CHARGE and Kallmann Syndromes via the CHD7 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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NGS Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
4633 CHD7$640.00 81407 Add to Order
Pricing Comment

Our most cost-effective testing approach is NextGen sequencing with Sanger sequencing supplemented as needed to ensure sufficient coverage and to confirm NextGen calls that are pathogenic, likely pathogenic or of uncertain significance. If, however, full gene Sanger sequencing only is desired (for purposes of insurance billing or STAT turnaround time for example), please see link below for Test Code, pricing, and turnaround time information.

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Sensitivity

The sensitivity of this test varies based on the criteria used for diagnosis. Mutations 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 mutations 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).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 CHD7$990.00 81479 Add to Order
Pricing Comment

# of Genes Ordered

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Over 100

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Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Sensitivity

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).

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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; growth and developmental delay; a wide variety of heart defects; cleft lip or palate; and distinctive facial features. 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 adult individuals 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 (

Kallmann syndrome has clinical overlap with CHARGE syndrome. It 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, respectively. 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 (Dode et al. 2003; Kaplan et al. 2010).


CHARGE and Kallmann syndromes are autosomal dominant conditions. More than 95% of patients with a clinical diagnosis of CHARGE syndrome based on the Blake or Verloes criteria have heterozygous mutations in the CHD7 gene (Blake 1998; Verloes, 2005; Blake 2011). Over 680 different causative mutations, located throughout the length of the gene, are listed in public databases (Human Gene Mutation Database; CHD7 Mutation Database). The great majority result in truncated proteins, and include nonsense, splicing, small deletions and insertions. About 2% of all pathogenic variants are large deletions, some of which include the entire CHD7 gene (Wincent et al. 2008). Chromosomal abnormalities as the result of balanced translocations, rearrangements, or interstitial deletions have been reported (Hurst et al. 1991; Johnson 2005; 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, have been detected (Jongmans et al 2006; Pauli et al. 2009).

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

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

Testing Strategy

For this NextGen test, the full coding regions plus ~10 bp of non-coding DNA flanking each exon are sequenced for the gene listed below. Sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments. Additional Sanger sequencing is performed for any regions not captured or with insufficient number of sequence reads. All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by 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). For Kallmann syndrome, hypogonadotropic hypogonadism and impaired sense of smell.


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


Name Inheritance OMIM ID
CHARGE Association 214800

Related Tests

FGFR1-Related Disorders via the FGFR1 Gene
CHARGE Syndrome via the SEMA3E Gene


Genetic Counselors
  • Amiel J, Attieé-Bitach T, Marianowski R, Cormier-Daire V, Abadie V, Bonnet D, Gonzales M, Chemouny S, Brunelle F, Munnich A, Manach Y, Lyonnet S. 2001. Temporal bone anomaly proposed as a major criteria for diagnosis of CHARGE syndrome. Am. J. Med. Genet. 99: 124–127. PubMed ID: 11241470
  • Arrington CB, Cowley BC, Nightingale DR, Zhou H, Brothman AR, Viskochil DH. 2005. Interstitial deletion 8q11.2-q13 with congenital anomalies of CHARGE association. American Journal of Medical Genetics Part A 133A: 326–330. PubMed ID: 15672384
  • Bergman JEH, Wijs I de, Jongmans MCJ, Admiraal RJ, Hoefsloot LH, Ravenswaaij-Arts CMA van. 2008. Exon copy number alterations of the CHD7 gene are not a major cause of CHARGE and CHARGE-like syndrome. Eur J Med Genet 51: 417–425. PubMed ID: 18472328
  • Blake K, Ravenswaaij-Arts CM van, Hoefsloot L, Verloes A. 2011. Clinical utility gene card for: CHARGE syndrome. European Journal of Human Genetics 19: PubMed ID: 21407266
  • Blake KD, Davenport SL, Hall BD, Hefner MA, Pagon RA, Williams MS, Lin AE, Graham JM Jr. 1998. CHARGE association: an update and review for the primary pediatrician. Clin Pediatr (Phila) 37: 159–173. PubMed ID: 9545604
  • CHARGE Syndrome Foundation
  • CHD7 Mutation Database
  • Dodé C, Levilliers J, Dupont J-M, Paepe AD, Dû NL, Soussi-Yanicostas N, Coimbra RS, Delmaghani S, Compain-Nouaille S, Baverel F, Pêcheux C, Tessier DL, et al. 2003. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nature Genetics 33: 463–465. PubMed ID: 12627230
  • Hughes SS, Welsh HI, Safina NP, Bejaoui K, Ardinger HH. 2014. Family history and clefting as major criteria for CHARGE syndrome. American Journal of Medical Genetics Part A 164: 48–53. PubMed ID: 24214489
  • Human Gene Mutation Database (Bio-base).
  • Hurst JA, Meinecke P, Baraitser M. 1991. Balanced t(6;8)(6p8p;6q8q) and the CHARGE association. J. Med. Genet. 28: 54–55. PubMed ID: 1999835
  • Issekutz KA, Graham JM, Prasad C, Smith IM, Blake KD. 2005. An epidemiological analysis of CHARGE syndrome: Preliminary results from a Canadian study. American Journal of Medical Genetics Part A 133A: 309–317. PubMed ID: 15637722
  • Johnson D. 2005. Confirmation of CHD7 as a cause of CHARGE association identified by mapping a balanced chromosome translocation in affected monozygotic twins. Journal of Medical Genetics 43: 280–284. PubMed ID: 16118347
  • Jongmans MCJ, Hoefsloot LH, Donk KP van der, Admiraal RJ, Magee A, Laar I van de, Hendriks Y, Verheij JBGM, Walpole I, Brunner HG, Ravenswaaij CMA van. 2008. Familial CHARGE syndrome and theCHD7 gene: A recurrent missense mutation, intrafamilial recurrence and variability. American Journal of Medical Genetics Part A 146A: 43–50. PubMed ID: 18074359
  • Jongmans MCJ. 2005. CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene. Journal of Medical Genetics 43: 306–314. PubMed ID: 16155193
  • Källén K, Robert E, Mastroiacovo P, Castilla EE, Källén B. 1999. CHARGE Association in newborns: a registry-based study. Teratology 60: 334–343. PubMed ID: 10590394
  • Kaplan JD, Bernstein JA, Kwan A, Hudgins L. 2010. Clues to an early diagnosis of Kallmann syndrome. Am. J. Med. Genet. A 152A: 2796–2801. PubMed ID: 20949504
  • Lalani SR, Hefner MA, Belmont JW, Davenport SL. 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, Gonzales M, Goudefroye G, Bilan F, Parisot P, Perez M-J, Bonnière M, Bessières B, Martinovic J, Delezoide A-L, Jossic F, Fallet-Bianco C, Bucourt M, Tantau J, Loget P, Loeuillet L, Laurent N, Leroy B, Salhi H, Bigi N, Rouleau C, Guimiot F, Quélin C, Bazin A, Alby C, Ichkou A, Gesny R, Kitzis A, Ville Y, Lyonnet S, Razavi F, Gilbert-Dussardier B, Vekemans M, Attié-Bitach T. 2012. Antenatal spectrum of CHARGE syndrome in 40 fetuses with CHD7 mutations. J. Med. Genet. 49: 698–707. PubMed ID: 23024289
  • Marcos S, Sarfati J, Leroy C, Fouveaut C, Parent P, Metz C, Wolczynski S, Gérard M, Bieth E, Kurtz F, Verier-Mine O, Perrin L, Archambeaud F, Cabrol S, Rodien P, Hove H, Prescott T, Lacombe D, Christin-Maitre S, Touraine P, Hieronimus S, Dewailly D, Young J, Pugeat M, Hardelin JP, Dodé C. 2014. The Prevalence of CHD7 Missense Versus Truncating Mutations Is Higher in Patients With Kallmann Syndrome Than in Typical CHARGE Patients. The Journal of Clinical Endocrinology & Metabolism 99: E2138–E2143. PubMed ID: 25077900
  • Pauli S, Pieper L, Häberle J, Grzmil P, Burfeind P, Steckel M, Lenz U, Michelmann H. 2009. Proven germline mosaicism in a father of two children with CHARGE syndrome. Clinical Genetics 75: 473–479. PubMed ID: 19475719
  • Verloes A. 2005. Updated diagnostic criteria for CHARGE syndrome: A proposal. American Journal of Medical Genetics Part A 133A: 306–308. PubMed ID: 15666308
  • Vissers LELM, Ravenswaaij CMA van, Admiraal R, Hurst JA, Vries BBA de, Janssen IM, Vliet WA van der, Huys EHLPG, Jong PJ de, Hamel BCJ, Schoenmakers EFPM, Brunner HG, Veltman JA, van Kessel AG. 2004. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nature Genetics 36: 955–957. PubMed ID: 15300250
  • Wincent J, Holmberg E, Strömland K, Soller M, Mirzaei L, Djureinovic T, Robinson K, Anderlid B, Schoumans J. 2008. CHD7 mutation spectrum in 28 Swedish patients diagnosed with CHARGE syndrome. Clinical Genetics 74: 31–38. PubMed ID: 18445044
  • Wincent J, Schulze A, Schoumans J. 2009. Detection of CHD7 deletions by MLPA in CHARGE syndrome patients with a less typical phenotype. Eur J Med Genet 52: 271–272. PubMed ID: 19248844
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NextGen Sequencing using PG-Select Capture Probes

Test Procedure

We use a combination of Next Generation Sequencing (NGS) and Sanger sequencing technologies to cover the full coding regions of the listed genes plus ~20 bases of non-coding DNA flanking each exon.  As required, genomic DNA is extracted from the patient specimen.  For NGS, patient DNA corresponding to these regions is captured using an optimized set of DNA hybridization probes.  Captured DNA is sequenced using Illumina’s Reversible Dye Terminator (RDT) platform (Illumina, San Diego, CA, USA).  Regions with insufficient coverage by NGS are covered by Sanger sequencing.  All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by Sanger sequencing.

For Sanger sequencing, Polymerase Chain Reaction (PCR) is used to amplify targeted regions.  After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Patient DNA sequence is aligned to the genomic reference sequence for the indicated gene region(s). All differences from the reference sequences (sequence variants) are assigned to one of five interpretation categories, listed below, per ACMG Guidelines (Richards et al. 2015).

(1) Pathogenic Variants
(2) Likely Pathogenic Variants
(3) Variants of Uncertain Significance
(4) Likely Benign Variants
(5) Benign, Common Variants

Human Genome Variation Society (HGVS) recommendations are used to describe sequence variants (  Rare variants and undocumented variants are nearly always classified as likely benign if there is no indication that they alter protein sequence or disrupt splicing.

Analytical Validity

As of March 2016, 6.36 Mb of sequence (83 genes, 1557 exons) generated in our lab was compared between Sanger and NextGen methodologies. We detected no differences between the two methods. The comparison involved 6400 total sequence variants (differences from the reference sequences). Of these, 6144 were nucleotide substitutions and 256 were insertions or deletions. About 65% of the variants were heterozygous and 35% homozygous. The insertions and deletions ranged in length from 1 to over 100 nucleotides.

In silico validation of insertions and deletions in 20 replicates of 5 genes was also performed. The validation included insertions and deletions of lengths between 1 and 100 nucleotides. Insertions tested in silico: 2200 between 1 and 5 nucleotides, 625 between 6 and 10 nucleotides, 29 between 11 and 20 nucleotides, 25 between 21 and 49 nucleotides, and 23 at or greater than 50 nucleotides, with the largest at 98 nucleotides. All insertions were detected. Deletions tested in silico: 1813 between 1 and 5 nucleotides, 97 between 6 and 10 nucleotides, 32 between 11 and 20 nucleotides, 20 between 21 and 49 nucleotides, and 39 at or greater than 50 nucleotides, with the largest at 96 nucleotides. All deletions less than 50 nucleotides in length were detected, 13 greater than 50 nucleotides in length were missed. Our standard NextGen sequence variant calling algorithms are generally not capable of detecting insertions (duplications) or heterozygous deletions greater than 100 nucleotides. Large homozygous deletions appear to be detectable.   

Analytical Limitations

Interpretation of the test results is limited by the information that is currently available.  Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.

When Sanger sequencing does not reveal any difference from the reference sequence, or when a sequence variant is homozygous, we cannot be certain that we were able to detect both patient alleles.  Occasionally, a patient may carry an allele which does not amplify, due to a large deletion or insertion.   In these cases, the report will contain no information about the second allele.  Our Sanger and NGS Sequencing tests are generally not capable of detecting Copy Number Variants (CNVs).

We sequence all coding exons for each given transcript, plus ~20 bp of flanking non-coding DNA for each exon.  Test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions or any currently uncharacterized alternative exons.

In most cases, we are unable to determine the phase of sequence variants.  In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants due to somatic mosaicism is limited.  Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes from whole blood).   Test reports contain no information about the DNA sequence in other cell-types.

We cannot be certain that the reference sequences are correct.

Rare, low probability interpretations of sequencing results, such as for example the occurrence of de novo mutations in recessive disorders, are generally not included in the reports.

We have confidence in our ability to track a specimen once it has been received by PreventionGenetics.  However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

Ordering Options

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.
  • 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.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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