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Molecular Genetics Laboratory

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CHARGE Syndrome (CHD7 Sequence and Deletion Analysis)

  • Synonyms: Kallmann syndrome, Hall-Hittner syndrome
  • LIS Mnemonic: MBCHARGEFS

    Collect

    Collect whole blood in a purple top (EDTA) tube (preferred). Extracted DNA is also accepted.

    Volume Required

    5 ml whole blood or 9 ug DNA

    Minimum Required

    3 ml whole blood

    Transport

    Refrigerate sample until shipment. Send the sample at room temperature with overnight delivery for receipt Monday through Friday within 24 hours of collection.

    Stability

    Whole blood can be refrigerated until shipment.

    Unacceptable conditions

    Heparinized specimens, severely hemolyzed specimens, frozen, clotted or possibly commingled specimens, blood in non-sterile or leaky containers, mislabeled or inappropriately labeled specimens.

    Specimen Handling

    Do not heat, freeze or centrifuge blood before shipment. Refrigerate sample until shipment.

Days Performed

Mon - Fri 9:00am to 4:00pm

Reported

8-10 weeks

CPT

81407, 81479

Disease Information

Clinical Features:

CHARGE is a multi system disorder consisting of Coloboma, Heart defects, choanal Atresia, Retarded growth and development, Genital abnormalities, and Ear anomalies. The majority of cases are sporadic and only a few familial cases have been reported. A consistent feature in CHARGE syndrome is semicircular canal hypoplasia resulting in vestibular areflexia. Other commonly associated congenital anomalies are facial nerve palsy, cleft lip/palate, and tracheo-oesophageal fistula. Specific behavioural problems, including autistic-like behavior, have been described. Mutations in the CHD7 gene are associated with CHARGE syndrome. Apart from the typical features of CHARGE syndrome, there is evidence to show that mutations in the CHD7 gene also result in Idiopathic Hypogonadotropic-Hypogonadism (IHH) and Kallmann Syndrome (KS) (postulated to be milder allelic variants of CHARGE syndrome). IHH patients present with absent or impaired sexual development and infertility. KS patients have IHH coupled with the inability to smell (anosmia).

Molecular Genetics:

CHD7, encoding the chromodomain helicase DNA binding protein, is the only gene currently known to be associated with CHARGE syndrome. CHD7 consists of 38 exons and encodes a 2997-residue protein. Missense, nonsense, splice-site mutation, small insertion/deletion mutations and large deletions of the CHD7 gene have been identified throughout the gene. Germline mosaicism has been reported previously.

Test Methods:

We offer DNA sequence analysis and deletion/duplication testing of the entire coding region of the CHD7 gene. These tests can be ordered as a panel or individually. PCR amplification and sequence analysis is performed on all coding exons including splice junctions. The patient’s gene sequence is then compared to a reference sequence. Sequence variants are classified as mutations, variants of unknown significance or benign variants unrelated to disease. Variants of unknown significance may warrant further studies in the patient and other family members. Mutations in promoters, deep intronic regions and other regulatory regions will not be identified with this assay. Large deletions and duplications will be detected using multiplex ligation-dependent probe amplification assay (MLPA).

Detection Rate:

Sequence analysis of the CHD7 coding region detects mutations in approximately 60-65% of individuals suspected of having CHARGE syndrome. In classic cases of CHARGE, mutations in the CHD7 gene are found in greater than 90% of patients. Partial or complete gene deletions have been identified in ~ 6% of CHARGE patients. The molecular basis of IHH and KS has been identified in about 25-30% of patients in seven other genes. Missense and splice-site mutations in the CHD7 gene are responsible for ~7% of cases of IHH / KS without a CHARGE phenotype.

Related Tests:

Known mutation analysis of the CHD7 gene is available to family members for mutations previously identified by sequence analysis or deletion/duplication analysis. Prenatal Testing is available to individuals who are confirmed carriers of mutations in the CHD7 gene. Please contact the laboratory director to discuss appropriateness of testing prior to collecting a prenatal specimen.

Results:

Test results with interpretation will be mailed and/or faxed to the referring physician following completion of the test. Additional reports will be provided as requested.

Utility:

The clinical utility of the assay is to support a clinical diagnosis of the disease, facilitate genetic counseling, assess the risk to other first degree relatives and to facilitate testing of at - risk family members.

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215-590-5221