Abnormal Genitalia/ Disorders of Sex Development Panel

SEQmethod-seq-icon Our Sequence Analysis is based on a proprietary targeted sequencing method OS-Seq™ and offers panels targeted for genes associated with certain phenotypes. A standard way to analyze NGS data for finding the genetic cause for Mendelian disorders. Results in 21 days. DEL/DUPmethod-dup-icon Targeted Del/Dup (CNV) analysis is used to detect bigger disease causing deletions or duplications from the disease-associated genes. Results in 21 days. PLUSmethod-plus-icon Plus Analysis combines Sequence + Del/Dup (CNV) Analysis providing increased diagnostic yield in certain clinical conditions, where the underlying genetic defect may be detectable by either of the analysis methods. Results in 21 days.

Test code: EN0201

The Blueprint Genetics Abnormal Genitalia/ Disorders of Sex Development Panel is a 39 gene test for genetic diagnostics of patients with clinical suspicion of androgen insensitivity syndrome, congenital adrenal hyperplasia, female pseudohermaphroditism, indeterminate sex and pseudohermaphroditism or male pseudohermaphroditism.

Disorders of sex development (DSDs) and abnormal genitalia form a heterogenous group of conditions with various inheritance models. Inheritance of congenital adrenal hyperplasia (CAH) is autosomal recessive, while androgen insensitivity syndrome (AIS) is X-linked recessive. Approximately 1% of pathogenic variants causing CAH are de novo. In addition to primary DSD, this Panel have differential diagnostics power to several other rare diseases and syndromes that are characterized by abnormal genitalia.

About Abnormal Genitalia/ Disorders of Sex Development

Disorders of sex development (DSD) are a group of congenital conditions characterized by problems in the course of typical gender patterning, gonadal and sex development. It has been estimated that 1% - 2% of live births suffer from some aspects of DSD. Approximately 5% of infants with DSD have ambiguous genitalia and indeterminate sex at birth. However, the vast majority of these patiens never require corrective surgery. Patients with 46,XY DSD condition have often impaired androgen synthesis or action and may have normal female external genitalia, while patients with 46,XX DSD conditions have often androgen excess. In 46,XX females, congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency (21-OHD) is the most common cause of DSD. The estimated prevalence of CAH is 1:10 000 and 90%-95% of cases are due to mutations in CYP21A2. Severity of the phenotype often depends on the residual enzyme activity subdiving CYP21A2 mutations in severe (classic phenotype, enzyme activity 0%-10%) and mild (non-classic, enzyme activity 20%-50%) phenotypes. AIS caused by mutations in AR is characterized by feminization of external genitalia and abnormal sexual development in 46,XY individuals. The phenotype may be complete, partial or mild, depending on androgen insensitivity level. Mutations in the AR gene explain up to 95% of cases with complete androgen insensitivity, while for partial and mild subtypes the proportions are lower. The combined prevalence of various AIS subtypes is estimated to be 5:100 000.


Results in 3-4 weeks.

Genes in the Abnormal Genitalia/ Disorders of Sex Development Panel and their clinical significance
GeneAssociated phenotypesInheritanceClinVarHGMD
AMHPersistent Mullerian duct syndromeAR438
AMHR2Persistent Mullerian duct syndromeAR430
ANOS1*Kallmann syndromeXL/Digenic19
ARAndrogen insensitivityXL73556
ARXLissencephaly, Epileptic encephalopathy, Corpus callosum, agenesis of, with abnormal genitalia, Partington syndrome, Proud syndrome, Hydranencephaly with abnormal genitalia, Mental retardationXL5680
ATRXCarpenter-Waziri syndrome, Alpha-thalassemia/mental retardation syndrome, Holmes-Gang syndrome, Juberg-Marsidi syndrome, Smith-Fineman-Myers syndrome, Mental retardation-hypotonic facies syndromeXL42149
BCORMicrophthalmia, syndromic, Oculofaciocardiodental syndromeXL2244
CDKN1CBeckwith-Wiedemann syndrome, IMAGE syndromeAD2579
CEP41Joubert syndromeAR/Digenic710
CHD7Isolated gonadotropin-releasing hormone deficiency, CHARGE syndromeAD128746
CREBBPRubinstein-Taybi syndromeAD103332
CYP11B1*Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency, Glucocorticoid-remediable aldosteronismAD/AR23142
CYP17A1Adrenal hyperplasia, congenital, due to 17-alpha-hydroxylase deficiencyAR32123
CYP19A1Aromatase deficiencyAR1471
CYP21A2*Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiencyAR41288
DHCR7Smith-Lemli-Opitz syndromeAR42194
FIG4Amyotrophic lateral sclerosis, Polymicrogyria, bilateral occipital, Yunis-Varon syndrome, Charcot-Marie-Tooth diseaseAD/AR1954
FRAS1Fraser syndromeAR2041
GATA4Tetralogy of Fallot, Atrioventricular septal defect, Testicular anomalies with or without congenital heart disease, Ventricular septal defect, Atrial septal defectAD24147
GNRHRHypogonadotropic hypogonadismAD/AR/Digenic2154
HSD3B23-beta-hydroxysteroid dehydrogenase, II deficiencyAR1057
HSD17B317-Beta hydroxysteroid dehydrogenase III deficiencyAR1351
IL17RDHypogonadotropic hypogonadismAD/Digenic68
IRF6Orofacial cleft, Popliteal pterygium syndrome, van der Woude syndromeAD26327
LHCGRPrecocious puberty, male, Leydig cell hypoplasia, Luteinizing hormone resistance, femaleAR2868
MKS1Bardet-Biedl syndrome, Meckel syndromeAR3947
NR5A1Adrenocortical insufficiency, Premature ovarian failure, 46,XY sex reversalAD/AR21137
NR0B1Adrenal hypoplasia, congenital, 46,XY sex reversalXL34236
PORDisordered steroidogenesis due to cytochrome p450 oxidoreductase deficiencyAR1284
PROKR2Hypogonadotropic hypogonadismAD/AR948
RSPO1Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and 46,XX sex reversalAR33
SOX9Campomelic dysplasia, 46,XY sex reversalAD24135
SRD5A2Steroid 5-alpha-reductase 2 deficiencyAR16120
SRY46,XX disorder of sex development, 46,XY disorder of sex developmentYL22102
STARLipoid adrenal hyperplasiaAR1577
TACR3Hypogonadotropic hypogonadismAR731
WT1Denys-Drash syndrome, Frasier syndrome, Wilms tumorAD23165
ZFPM246,XY sex reversalAD1136
  • * Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Blueprint Genetics offers a comprehensive abnormal genitalia/ disorders of sex development panel that covers classical genes associated with androgen insensitivity syndrome, congenital adrenal hyperplasia, female pseudohermaphroditism, indeterminate sex and pseudohermaphroditism, male pseudohermaphroditism and persistent Mullerian duct syndrome. The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Please see our latest validation report showing sensitivity and specificity for SNPs and indels, sequencing depth, % of the nucleotides reached at least 15x coverage etc. If the Panel is not present in the report, data will be published when the Panel becomes available for ordering. Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. All the Panels available for ordering have sensitivity and specificity higher than > 0.99 to detect single nucleotide polymorphisms and a high sensitivity for indels ranging 1-19 bp. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile. Detection limit for Del/Dup analysis varies through the genome from one to six exon Del/Dups depending on exon size, sequencing coverage and sequence content.

The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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ICD & CPT codes

CPT codes


ICD codes

Commonly used ICD-10 codes when ordering the Abnormal Genitalia/ Disorders of Sex Development Panel

Q56Indeterminate sex and pseudohermaphroditism
Q56.1Male pseudohermaphroditism
Q56.2Female pseudohermaphroditism
E34.5Androgen insensitivity syndrome
E25.0Congenital adrenal hyperplasia

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.