Abnormal Genitalia/ Disorders of Sex Development Panel

  • bpg-method PLUS
  • bpg-method SEQ
  • bpg-method DEL/DUP

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.

Availability

Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more: http://blueprintgenetics.com/faqs/#prenatal

Genes in the Abnormal Genitalia/ Disorders of Sex Development Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
AMH Persistent Mullerian duct syndrome AR 4 38
AMHR2 Persistent Mullerian duct syndrome AR 4 30
ANOS1* Kallmann syndrome XL/Digenic 19
AR Androgen insensitivity XL 73 556
ARX Lissencephaly, Epileptic encephalopathy, Corpus callosum, agenesis of, with abnormal genitalia, Partington syndrome, Proud syndrome, Hydranencephaly with abnormal genitalia, Mental retardation XL 56 80
ATRX Carpenter-Waziri syndrome, Alpha-thalassemia/mental retardation syndrome, Holmes-Gang syndrome, Juberg-Marsidi syndrome, Smith-Fineman-Myers syndrome, Mental retardation-hypotonic facies syndrome XL 42 149
BCOR Microphthalmia, syndromic, Oculofaciocardiodental syndrome XL 22 44
CDKN1C Beckwith-Wiedemann syndrome, IMAGE syndrome AD 25 79
CEP41 Joubert syndrome AR/Digenic 7 10
CHD7 Isolated gonadotropin-releasing hormone deficiency, CHARGE syndrome AD 128 746
CREBBP Rubinstein-Taybi syndrome AD 103 332
CYP11B1* Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency, Glucocorticoid-remediable aldosteronism AD/AR 23 142
CYP17A1 Adrenal hyperplasia, congenital, due to 17-alpha-hydroxylase deficiency AR 32 123
CYP19A1 Aromatase deficiency AR 14 71
CYP21A2* Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency, Hyperandrogenism, nonclassic , due to 21-hydroxylase deficiency AR 41 288
DHCR7 Smith-Lemli-Opitz syndrome AR 42 194
DYNC2H1 Short -rib thoracic dysplasia with or without polydactyly type 1, Short -rib thoracic dysplasia with or without polydactyly type 3, Asphyxiating thoracic dysplasia (ATD; Jeune), SRPS type 2 (Majewski) AR/Digenic 34 98
FIG4 Amyotrophic lateral sclerosis, Polymicrogyria, bilateral occipital, Yunis-Varon syndrome, Charcot-Marie-Tooth disease AD/AR 19 54
FRAS1 Fraser syndrome AR 20 41
GATA4 Tetralogy of Fallot, Atrioventricular septal defect, Testicular anomalies with or without congenital heart disease, Ventricular septal defect, Atrial septal defect AD 24 147
GNRHR Hypogonadotropic hypogonadism AD/AR/Digenic 21 54
HSD3B2 3-beta-hydroxysteroid dehydrogenase, II deficiency AR 10 57
HSD17B3 17-Beta hydroxysteroid dehydrogenase III deficiency AR 13 51
IL17RD Hypogonadotropic hypogonadism AD/Digenic 6 8
IRF6 Orofacial cleft, Popliteal pterygium syndrome, van der Woude syndrome AD 26 327
LHCGR Precocious puberty, male, Leydig cell hypoplasia, Luteinizing hormone resistance, female AR 28 68
MKS1 Bardet-Biedl syndrome, Meckel syndrome AR 39 47
NR5A1 Adrenocortical insufficiency, Premature ovarian failure, 46,XY sex reversal AD/AR 21 137
NR0B1 Adrenal hypoplasia, congenital, 46,XY sex reversal XL 34 236
POR Disordered steroidogenesis due to cytochrome p450 oxidoreductase deficiency, Antley-Bixler syndrome AR 12 84
PROKR2 Hypogonadotropic hypogonadism AD/AR 9 48
RSPO1 Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and 46,XX sex reversal AR 3 3
SOX9 Campomelic dysplasia, 46,XY sex reversal, Brachydactyly with anonychia (Cooks syndrome) AD 24 135
SRD5A2 Steroid 5-alpha-reductase 2 deficiency AR 16 120
SRY 46,XX disorder of sex development, 46,XY disorder of sex development YL 22 102
STAR Lipoid adrenal hyperplasia AR 15 77
TACR3 Hypogonadotropic hypogonadism AR 7 31
WT1 Denys-Drash syndrome, Frasier syndrome, Wilms tumor AD 23 165
ZFPM2 46,XY sex reversal AD 11 36

*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.

Gene Genomic location HG19 HGVS RefSeq RS-number Comment Reference
CHD7 Chr8:61763035 c.5405-17G>A NM_017780.3 rs794727423

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.

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. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. 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.

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

SEQ 81479
DEL/DUP 81479


ICD codes

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

ICD-10 Disease
Q56 Indeterminate sex and pseudohermaphroditism
Q56.1 Male pseudohermaphroditism
Q56.2 Female pseudohermaphroditism
E34.5 Androgen insensitivity syndrome
E25.0 Congenital 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.

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