CHARGE syndrome is a complex genetic syndrome with pattern of birth defects that are often life threatening. CHARGE is an acronym representing the major characteristics common to the disorder: coloboma, heart defects, choanal atresia, growth retardation, genital abnormalities, and ear abnormalities. Less common (minor) characteristics include kidney abnormalities; immune system problems; scoliosis or kyphosis; and limb abnormalities such as polydactyly or oligodactyly, clubfoot, and abnormalities of the long bones of the arms and legs. Affected individuals usually have more than one major characteristic or a combination of major and minor characteristics.
A clinical diagnosis of CHARGE syndrome is established or suspected based on the presence of at least two major and several minor characteristics. Due to clinical variability among patients, CHD7 testing is recommended to aid in diagnosis; however, a negative result does not exclude the diagnosis of CHARGE syndrome. The characteristics of this syndrome overlap with other disorders, including 22q11.2 deletion syndrome, Kabuki syndrome, and VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities).
CHARGE is an acronym for the major features of the condition:
- Heart defects
- Choanal atresia
- Restricted growth and delayed development
- Genital abnormalities
- Ear anomalies
Diagnosis is based primarily on clinical findings and temporal bone imaging.
Clinical criteria for CHARGE syndrome are four major characteristics, or three major and three minor characteristics.
Clinical criteria for possible/probable CHARGE syndrome are two major and several minor characteristics.
|Major Characteristics||Minor Characteristics|
- Usually de novo
- Rare parent-to-child transmission has been reported
100%; severity of the condition is highly variable
- Most variants are sequence variants
- Partial or full deletions of CHD7 are rare
- Clinical sensitivity:
- Analytical sensitivity/specificity: >99%
- One copy of a pathogenic variant detected: confirms a diagnosis of CHARGE syndrome
- No pathogenic variant detected: likelihood of CHARGE syndrome is reduced, but not excluded
- Variant of uncertain clinical significance detected; unclear if variant is benign or disease causing
- Diagnostic errors can occur due to:
- Rare sequence variants or repeat element insertions
- Primer- or probe-site variants
- Not detected:
- Large deletions and duplications
- Deep intronic and regulatory region variants
Issekutz KA, Graham JM Jr, Prasad C, et al. An epidemiological analysis of CHARGE syndrome: preliminary results from a Canadian study. Am J Med Genet A. 2005;133A(3):309-317.PubMed
Zentner GE, Layman WS, Martin DM, et al. Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome. Am J Med Genet A. 2010;152A(3):674-686.PubMed
Bergman JE, Janssen N, Hoefsloot LH, et al. CHD7 mutations and CHARGE syndrome: the clinical implications of an expanding phenotype. J Med Genet. 2011;48(5):334-342.
Janssen N, Bergman JE, Swertz MA, et al. Mutation update on the CHD7 gene involved in CHARGE syndrome. Hum Mutat. 2012;33(8):1149-1160.