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Test Code CYPZ 21-Hydroxylase Gene (CYP21A2), Full Gene Analysis

Secondary ID

37445

Useful For

Carrier screening and diagnosis of 21-hydroxylase deficient congenital adrenal hyperplasia (CAH) in individuals with a personal or family history of 21-hydroxylase deficiency, or as follow-up to positive CAH newborn screens and/or measurement of basal and adrenocorticotropic hormone- 1-24 stimulated 17-hydroxyprogesterone, androstenedione, and other adrenal steroid levels

 

May be used to identify CYP21A2 mutations in individuals with a suspected diagnosis of 21-hydroxylase deficient CAH when a common mutation panel is negative or only identifies 1 mutation.

 

In prenatal cases of ambiguous genitalia detected by ultrasound, particularly when the fetus is confirmed XX female by chromosome analysis.

 

This test code should also be used for known/familial variant analysis for CYP21A2. Due to the complexity of the CYP21A2 locus, site specific testing for known/familial variants is not offered for this gene.

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
MATCC Maternal Cell Contamination, B Yes No
CULFB Fibroblast Culture for Genetic Test Yes No
CULAF Amniotic Fluid Culture/Genetic Test Yes No

Testing Algorithm

For prenatal specimens only: If amniotic fluid (nonconfluent cultured cells) is received, amniotic fluid culture will be added and charged separately. If chorionic villus specimen (nonconfluent cultured cells) is received, fibroblast culture will be added and charged separately. For any prenatal specimen that is received, maternal cell contamination studies will be added.

Method Name

Polymerase Chain Reaction (PCR) Amplification Followed by DNA Sequence Analysis and Gene Dosage Analysis by Multiplex Ligation-Dependent Probe Amplification (MLPA)

Reporting Name

CYP21A2 Gene, Full Gene Analysis

Specimen Type

Varies


Advisory Information


This test is a molecular analysis of the CYP21A2 gene and does not include biochemical analysis of steroids. For biochemical analysis for congenital adrenal hyperplasia (CAH) which includes cortisol, androstenedione and 17-Hydroxyprogesterone, see CAH21 / Congenital Adrenal Hyperplasia (CAH) Profile for 21-Hydroxylase Deficiency.



Additional Testing Requirements


All prenatal specimens must be accompanied by a maternal blood specimen; order MATCC / Maternal Cell Contamination, Molecular Analysis on the maternal specimen.



Shipping Instructions


Specimen preferred to arrive within 96 hours of collection.

 

Prenatal specimens can be sent Monday through Thursday and must be received by 5 p.m. CST on Friday in order to be processed appropriately.



Specimen Required


Specimen Type: Whole Blood

Container/Tube:

Preferred: Lavender top (EDTA)

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.

 

Prenatal Specimens

Specimen Type: Amniotic fluid

Container/Tube: Amniotic fluid container

Specimen Volume: 20 mL

Specimen Stability Information: Refrigerated (preferred)/Ambient

 

Specimen Type: Chorionic villi

Container/Tube: 15-mL tube containing 15 mL of transport media

Specimen Volume: 20 mg

Specimen Stability Information: Refrigerated

 

Acceptable

Specimen Type: Confluent cultured cells

Container/Tube: T-25 flask

Specimen Volume: 2 flasks

Collection Instructions: Submit confluent cultured cells from another laboratory.

Specimen Stability Information: Ambient (preferred)/Refrigerated


Specimen Minimum Volume

Amniotic Fluid: 10 mL; Blood: 1 mL; Chorionic Villi: 5 mg

Specimen Stability Information

Specimen Type Temperature Time
Varies Ambient (preferred)
  Frozen 
  Refrigerated 

Reject Due To

No specimen should be rejected.

Clinical Information

Congenital adrenal hyperplasia (CAH), with an incidence rate of 1 in 10,000 to 18,000 live births, is one of the most common inherited syndromes. The condition is characterized by impaired cortisol production due to inherited defects in steroid biosynthesis. The clinical consequences of CAH, besides diminished cortisol production, depend on which enzyme is affected and whether the loss of function is partial or complete.

 

In greater than 90% of CAH cases, the affected enzyme is 21-steroid hydroxylase, encoded by the CYP21A2 gene located on chromosome 6 within the highly recombinant human histocompatibility complex locus. 21-hydroxylase deficient CAH is inherited in an autosomal recessive pattern and has a spectrum of clinical phenotypes depending upon residual enzyme activity. Excessive adrenal androgen biosynthesis results in varying degrees of virilization. If there is some residual enzyme activity, a non-classical phenotype results, with signs of hyperandrogenism typically starting in later childhood or adolescence. Individuals with severe enzyme deficiency have classical CAH, with prenatal onset of virilization. Classical CAH which is subdivided into simple-virilizing (minimal residual enzyme activity) and salt-wasting (no residual enzyme activity) forms. Patients with salt-wasting CAH have both cortisol and mineral corticosteroid deficiency and are at risk for life-threatening salt-wasting crises if untreated.

 

Because of its high incidence rate, 21-hydroxylase deficiency is screened for in most US newborn screening programs, typically by measuring 17-hydroxyprogesterone concentrations in blood spots by immunoassay. Confirmation by other testing strategies (eg, LC-MS/MS, CAHBS / Congenital Adrenal Hyperplasia [CAH] Newborn Screening, Blood Spot), or retesting after several weeks, is required for most positive screens because of the high false-positive rates of the immunoassays (due to physiological elevations of 17-hydroxyprogesterone in premature babies and immunoassay cross-reactivity with other steroids). In a small percentage of cases, additional testing will fail to provide a definitive diagnosis. In addition, screening strategies can miss many non-classical cases, which may present later in childhood or adolescence and require more extensive steroid hormone profiling, including testing before and after adrenal stimulation with adrenocorticotropic hormone (ACTH)-1-24.

 

For these reasons, genetic diagnosis plays an important ancillary role in both classical and non-classical cases. In addition, the high carrier frequency (approximately 1 in 50) for CYP21A2 mutations makes genetic diagnosis important for genetic counseling. Genetic testing can also play a role in prenatal diagnosis of 21-hydroxylase deficiency. However, accurate genetic diagnosis continues to be a challenge because most of the mutations arise from recombination events between CYP21A2 and its highly homologous pseudogene, CYP21A1P (transcriptionally inactive). In particular, partial or complex rearrangements (with or without accompanying gene duplication events), which lead to reciprocal exchanges between gene and pseudogene, can present severe diagnostic challenges. Comprehensive genetic testing strategies must therefore allow accurate assessment of most, or all, known rearrangements and mutations, as well as unequivocal determination of whether the observed changes are located within a potentially transcriptionally active genetic segment. Testing of additional family members is often needed for clarification of genetic test results.

Reference Values

An interpretive report will be provided.

Interpretation

All detected alterations will be evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations. Variants will be classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Clinical Reference

1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015 May;17(5):405-424

2. Collett-Solberg PF: Congenital adrenal hyperplasias: from clinical genetics and biochemistry to clinical practice, part I. Clin Pediatr 2001;40:1-16

3. Mercke DP, Bornstein SR, Avila NA, Chrousos GP: NIH conference: future directions in the study and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Ann Intern Med 2002;136:320-334

4. Speiser PW, White PC: Medical progress: congenital adrenal hyperplasia. N Engl J Med 2003;349:776-788

Day(s) and Time(s) Performed

Performed weekly; Varies

Analytic Time

14 days

Performing Laboratory

Mayo Medical Laboratories in Rochester

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

CPT Code Information

81405-CYP21A2 (cytochrome P450, family 21, subfamily A, polypeptide2) (eg, steroid 21-hydroxylase isoform, congenital adrenal hyperplasia), full gene sequence

81402-CYP21A2 (cytochrome P450, family 21, subfamily A, polypeptide2) (eg, congenital adrenal hyperplasia, 21-hydroxylase deficiency), common variants (eg, IVS2-13G, P30L, I172N, exon 6 mutation cluster [I235N, V236E, M238K], V281L, L307FfsX6, Q318X, R356W, P453S, G110VfsX21, 30-kb deletion variant)

 

Fibroblast Culture for Genetic Test

88233-Tissue culture, skin or solid tissue biopsy (if appropriate)

88240-Cryopreservation (if appropriate)

 

Amniotic Fluid Culture/Genetic Test

88235-Tissue culture for amniotic fluid (if appropriate)

88240-Cryopreservation (if appropriate)

 

Maternal Cell Contamination, B

81265-Comparative analysis using Short Tandem Repeat (STR) markers; patient and comparative specimen (eg, pre-transplant recipient and donor germline testing, post-transplant non-hematopoietic recipient germline [eg, buccal swab or other germline tissue sample] and donor testing, twin zygosity testing or maternal cell contamination of fetal cells (if appropriate)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
CYPZ CYP21A2 Gene, Full Gene Analysis In Process

 

Result ID Test Result Name Result LOINC Value
37488 Result Summary 50397-9
37489 Result In Process
37490 Interpretation In Process
37491 Additional Information 48767-8
37492 Specimen 31208-2
37493 Source 31208-2
37494 Released By No LOINC Needed

Forms

1. CYP21A2 Gene Testing for Congenital Adrenal Hyperplasia Patient Information (T663) is required and available in Special Instructions

2. New York Clients: Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (T576) is available in Special Instructions.