CHARGE & Kallman syndromes


CHARGE syndrome is a constellation of congenital malformations. The name of the condition is an acronym of some of the most common features:

C = Coloboma of the eye and Cranial nerve abnormalities,
H = Heart malformation,
A = Choanal Atresia (blockage of the nasal passageways),
R = Retardation of growth after birth and Retardation of development,
G = Genital hypoplasia (underdevelopment) in males and urinary tract malformations,
E = Ear malformations and/or deafness.

In addition, there may be cleft lip or palate; small chin; facial palsy; and esophageal atresia. Other problems reported in children with CHARGE syndrome include abnormally small head, drooping of the eyelids, trouble breathing (due to the choanal atresia), feeding problems in infancy, omphalocele, anal stenosis or blockage, and deficiency of growth hormone. Children with CHARGE syndrome may die in the newborn period or later in childhood. Children who survive usually show some degree of mental deficiency. The range of the mental handicap is very broad. Most children with CHARGE syndrome have no family history of the disorder.Very few people with CHARGE will have 100% of its known features.

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.

Mutations on the CHD7 gene (located on Chromosome 8) have been identified in patients with CHARGE syndrome. About 30 CHD7 pathogenic variants have been reported in patients with Kallmann syndrome; they account for ~ 11% of patients with a clinical diagnosis.

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. Large deletions have been reported in up to 25% of X-linked KS patients analyzed. Female carriers of ANOS1 pathogenic variants are usually not affected.

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. A different missense variant was reported in one patient with Kallmann syndrome.

Genes: ANOS1, CHD7, SEMA3E

Disorders: CHARGE Association, Kallman Syndrome 1, Kallman syndrome 5

Methodology: Next-Generation Sequencing

Purpose: Confirmation of Clinical Diagnosis

Test Requisition: Sequencing Requisition

Specimen Requirements: 2-5 mL Blood- Lavender Top Tube

CPT Codes: 81406,81407,81479 Cost: $1400.00  (Oklahoma Medicaid requires preauthorization for this test)

Turn-around-time: 5-6 weeks

Shipping Information


1. Pagon RA, Graham JM, Zonana J, Yong SL (1981). "Coloboma, congenital heart disease, and choanal atresia with multiple anomalies: CHARGE association". J. Pediatr. 99 (2): 223–7.

2. Hall BD (1979). "Choanal atresia and associated multiple anomalies". J. Pediatr. 95 (3): 395–8.

3. Vissers, L. E., van Ravenswaaij, C. M., Admiraal, R., Hurst, J. A., de Vries, B. B., Janssen, I. M., et al. (2004). "Mutations in a new member of the chromodomain gene family cause CHARGE syndrome.". Nature Genetics 36 (9): 955–957.

4. Zentner GE, Layman WS, Martin DM, Scacheri PC (2010). "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome". Am J Med Genet A 152 (3): 674–686.

5. Janssen, N; Bergman, JE; Swertz, MA; Tranebjaerg, L; Lodahl, M; Schoots, J; Hofstra, RM; van Ravenswaaij-Arts, CM; Hoefsloot, LH (2012). "Mutation update on the CHD7 gene involved in CHARGE syndrome.". Human mutation 33 (8): 1149–1160.

6. Kaplan J.D. et al. 2010. American Journal of Medical Genetics. Part A. 152A: 2796-801. PubMed ID: 20949504

7. Marcos S. et al. 2014. The Journal of Clinical Endocrinology and Metabolism. 99: E2138-43. PubMed ID: 25077900

8. Dodé C., Hardelin J.P. 2009. European Journal of Human Genetics. 17: 139-46. PubMed ID: 18985070

9. Ahmadzadeh A. et al. 2015. International Journal of Molecular and Cellular Medicine. 4: 152-9. PubMed ID: 26629483

10. Oliveira L.M. et al. 2001. The Journal of Clinical Endocrinology and Metabolism. 86: 1532-8. PubMed ID: 11297579

11. 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

Contact Information
Genetics Laboratory
University of Oklahoma Health Sciences Center
1122 NE 13 Street, Suite 1400, Oklahoma City, OK 73104
Phone: (405) 271-3589 |Fax: (405) 271-7117 Email: Dr. Shibo Li

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