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GeneDx
207 Perry Parkway
Gaithersburg, MD 20877
Phone: 301-519-2100
Fax: 301-519-2892
E-mail: [email protected]
www.genedx.com
Test Information Sheet
Prenatal Testing for AR Gene Mutations: Androgen Insensitivity Syndrome (AIS)
Also known as: Testicular Feminization syndrome (TFM); Reifenstein syndrome
Mendelian Inheritance in Man Number: 300068 – Androgen Insensitivity syndrome; 312300 – Reifenstein syndrome;
313700 – AR gene
Clinical features in Children and Adults:
Androgen insensitivity syndrome may be complete or partial. Patients with AIS may come to attention in utero or at birth
because of inconsistency between prenatal karyotype (male) and ultrasound findings of a female fetus, or at birth because
of ambiguous genitalia. Alternatively, patients may present during the pubertal years with a presumed inguinal hernia
(abdominal or inguinal testes), absence of pubic/auxiliary hair, or lack of onset of menses. The mature phenotype is often
“voluptuously” feminine with very well-developed breastsand luxuriant scalp hair. In the partial form, patients may exhibit
hypospadias, micropenis, or fusion of the labial folds, associated with the occurrence of virilization at puberty.
Heterozygous females may exhibit patchy changes in hair distribution and irregular menses due to skewed inactivation of
the X-chromosome. Of note, Kennedy disease is an independent disorder due to an expansion of a CAG repeat in the AR
gene and is not diagnosed with this test.
Prenatal Ultrasound Findings:
Androgen insensitivity syndrome may be suspected when the fetal karyotype is 46,XY but ultrasound reveals apparently
female or ambiguous genitalia. Ultrasound examination may be normal in affected fetuses; therefore, pregnancies at risk
to inherit a specific known familial mutation can be offered targeted molecular testing regardless of ultrasound findings, if
desired.
Inheritance Pattern: X-linked recessive
Indications for Fetal Testing:
 Full gene sequencing testing for fetuses with prenatal ultrasound findings suggestive of AIS.
 Mutation-specific testing for fetuses with a family history of a known AR mutation
Test Method:
Using genomic DNA, analysis is performed by bi-directional sequencing of the coding region (exons 1-8) and the flanking
splice sites of the AR gene. For known familial mutations, the relevant portion of the AR gene will be analyzed in
duplicate.
Additionally, genotype analysis of maternal and fetal DNA for several polymorphic markers to test for maternal cell
contamination will be performed. Therefore, in all prenatal cases a maternal sample should accompany the fetal
sample.
Test Sensitivity:
Approximately 83-95% of individuals with complete AIS are expected to have a mutation in the AR gene identifiable by
sequencing. The detection rate for individuals with milder phenotypes (i.e. partial androgen insensitivity and mild
androgen insensitivity) is not well established but is likely less than 50% (Ahmed et al., 2000; Batch et al., 1992).
Additionally, 5-6% of males with hypospadias have been found to harbor an identifiable mutation in the AR gene (Hiort et
al., 1994; Albers et al., 1997; Wang et al., 2004). The sensitivity of AR gene analysis in prenatal cases ascertained based
on an inconsistency between the fetal gender by ultrasound and by karyotype is currently unknown.
Information Sheet Prenatal Diagnosis AIS
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GeneDx revision date 05/2013
Mutation Spectrum:
Many distinct mutations scattered across the AR gene have been identified in both complete and partial androgen
insensitivity syndrome. The vast majority of the mutations are missense substitutions, although nonsense and splice-site
mutations, whole and partial gene deletions, and two partial gene duplications also have been reported (Gottleib et al.,
2004; Ahmed et al., 2000; Avila et al., 2002; Hannema et al., 2004).
Specimen Requirements and Shipping/Handling:
 Prenatal Specimen – Based on Abnormal Ultrasound/Other Findings (test #2201): 20 mg villi preferred (minimum 15
mg) or 20 mL amniotic fluid or 2 T25 flasks of cultured CV or cultured amniocytes. Ship overnight at ambient temperature,
using a cool pack in hot weather.
 Prenatal Specimen- Based on Specific Known Mutation (test #902): 20mg villi preferred (minimum 15mg) or 20 mL
amniotic fluid or 2 T25 flasks of cultured CV or cultured amniocytes. Ship overnight at ambient temperature, using a cool
pack in hot weather.
 Maternal cell contamination studies (required for all prenatal testing): 1-4 ml maternal blood in a lavender-top EDTA
tube. Ship overnight at ambient temperature, using a cool pack in hot weather. Specimens may be refrigerated for 7 days
prior to shipping. Alternatively, buccal brushes (GeneDx kit only) or DNA can be used. The maternal sample should
accompany the prenatal specimen or be shipped to arrive prior to or concurrently with the prenatal sample.
*If more than one prenatal test is ordered, 30 mL amniotic fluid, 30mg villi or 3 T-25 flasks of cultured cells are requested*
Required Forms:
 Sample Submission (Requisition) Form – complete all pages
 Payment Options Form or Institutional Billing Instructions (last page of submission form)
CPT Codes and Turn-Around-Times: (All codes and units apply)
Test #
Description
CPT codes
2201
Prenatal diagnosis based on
ultrasound findings suggestive of AIS
Prenatal diagnosis for a specific
known AR mutation
81405x1, 81265x1,
88235x1
81265, 81479
902
Turnaround
time
Approx. 2-3 weeks
Approx. 2 weeks
Possible ICD9 Codes: Abnormal ultrasound findings = 655.83 Family history possibly affecting fetus = 655.23
References
Ahmed et al., (2000) JCEM. 85:658-665. Batch et al., (1992) Hum Molec Genet 1:497-503. Hiort et al., (1994) Eur J Pediatr 153:317-321.
Albers et al., (1997) J Pediatr 131:386-392. Wang et al., (2004) Eur J Hum Genet 12:706-712. Avila et al., (2002) JCEM 87:182-188. Hannema
et al., (2004) JCEM 89:5815-5822. Gottlieb et al (2004) Hum Mutat 23:527-533. Gottleib et al. (Updated [May 24, 2008]). Androgen
Insensitivity Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of
Washington, Seattle. 1997-2009. Available at http://www.genetests.org. Accessed [December 2009].
Information Sheet Prenatal Diagnosis AIS
Page 2 of 2
GeneDx revision date 05/2013