CHARGE and Kallmann Syndromes Panel

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
3267 ANOS1 81406,81479 Order Options and Pricing
CHD7 81407,81479
SEMA3E 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
3267Genes x (3)81479 81406, 81407, 81479 $990 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available.

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

CHARGE syndrome is a severe developmental disorder characterized by multiple congenital defects involving sensory and mediastinal organs. It is a clinically heterogeneous disorder in regards to symptoms and severity. Hallmark features include ocular coloboma; choanal atresia; cranial nerve abnormalities leading to facial palsy, loss of sense of smell, feeding, swallowing and breathing difficulties; and external and inner ear malformations resulting in hearing loss and reduced sense of balance. Additional features include hypogonadotropic hypogonadism, which manifests as incomplete or absent puberty and infertility; genital hypoplasia; distinctive facial features growth and developmental delay; a wide variety of heart defects; cleft lip and/or palate; and olfactory dysfunction in the form of aplasia or hypoplasia (Blake et al. 1998; Pinto et al. 2005). CHARGE syndrome is usually diagnosed during childhood. Diagnosis is made based on the presence of a combination of major and minor clinical features (Blake et al. 1998; Verloes et al. 2005). Magnetic resonance imaging (MRI) of the temporal bones reveals abnormalities in the semicircular canal (Amiel et al 2001). In rare cases, CHARGE syndrome has been detected in adults only after the birth of a child with the major characteristic features of the disease (Hughes et al. 2014). It has also been diagnosed antenatally (Legendre et al. 2012). CHARGE syndrome affects individuals worldwide with an incidence of approximately 1 case in 12,500 live births (Källén et al. 1999). Higher incidences have been reported in the Atlantic provinces of Newfoundland and Labrador, and the Maritime Provinces (Issekutz et al. 2005). See also (Lalani et al. 2012) and the CHARGE Syndrome Foundation (http://www.chargesyndrome.org/foundation.asp).

Kallmann syndrome (KS) is characterized by hypogonadotropic hypogonadism and impaired sense of smell as the result of deficient hypothalamic gonadotropin-releasing hormone and agenesis of the olfactory lobes. Additional features include unilateral failure of kidney development; abnormalities in tooth development; cleft lip and/or palate; and bimanual synkinesis, which is manifested by involuntary movements of one hand that mimic the other hand (Kaplan et al. 2010).

CHARGE syndrome has phenotypic overlap with Kallmann syndrome and hypogonadotropic hypogonadism (Kim et al. 2008; Jongmans et al. 2009). It has been argued that some patients presenting with a clinical diagnosis of Kallmann syndrome may represent unrecognized mild cases of CHARGE syndrome (Ogata et al. 2006).

Genetics

CHARGE syndrome is an autosomal dominant condition. About 95% of patients with a clinical diagnosis of CHARGE syndrome based on the Blake or Verloes criteria have heterozygous pathogenic variants in the CHD7 gene (Vissers et al. 2004; Verloes et al. 2005; Blake et al. 2011). Over 680 different causative variants, located throughout the length of the gene, are listed in public databases (Human Gene Mutation Database; CHD7 Mutation Database). The great majority result in premature termination of protein synthesis, and include nonsense, splicing, small deletions and insertions. Large pathogenic deletions have been reported in less than 5% of patients with a clinical diagnosis of CHARGE syndrome (Bergman et al. 2008; Wincent et al. 2009; Blake et al. 2011). Chromosomal abnormalities as the result of balanced translocations, rearrangements, or interstitial deletions have also been reported in rare cases (Hurst et al. 1991; Johnson 2006; Arrington et al. 2005). Although most disease-causing variants are de novo, familial cases have been reported (Jongmans et al. 2008; Hughes et al. 2014). In these families, clinical features are usually variable among affected individuals and may be very mild. Parental mosaicism, both somatic and germline, has been detected (Jongmans et al 2006; Pauli et al. 2009).

CHD7 encodes the chromodomain helicase DNA-binding protein 7 that is required for normal mammalian development.

Kallmann syndrome is genetically heterogeneous with various inheritance patterns. Several genes have been associated with the disorder, including ANOS1, CHD7, and SEMA3E.

About 30 CHD7 pathogenic variants have been reported in patients with Kallmann syndrome; they account for ~ 11% of patients with a clinical diagnosis (Marcos et al. 2014). Unlike CHARGE-causative variants, the majority of Kallmann syndrome causative variants are missense. To date, no large deletions, duplications, or complex rearrangements were reported. Most cases are sporadic.

Pathogenic variants in the SEMA3E gene appear to be a rare cause of CHARGE or Kallmann syndromes. To date, only one patient with CHARGE syndrome was reported to have a pathogenic missense variant in SEMA3E (Lalani et al. 2004). A different missense variant was reported in one patient with Kallmann syndrome (Cariboni et al. 2015).

The semaphorin 3E protein is involved in the control of vascular patterning, which is critical for normal organogenesis (Gu et al. 2005).

Over 150 pathogenic variants in the ANOS1 gene have been reported in patients with Kallmann syndrome. The majority of these variants are truncating (HGMD). They account for ~ 8% of all KS cases (Dode et al. 2009). Large deletions have been reported in up to 25% of X-linked KS patients analyzed (Ahmadzadeh et al. 2015). Female carriers of ANOS1 pathogenic variants are usually not affected (Oliveira et al. 2011).

The ANOS1 gene is located on the X chromosome. It encodes anosmin-1, which is involved in the growth and migration of olfactory neurons.

Clinical Sensitivity - Sequencing with CNV PG-Select

The sensitivity of this test varies based on the criteria used for diagnosis. Pathogenic variants in CHD7 are detected in over 95% of patients with a clinical diagnosis based on Blake or Verloes criteria (Blake et al. 1998; Verloes et al. 2005). CHD7 pathogenic variants are found in 60-70% of patients who are suspected to have CHARGE syndrome (Blake et al. 2011). About 11% of patients with a clinical diagnosis of Kallmann syndrome have pathogenic variants in CHD7 (Marcos et al. 2014).

Pathogenic variants in the ANOS1 gene account for ~ 8% of all KS cases (Dode et al. 2009). Pathogenic variants in the SEMA3E gene appear to be a rare cause of CHARGE or Kallmann syndromes.

Large pathogenic deletions in CHD7 have been reported in less than 5% of patients with a clinical diagnosis of CHARGE syndrome (Bergman et al. 2008; Wincent et al. 2009; Blake et al. 2011).

Large deletions in the ANOS1 gene have been reported in up to 25% of X-linked Kallmann syndrome patients analyzed (Ahmadzadeh et al. 2015).

Large pathogenic deletions in the SEMA3E gene have not been reported.

Testing Strategy

This panel provides 100% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.

Indications for Test

Patients presenting with the major clinical criteria or a combination of minor and major criteria for CHARGE syndrome as described (Blake et al. 1998; Verloes et al. 2005). Patients with hypogonadotropic hypogonadism with or without impaired sense of smell are also candidates for this test (Ogata et al. 2006).

Genes

Official Gene Symbol OMIM ID
ANOS1 300836
CHD7 608892
SEMA3E 608166
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Diseases

Name Inheritance OMIM ID
CHARGE Association AD 214800
Kallmann Syndrome 1 XL 308700
Kallmann Syndrome 5 AD 612370

Related Test

Name
PGxome®

Citations

  • Ahmadzadeh A. et al. 2015. International Journal of Molecular and Cellular Medicine. 4: 152-9. PubMed ID: 26629483
  • Amiel J. et al. 2001. American Journal of Medical Genetics. 99: 124-7. PubMed ID: 11241470
  • Arrington C.B. et al. 2005. American Journal of Medical Genetics Part A. 133A: 326-30. PubMed ID: 15672384
  • Bergman et al. 2008. PubMed ID: 18472328
  • Blake K. et al. 2011. European Journal of Human Genetics. 19: N/A. PubMed ID: 21407266
  • Blake K.D. et al. 1998. Clinical Pediatrics. 37: 159-73. PubMed ID: 9545604
  • Cariboni A. et al. 2015. The Journal of Clinical Investigation. 125: 2413-28. PubMed ID: 25985275
  • CHARGE Syndrome Foundation
  • CHD7 Mutation Database
  • Dodé C., Hardelin J.P. 2009. European Journal of Human Genetics. 17: 139-46. PubMed ID: 18985070
  • Gu C. et al. 2005. Science. 307: 265-8. PubMed ID: 15550623
  • Hughes S.S. et al. 2014. American Journal of Medical Genetics. Part A. 164A: 48-53. PubMed ID: 24214489
  • Human Gene Mutation Database (Bio-base).
  • Hurst J.A. et al. 1991. Journal of Medical Genetics. 28: 54-5. PubMed ID: 1999835
  • Issekutz K.A. et al. 2005. American Journal of Medical Genetics. Part A. 133A: 309-17. PubMed ID: 15637722
  • Johnson D. et al. 2006. Journal of Medical Genetics. 43: 280-4. PubMed ID: 16118347
  • Jongmans M.C et al. 2009. Clinical Genetics. 75: 65-71. PubMed ID: 19021638
  • Jongmans M.C. et al. 2006. Journal of Medical Genetics. 43: 306-14. PubMed ID: 16155193
  • Jongmans M.C. et al. 2008. American Journal of Medical Genetics. Part A. 146A: 43-50. PubMed ID: 18074359
  • Källén K. et al. 1999. Teratology. 60: 334-43. PubMed ID: 10590394
  • Kaplan J.D. et al. 2010. American Journal of Medical Genetics. Part A. 152A: 2796-801. PubMed ID: 20949504
  • Kim H.G. et al. 2008. American Journal of Human Genetics. 83: 511-9. PubMed ID: 18834967
  • Lalani S. et al. 2004. Journal of Medical Genetics. 41: e94. PubMed ID: 15235037
  • Lalani S.R. et al. 2012. CHARGE Syndrome. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301296
  • Legendre M. et al. 2012. Journal of Medical Genetics. 49: 698-707. PubMed ID: 23024289
  • Marcos S. et al. 2014. The Journal of Clinical Endocrinology and Metabolism. 99: E2138-43. PubMed ID: 25077900
  • Ogata T. et al. 2006. Endocrine Journal. 53: 741-3. PubMed ID: 16960397
  • Oliveira L.M. et al. 2001. The Journal of Clinical Endocrinology and Metabolism. 86: 1532-8. PubMed ID: 11297579
  • Pauli S. et al. 2009. Clinical Genetics. 75: 473-9. PubMed ID: 19475719
  • Pinto G. et al. 2005. The Journal of Clinical Endocrinology and Metabolism. 90: 5621-6. PubMed ID: 16030162
  • Verloes A. 2005. American Journal of Medical Genetics. Part A. 133A: 306-8. PubMed ID: 15666308
  • Vissers L.E. et al. 2004. Nature Genetics. 36: 955-7. PubMed ID: 15300250
  • Wincent et al. 2009. PubMed ID: 19248844

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

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.

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.

For Requisition Forms, visit our Forms page


Specimen Types

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