CHD7

The CHD7 gene, located on chromosome 8q12.2, encodes the chromodomain helicase DNA-binding protein 7, a key player in embryonic development and chromatin remodeling. 

Mutations in CHD7 are the primary cause of CHARGE syndrome, a condition marked by a range of developmental anomalies including defects in the inner ear, craniofacial structures, and heart. 

These mutations lead to varying phenotypic presentations, from mild to severe, affecting multiple systems such as the central nervous system, brain, and skeletal muscle. 

CHD7's role involves regulating transcription and ribosomal RNA biogenesis, interacting with enhancer elements, and cooperating with other proteins like SOX2 to activate neural crest transcriptional circuits. 

Insights from animal models, particularly mice, have provided valuable understanding of CHD7’s function and its crucial involvement in developmental processes, highlighting the gene's significance in health and disease.

What is the CHD7 Gene and Protein? [4., 5., 6., 7.]

The CHD7 gene and its protein product play crucial roles in embryonic development and chromatin remodeling. 

The CHD7 gene, located on chromosome 8q12.2, encodes the chromodomain helicase DNA-binding protein 7, which plays a crucial role in regulating transcription and ribosomal RNA (rRNA) biogenesis. 

Nucleosome remodeling is a key function of CHD7 in development, providing a molecular basis for understanding the impact of disease-causing mutations. [2.] 

Mutations in the CHD7 gene are associated with CHARGE syndrome, a condition characterized by developmental defects such as inner ear problems, craniofacial anomalies, and heart defects. 

These mutations result in a wide range of phenotypic presentations, from severe to mild. 

The gene is expressed in various tissues, including the central nervous system, brain, kidney, and skeletal muscle. 

CHD7 functions as a transcriptional regulator, binding to enhancer elements and cooperating with other proteins like SOX2 to activate neural crest transcriptional circuits. 

Animal models, particularly mice with CHD7 defects, exhibit features similar to those seen in human CHARGE syndrome, providing valuable insights into the gene's function and the disorder's pathophysiology.

Role in Chromatin Remodeling [8., 10.] 

CHD7 belongs to the chromodomain helicase DNA-binding (CHD) family of proteins, which are involved in chromatin remodeling. 

As a chromatin remodeler, CHD7 utilizes ATP to alter the structure and positioning of nucleosomes, thereby regulating gene expression. This process is critical for maintaining proper cellular function and differentiation. 

CHD7 specifically interacts with enhancer regions of genes, influencing their activation or repression. By modulating chromatin accessibility, 

CHD7 plays a pivotal role in orchestrating complex gene expression programs during development.

Importance in Embryonic Development [1., 8., 10.]

During embryonic development, CHD7 is expressed in various tissues and organs, including the neural crest, brain, heart, and sensory organs. Its activity is particularly crucial during the formation of these structures. 

CHD7 regulates the expression of key developmental genes, influencing cell fate decisions and tissue patterning. Mutations in CHD7 can lead to widespread developmental abnormalities, as seen in CHARGE syndrome. 

CHD7 in Health and Disease

CHARGE Syndrome [1., 3., 8., 9., 10.] 

CHARGE syndrome is a rare congenital condition characterized by multiple organ anomalies and health issues. The acronym CHARGE stands for Coloboma, Heart defects, Atresia choanae (choanal atresia), Restricted growth and development, Genital abnormalities, and Ear abnormalities. 

These features are the major characteristics, though symptoms and severity can vary widely among individuals.

The syndrome is primarily caused by mutations in the CHD7 gene, which occur in more than half of the cases. These mutations are typically new genetic changes rather than inherited ones. 

CHARGE syndrome occurs in approximately 0.1-1.2 per 10,000 live births and is a leading cause of congenital deafblindness in the United States. [MALACARDS>>>>>>>>>>

Diagnosis relies on identifying a combination of major and minor characteristics:

Major characteristics include:

• Coloboma, affecting one or both eyes and impairing vision.

• Choanal atresia or stenosis, leading to breathing difficulties.

• Cranial nerve dysfunction, resulting in swallowing problems, facial paralysis, diminished or absent sense of smell, and hearing loss.

• Characteristic ear anomalies.

Minor characteristics include:

• Cleft lip and/or palate.

• Hypogonadotropic hypogonadism affecting sexual development.

• Tracheoesophageal fistula.

• Distinctive facial features such as facial asymmetry.

• Cognitive functions ranging from normal intelligence to severe learning disabilities.

Less common features like kidney abnormalities, immune system problems, skeletal anomalies (scoliosis, kyphosis), and limb abnormalities.

CHARGE syndrome's pattern of malformations is distinct, making it a unique clinical entity despite the variability in symptoms and severity.

Key insights into CHD7 mutations:

• Neuronal and Glial Differentiation: Loss of CHD7 in embryonic stem cells results in decreased differentiation into neurons and glia, crucial for proper development of these cell types.

• Chromatin Accessibility and Gene Expression: CHD7 mutations alter chromatin accessibility and change neural-specific gene expression, promoting neural progenitor differentiation.

• Neurite Complexity: CHD7-deficient neurons exhibit reduced neurite length, complexity, and branching, underscoring its role in neuronal morphogenesis.

• RNA Polymerase II Activity: CHD7 may regulate RNA polymerase II during transcription, influencing gene expression.

CHD7 mutations disrupt normal chromatin remodeling, leading to significant developmental defects characteristic of CHARGE syndrome. Understanding CHD7's role in chromatin remodeling and its interaction with transcription factors is critical for comprehending the mechanisms underlying this syndrome.

Other Conditions Involving CHD7 Mutations

CHD7 mutations have been associated with some cases of Kallman syndrome and coloboma. [6.] 

Genetic Alterations in the CHD7 Gene

The gene for the CHD7 protein may contain alterations or mutations that cause increase or decrease of function of the CHD7 protein.  

Testing for genetic alterations in the form of SNPs is increasingly available and can shed light on an individual’s potential for health and disease.  

What is a SNP?

A SNP, or single nucleotide polymorphism, refers to a variation at a single position in a gene along its DNA sequence.  A gene encodes a protein, so an alteration in that gene programs the production of an altered protein.  

As a type of protein with great functionality in human health, alterations in genes for enzymes may confer a difference in function of that enzyme.  The function of that enzyme may be increased or decreased, depending on the altered protein produced.  

SNPs are the most common type of genetic variation in humans and can occur throughout the genome, influencing traits, susceptibility to diseases, and response to medications.

The completion of the Human Genome Project has significantly expanded opportunities for genetic testing by providing a comprehensive map of the human genome that facilitates the identification of genetic variations associated with various health conditions, including identifying SNPs that may cause alterations in protein structure and function.  

Genetic testing for SNPs enables the identification of alterations in genes, shedding light on their implications in health and disease susceptibility.

Specific SNPs Associated with Alterations in Function of the CHD7 Protein

More than 600 mutations of the CHD7 gene have been implicated in causing CHARGE syndrome. [6.] A few of the well-known mutations are discussed here. 

c.2701A>T (p.S834F) [2.] 

This is a missense mutation where serine is replaced by phenylalanine at position 834.

Impact: This mutation completely abolishes both ATPase and nucleosome remodeling activities of CHD7.

This mutation was identified in CHARGE syndrome patients, indicating a loss of CHD7 function, which contributes to the development of CHARGE syndrome.

c.2719A>T (p.K907T) [2.] 

This is a missense mutation where lysine is replaced by threonine at position 907.

It results in a significant reduction in ATPase activity (about 3.5-fold decrease) and reduced nucleosome remodeling capabilities.

This mutation was found in CHARGE syndrome patients and affects the functionality of CHD7, leading to CHARGE syndrome symptoms.

c.2750C>T (p.T917M) [2.] 

This is a missense mutation where threonine is replaced by methionine at position 917.

It causes a limited decrease in ATPase activity (about 1.5-fold decrease) and reduced nucleosome remodeling capabilities.

This mutation was reported in CHARGE syndrome patients, affecting CHD7 function and contributing to the syndrome.

Laboratory Testing for CHD7

Genetic testing for single nucleotide polymorphisms (SNPs) typically involves obtaining a sample of DNA which can be extracted from blood, saliva, or cheek swabs. 

The sample may be taken in a lab, in the case of a blood sample.  Alternatively, a saliva or cheek swab sample may be taken from the comfort of home.  

Test Preparation

Prior to undergoing genetic testing, it's important to consult with a healthcare provider or genetic counselor to understand the purpose, potential outcomes, and implications of the test.  This consultation may involve discussing medical history, family history, and any specific concerns or questions. 

Additionally, individuals may be advised to refrain from eating, drinking, or chewing gum for a short period before providing a sample to ensure the accuracy of the test results.  Following sample collection, the DNA is processed in a laboratory where it undergoes analysis to identify specific genetic variations or SNPs. 

Once the testing is complete, individuals will typically receive their results along with interpretation and recommendations from a healthcare professional. 

It's crucial to approach genetic testing with proper understanding and consideration of its implications for one's health and well-being.

Patient-Centric Approaches

A patient-centered approach to SNP genetic testing emphasizes individualized medicine, tailoring healthcare decisions and interventions based on an individual's unique genetic makeup.

When that is combined with the individual’s health status and health history, preferences, and values, a truly individualized plan for care is possible. 

By integrating SNP testing into clinical practice, healthcare providers can offer personalized risk assessment, disease prevention strategies, and treatment plans that optimize patient outcomes and well-being. 

Genetic testing empowers a deeper understanding of genetic factors contributing to disease susceptibility, drug response variability, and overall health, empowering patients to actively participate in their care decisions. 

Furthermore, individualized medicine recognizes the importance of considering socioeconomic, cultural, and environmental factors alongside genetic information to deliver holistic and culturally sensitive care that aligns with patients' goals and preferences. 

Through collaborative decision-making and shared decision-making processes, patients and providers can make informed choices about SNP testing, treatment options, and lifestyle modifications, promoting patient autonomy, engagement, and satisfaction in their healthcare journey.

Genetic Panels and Combinations

Integrating multiple biomarkers into panels or combinations enhances the predictive power and clinical utility of pharmacogenomic testing. Biomarker panels comprising a variety of transporter proteins and enzymes including drug metabolizing enzymes offer comprehensive insights into individual drug response variability and treatment outcomes. 

Combining genetic SNP testing associated with drug transport, metabolism, and pharmacodynamics enables personalized medicine approaches tailored to individual patient characteristics and genetic profiles.

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