end of the phenotypes. Phenotypically females present in adolescence with absent pubertal development and primary amenorrhea, although they have functional female genitalia and structures. Notably, some patients affected by NR5A1-related 46,XY partial or complete gonadal dysgenesis can have primary adrenal failure (Achermann et al., 1999; Lin et al., 2006; Köhler et al., 2008).

NR5A1-related spermatogenic failure (OMIM# 613957) is a disease of male infertility characterized by azoospermia or oligozoospermia (Bashamboo et al., 2010). Some patients may have elevated gonadotropins and low testosterone. Affected men may be at risk of developing suboptimal testosterone levels in adult life.

NR5A1 defects have also been found in familial 46,XX primary ovarian insufficiency (OMIM# 612964) and sporadic premature ovarian failure (Lourenço et al., 2009). All of these affected women have no evidence of adrenal dysfunction.
The NR5A1 gene has 6 coding exons and encodes steroidogenic factor 1 (SF1), which is a key transcriptional regulator of genes involved in the hypothalamic-pituitary-steroidogenic axis. Genetic aberrations throughout this gene include missense, nonsense, splicing mutations and small deletion/insertions. Large deletions involving the NR5A1 gene have also been reported but are relatively uncommon (Human Gene Mutation Database). In most cases, NR5A1-related disorders are caused by de novo mutations or dominantly inherited mutations (El-Khairi et al., 2012).

In 10-15% of cases, 46,XY complete or partial gonadal dysgenesis is caused by NR5A1 defects (El-Khairi et al., 2012). Haploinsufficiency of NR5A1 is the principle mechanism explaining gonadal phenotypes. The majority of these NR5A1 defects are de novo changes while about one-third of cases have been found transmitted from mothers.

NR5A1 defects have been found in approximately 4% of men with idiopathic spermatogenic failure (Bashamboo et al., 2010). These mutations clustered within the hinge domain of the protein. In some cases, heterozygous NR5A1 mutations can be transmitted from young fathers to their children and an affected child can inherit a NR5A1 mutation from his mosaic father (El-Khairi et al., 2012).

46,XY complete or partial gonadal dysgenesis can be caused by mutations in different genes with different inheritance patterns including autosomal dominant (the WNT4 and NR5A1 genes), autosomal recessive (the DHH gene), X-linked (the NR0B1 gene) or Y-linked (the SRY gene) (Paliwal et al., 2011; Ostrer et al., 2008).
Testing Strategy
This test involves bidirectional Sanger DNA sequencing of six coding exons of NR5A1. The entire coding region and ~10 bp of flanking non-coding DNA on either side of the single exon will be sequenced. We will also sequence any single exon (Test #100) in family members of patients with a known mutation or to confirm research results.
Indications for Test
Candidates for this test are patients with 46,XY complete or partial gonadal dysgenesis, spermatogenic failure, or ovarian insufficiency (familial or sporadic). Testing is also indicated for family members of patients who have known NR5A1 mutations.


Official Gene Symbol OMIM ID
NR5A1 184757
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Genetic Counselors
  • Achermann JC, Ito M, Ito M, Hindmarsh PC, Jameson JL. 1999. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat. Genet. 22: 125–126. PubMed ID: 10369247
  • Barbaro M, Cools M, Looijenga LHJ, Drop SLS, Wedell A. 2011. Partial deletion of the NR5A1 (SF1) gene detected by synthetic probe MLPA in a patient with XY gonadal disorder of sex development. Sex Dev 5: 181–187. PubMed ID: 21654157
  • Bashamboo A, Ferraz-de-Souza B, Lourenço D, Lin L, Sebire NJ, Montjean D, Bignon-Topalovic J, Mandelbaum J, Siffroi J-P, Christin-Maitre S, Radhakrishna U, Rouba H, et al. 2010. Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1. Am. J. Hum. Genet. 87: 505–512. PubMed ID: 20887963
  • Cotinot C, Pailhoux E, Jaubert F, Fellous M. 2002. Molecular genetics of sex determination. Semin. Reprod. Med. 20: 157–168. PubMed ID: 12428196
  • Domenice S, Yumie Nishi M, Correia Billerbeck AE, Latronico AC, Aparecida Medeiros M, Russell AJ, Vass K, Marino Carvalho F, Costa Frade EM, Prado Arnhold IJ, Bilharinho Mendonca B. 1998. A novel missense mutation (S18N) in the 5’ non-HMG box region of the SRY gene in a patient with partial gonadal dysgenesis and his normal male relatives. Hum. Genet. 102: 213–215. PubMed ID: 9521592
  • El-Khairi R, Achermann JC. 2012. Steroidogenic factor-1 and human disease. Semin. Reprod. Med. 30: 374–381. PubMed ID: 23044873
  • Human Gene Mutation Database (Bio-base).
  • Köhler B, Lin L, Ferraz-de-Souza B, Wieacker P, Heidemann P, Schröder V, Biebermann H, Schnabel D, Grüters A, Achermann JC. 2008. Five novel mutations in steroidogenic factor 1 (SF1, NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency. Hum. Mutat. 29: 59–64. PubMed ID: 17694559
  • Lin L, Gu W-X, Ozisik G, To WS, Owen CJ, Jameson JL, Achermann JC. 2006. Analysis of DAX1 (NR0B1) and steroidogenic factor-1 (NR5A1) in children and adults with primary adrenal failure: ten years’ experience. J. Clin. Endocrinol. Metab. 91: 3048–3054. PubMed ID: 16684822
  • Lourenço D, Brauner R, Lin L, Perdigo A De, Weryha G, Muresan M, Boudjenah R, Guerra-Junior G, Maciel-Guerra AT, Achermann JC, McElreavey K, Bashamboo A. 2009. Mutations in NR5A1 associated with ovarian insufficiency. N. Engl. J. Med. 360: 1200–1210. PubMed ID: 19246354
  • McElreavey K, Vilain E, Barbaux S, Fuqua JS, Fechner PY, Souleyreau N, Doco-Fenzy M, Gabriel R, Quereux C, Fellous M, Berkovitz GD. 1996. Loss of sequences 3’ to the testis-determining gene, SRY, including the Y pseudoautosomal boundary associated with partial testicular determination. Proc. Natl. Acad. Sci. U.S.A. 93: 8590–8594. PubMed ID: 8710915
  • Ostrer H. 1993. 46,XY Disorder of Sex Development and 46,XY Complete Gonadal Dysgenesis. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301714
  • Paliwal P, Sharma A, Birla S, Kriplani A, Khadgawat R, Sharma A. 2011. Identification of novel SRY mutations and SF1 (NR5A1) changes in patients with pure gonadal dysgenesis and 46,XY karyotype. Mol. Hum. Reprod. 17: 372–378. PubMed ID: 21242195
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 10 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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Ordering Options

myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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