Genetics: Diagnosis, Testing & Recurrence

Diagnosis

(also see Medical Professionals)

Who might have CHARGE? CHARGE syndrome should be considered in anyone with multiple anomalies who also has at least one of the major features (see Signs & Symptoms).

• Coloboma
• Choanal Atresia
• Typical CHARGE external ears: CHARGE Ears
• CHARGE vestibular phenotype (small or absent semicircular canals)

Diagnosis of CHARGE can be challenging because:

• Features overlap with many other syndromes (also see For Professionals>Medical Professionals>Diagnosis and Testing), especially 22q11.2 deletion syndrome, Kabuki syndrome and VACTERL association.
• Every feature of CHARGE can vary from severe to absent – no one feature is seen in every child with CHARGE
• Each affected individual has a unique set of features – no two children are alike
• CHD7 gene testing is not perfect
  10-20% of individuals with CHARGE do not have an identifiable pathogenic CHD7 variant
  Not every CHD7 variant causes CHARGE

Clinical Diagnosis

CHARGE is primarily a clinical diagnosis, based on having at least two major and several minor features (see Signs & Symptoms). CHD7 testing is recommended and extremely helpful, but the diagnosis is often certain even with negative DNA testing. The features that make up the name CHARGE are not used for diagnosis. For a summary of the clinical criteria most often used, see CHARGE Factsheet 3 Clinical Diagnosis and features. Clinical evaluation and testing by a medical geneticist (see www.abmgg.org) is recommended for all individuals with possible CHARGE syndrome.

Testing

In order to determine which signs and symptoms of CHARGE are present, many tests are helpful. Your geneticist is likely to order imaging (echocardiogram, kidney ultrasound, inner ear MRI) and lab testing (chromosomal microarray, CHD7 gene sequencing with deletion duplication testing, and perhaps whole exome sequencing, WES). The medical geneticist will take all of the information and make a determination about the likelihood of CHARGE syndrome as the best diagnosis for your child.

CHD7 testing is recommended in all individuals with CHARGE or possible CHARGE. Why?

• If the clinical diagnosis is not certain, identifying a CHD7 variant can confirm the diagnosis
• Knowing the CHD7 variant provides information for the affected child and the family
  Provides reproductive information and options
  Allows for testing other family members
  Parents, siblings and other family members can have targeted mutation analysis – testing only for the CHD7 variant identified in the person with CHARGE.
• If CHD7 testing is negative, that does not rule out CHARGE. Additional testing options should then be discussed with your geneticist.

CHD7 Frequently Asked Questions Document

Recurrence Risks

The chance of having a baby with CHARGE depends on the family situation and knowledge of CHD7 status. Always confirm the information relevant to your family with your medical geneticist or genetic counselor.

+ Most families have a 1/10,000 risk for another child with CHARGE.  A few have gonadal mosaicism (other sperm or eggs that carry the CHD7 variant) and a 50-50 risk.  Because it is not currently possible to distinguish between those groups, the best we can do is look empirically. Based on the experience of thousands of families, the recurrence risk is 1-2% on average.

* This is the chance of passing on the CHD7 variant.  It is not possible to predict which features an affected baby will have. Affected siblings often have quite different features.  Mildly affected parents have had more significantly involved children.

For more information about recurrence, prenatal testing, what to look for on ultrasound, and stories from parents about their family planning decisions, see the special Family Planning Issue of CHARGE Accounts.