CDH23

CDH23 (Cadherin 23) is a crucial protein involved in hearing and vision, playing a key role in the inner ear’s mechanotransduction process and retinal cell adhesion. 

Mutations in CDH23 are associated with Usher syndrome type 1D, nonsyndromic hearing loss (DFNB12), and may contribute to pituitary adenomas and age-related hearing loss, making genetic testing valuable for early diagnosis and management.

What is CDH23?

CDH23 (Cadherin 23) is a gene that encodes a protein involved in the development and function of the inner ear and the retina. In the ear, it is a critical component of the stereocilia in hair cells, which are essential for hearing and balance. 

CDH23 works in conjunction with other proteins, such as PCDH15, to form tip links that allow mechanotransduction—converting mechanical sound waves into electrical signals for the brain. 

This gene is also expressed in the retina. In the retina, CDH23 is thought to be involved in the proper adhesion of retinal cells, which is essential for normal retinal function. Mutations in CDH23 can lead to retinal degeneration.

The protein CDH23 is part of the cadherin superfamily, a group of cell adhesion molecules that help cells stick together. 

CDH23 Mutations

More than 60 mutations in CDH23 disrupt the production or function of cadherin 23. Mutations in CDH23 are linked to Usher syndrome type 1D (USH1D) and nonsyndromic deafness (DFNB12). Mutations have also been linked to some pituitary adenomas. 

Usher Syndrome Type 1D

Usher syndrome type 1D (USH1D) is a genetic disorder characterized by congenital profound hearing loss, vestibular dysfunction, and retinitis pigmentosa, which causes vision loss. These typically manifest in childhood.

Retinitis Pigmentosa is a group of inherited eye disorders that cause progressive degeneration of the retina, leading to vision loss. Early symptoms typically include difficulty seeing in low light and a gradual loss of peripheral vision, which can eventually lead to blindness.

Non-Syndromic Deafness (DFNB12)

DFNB12 is a type of nonsyndromic autosomal recessive deafness. This condition leads to congenital, profound sensorineural hearing loss without other associated symptoms like retinitis pigmentosa or vestibular dysfunction, which distinguishes it from other forms of deafness. 

DFNB12 hearing loss is often bilateral and progressive; it is usually present from birth (prelingual) and can range from mild to profound. 

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Pituitary Adenomas

Mutations in the CDH23 gene have been linked to both inherited and sporadic pituitary adenomas (PAs), which are common brain tumors. 

In a study, CDH23 mutations were found in 33% of families with multiple PA cases and 12% of people with sporadic (non-inherited) PAs. These mutations affect cell adhesion, which plays a role in PA development. 

Tumors in patients with CDH23 mutations were typically smaller and less likely to spread to nearby areas. This suggests that CDH23 mutations may increase the risk of developing PAs and could help guide diagnosis and treatment decisions.

Age-Related Hearing Loss (Presbycusis)

CDH23 mutations primarily cause hearing loss, with some variants linked to late-onset, moderate hearing loss resembling presbycusis.

Presbycusis is age-related hearing loss that typically affects both ears and is characterized by the gradual loss of the ability to hear high-frequency sounds. It is a common condition as people age and is related to changes in the inner ear, auditory nerve, or both. 

Presbycusis typically starts with difficulty hearing high-frequency sounds like speech, especially in noisy environments. As it progresses, it affects a broader range of frequencies, impairing sound localization and causing symptoms such as tinnitus and balance issues. This significantly impacts communication, social interactions, and safety.

Who Should Get CDH23 Genetic Testing?

Genetic testing for CDH23 mutations may be considered in the following cases:

Individuals with Congenital or Early-Onset Hearing Loss

Testing is recommended for individuals who experience hearing loss from birth or early childhood, especially if there is a family history of similar conditions.

Suspected Usher Syndrome

If hearing loss is accompanied by progressive vision loss, particularly in children or young adults, CDH23 testing should be part of the diagnostic workup for Usher syndrome type 1D.

Family Members of Known Carriers

If a family member is known to carry a CDH23 mutation, other relatives may undergo testing to assess their carrier status or risk of developing hearing loss.

Additionally, genetic counseling is essential before and after testing to ensure that patients and families understand the potential implications of the results.

What Do Specific CDH23 Mutations Mean?

Several mutations in the CDH23 gene can lead to different forms of hearing loss; for example, dozens of mutations have been linked to DFNB12, and at least 60 mutations in the CDH23 gene have been linked to Usher syndrome. 

A pathogenic mutation (disease-causing) is confirmed if two mutations—one inherited from each parent—are identified. This confirms a diagnosis of Usher syndrome type 1D or non-syndromic hearing loss. The severity of the symptoms can vary depending on the specific mutation present. Some mutations cause profound hearing loss at birth, while others may result in progressive hearing loss over time.

The individual is considered a carrier if only one pathogenic mutation is found. Carriers typically do not exhibit symptoms of the condition but may pass the mutation to their children, potentially affecting their offspring.

What Does a Negative CDH23 Test Mean?

A negative test result, where no pathogenic mutations are detected, does not rule out the possibility of Usher syndrome or genetic hearing loss like nonsyndromic hearing loss. There are other genes associated with these conditions, such as PCDH15, MYO7A, and several others that should be considered for further testing if clinical suspicion remains high.

It is important to understand that not all genetic causes of hearing loss are related to CDH23. Therefore, if a patient’s symptoms strongly suggest a genetic cause, but CDH23 testing is negative, additional genetic testing may be warranted to identify other potential mutations.

Test Procedure and Interpretation

The following section outlines the typical test procedure and interpretation for CDH23 genetic testing:

Testing Procedure

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for CDH23 genetic testing are considered to be without mutations that can alter the activity of the CDH23 proteins.

Clinical Implications of Positive CDH23 Mutations

The clinical implications of a positive CDH23 mutation test result will vary by individual, although CDH23 mutations in symptomatic patients signal an immediate need for further assessment and possibly treatment. 

Patients or practitioners with questions about the clinical implications of CDH23 mutations should seek further assessment with a genetic counselor or expert. 

Diagnostic Limitations

While CDH23 testing can provide valuable insights, it is important to interpret results carefully. The presence of CDH23 mutations should not be used in isolation for diagnosis. 

Clinicians must consider other biomarkers and clinical factors when making decisions about patient care. Additionally, sample handling and patient conditions can impact test results, so ensuring proper testing procedures is essential.