CHARGE syndrome is a complex genetic condition present from birth, characterized by a specific and non-random pattern of multiple congenital anomalies. It affects approximately one in every 8,000 to 10,000 newborns worldwide. The condition is non-progressive, meaning the underlying cause does not worsen over time, but the resulting physical and developmental challenges are lifelong.
The Primary Genetic Cause
The overwhelming majority of CHARGE syndrome cases are caused by a pathogenic variant in a single gene known as \(CHD7\). This gene is located on chromosome 8 and provides instructions for creating a protein called chromodomain helicase DNA binding protein 7. Genetic testing identifies a \(CHD7\) mutation in 80% to over 90% of individuals who meet the clinical criteria for CHARGE syndrome.
The \(CHD7\) gene encodes a large protein that functions as an ATP-dependent helicase. Pathogenic variants typically result in a loss-of-function, meaning the resulting protein is either non-functional or prematurely broken down by the cell.
The specific types of genetic changes commonly found directly interrupt the gene’s reading frame. These include nonsense mutations (premature stop signals) and frameshift mutations. The presence of a non-functional \(CHD7\) protein is the root cause of the developmental disruptions seen in the syndrome.
The Role of the CHD7 Gene
The \(CHD7\) protein is a member of the chromatin remodeling family of proteins, which are responsible for organizing and regulating DNA within the cell nucleus. This regulation is achieved by changing the structure of chromatin, the complex of DNA and protein that packages DNA into chromosomes. By remodeling chromatin, \(CHD7\) controls how tightly the DNA is coiled, thereby regulating the expression of numerous other genes.
This function is particularly important during the rapid and highly coordinated process of early embryonic development. The \(CHD7\) protein acts as a master regulator, ensuring that necessary developmental genes are turned on and off at the correct time and in the correct cells. A shortage of functional \(CHD7\) disrupts this precise timing and coordination, leading to the multiple defects observed across different organ systems.
One of the most significant roles of \(CHD7\) is its involvement with the development and migration of neural crest cells. These cells are a transient, multipotent cell population that migrates to form many structures, including parts of the craniofacial skeleton, the nervous system, and the heart. When \(CHD7\) is impaired, the guidance and development of these neural crest cells are disrupted, causing defects in organs derived from them.
The resulting \(CHD7\) malfunction explains the syndrome’s varied characteristics, which involve structures arising from the neural crest and ectoderm. Heart defects are common and linked to \(CHD7\)‘s role in regulating genes in the developing cardiac tissue. The protein is highly expressed in the precursors of the eye, inner ear, and cranial nerves, explaining the auditory, balance, and visual anomalies that are hallmarks of the condition.
Inheritance Patterns and Genetic Counseling
CHARGE syndrome is classified as an autosomal dominant disorder, meaning a pathogenic variant in only one copy of the \(CHD7\) gene is sufficient to cause the condition. The vast majority of cases are the result of a de novo mutation, a new genetic change that occurs for the first time in the affected individual.
For parents who have had one child with CHARGE syndrome and are unaffected themselves, the risk of recurrence in a future pregnancy is low, typically cited as 1% to 2%. This small risk is primarily attributed to the possibility of parental germline mosaicism. Germline mosaicism occurs when a parent has the \(CHD7\) mutation in a small proportion of their egg or sperm cells.
In the rare instances where an individual with CHARGE syndrome has a child, the autosomal dominant inheritance pattern applies. The affected parent has a 50% chance of passing the \(CHD7\) pathogenic variant on to their offspring. Genetic counseling provides families with specific risk assessments based on the family’s genetic testing results.
Confirming the Diagnosis
While the constellation of physical and developmental findings often suggests a diagnosis of CHARGE syndrome, confirmation requires molecular testing. Clinical criteria are used to identify individuals who should be tested, but definitive identification relies on genetic analysis. Testing for the \(CHD7\) gene is the standard procedure to confirm the diagnosis in a clinical setting.
Genetic sequencing of the \(CHD7\) gene looks for the specific pathogenic variants that cause the condition. This testing is highly effective and identifies a causative \(CHD7\) mutation in most individuals who meet the clinical diagnostic criteria. In a small percentage of cases, no \(CHD7\) mutation is found, suggesting other, rarer genetic or environmental factors may be responsible.