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CHD7
chromodomain helicase DNA binding protein 7
The CHD7 gene provides instructions for a protein involved in chromatin remodelling, crucial for foetal development and implicated in conditions like CHARGE syndrome and Kallmann syndrome. The CHD7 gene codes for the chromodomain helicase DNA binding protein 7, which plays a key role in regulating gene expression by modifying chromatin structure.
CHD7 is located on the long (q) arm of chromosome 8, at band 8q12.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The CHD7 gene encodes the chromodomain helicase DNA binding protein 7, a protein expressed widely in developmental tissues, including those of the eye, inner ear, and brain. This protein is essential for the proper development of various body systems. Alterations in the CHD7 gene can lead to a spectrum of conditions, such as CHARGE syndrome, which is characterised by distinct congenital anomalies affecting multiple organs, and Kallmann syndrome, which involves impaired sexual development and sense of smell.
Understanding the CHD7 gene's function and the impact of its variants is critical for genetic counselling and clinical management of individuals affected by these conditions.
What the gene does
The CHD7 protein is a significant component of chromatin remodelling complexes within the cell nucleus. Chromatin is the highly organised structure of DNA and proteins that condenses DNA to fit within the cell and regulates gene activity. As a chromatin remodeller, CHD7 helps to alter the packaging of DNA, which in turn influences whether genes are expressed or silenced. By adjusting how tightly DNA is packed, CHD7 can either promote or inhibit the transcription of specific genes.
This crucial function is observed in various developing tissues, notably in areas of the brain such as the olfactory bulb, which is vital for detecting odours. The protein's activity in these areas underscores its importance in organogenesis and neurological development. Dysregulation of CHD7 through genetic variants can therefore impact the expression of numerous downstream genes, contributing to the complex phenotypes observed in associated genetic conditions.
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Chromosome location
The CHD7 gene is located on chromosome 8 at position 8q12.2. This specific locus indicates its placement on the long (q) arm of chromosome 8, within region 12, band 2. The precise genomic location helps in identifying and characterising genetic changes within the gene.
Protein structure
The CHD7 protein is substantial, comprising 2997 amino acids, and features several distinct domains critical for its function. Among these are regions designated as Disordered (Region), found at amino acids 86-144, 160-186, 199-287, 375-419, 498-816, 938-959, 1576-1600, 1837-1863, and 2170-2290, suggesting flexible segments. Key functional domains include Chromo 1 (Domain) at 800-867 and Chromo 2 (Domain) at 882-947, which are typically involved in chromatin binding. A Helicase ATP-binding (Domain) is present from 980-1154, alongside a DEAH box (Motif) found at 1105-1108, both vital for its ATPase activity and DNA unwinding functions. Further downstream, a Helicase C-terminal (Domain) is located at 1294-1464, and a Coiled coil (Coiled coil) motif extends from 2401-2431, which often facilitates protein-protein interactions.
Key variants
Variants within the CHD7 gene can be diverse, ranging from small deletions or insertions to single nucleotide changes. These genetic alterations can affect the protein's structure or function, leading to a spectrum of clinical manifestations. Pathogenic variants can cause a loss of function, resulting in insufficient or non-functional CHD7 protein. The impact of a specific variant often correlates with its position within the gene and its effect on critical protein domains, influencing the severity and specific features of associated conditions.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1061del | p.Pro354fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1090C>T | p.Gln364Ter | Pathogenic | ★★☆☆ | not provided |
c.1170T>G | p.Tyr390Ter | Pathogenic | ★★☆☆ | not provided |
c.1312C>T | p.Gln438Ter | Pathogenic | ★★☆☆ | CHARGE syndrome |
c.1369C>T | p.Gln457Ter | Pathogenic | ★★☆☆ | not provided |
c.1465C>T | p.Gln489Ter | Pathogenic | ★★☆☆ | not provided |
c.1480C>T | p.Arg494Ter | Pathogenic | ★★☆☆ | CHARGE syndrome |
c.1735C>T | p.Gln579Ter | Pathogenic/Likely pathogenic | ★★☆☆ | CHARGE syndrome |
c.1803_1806del | p.Lys602fs | Pathogenic | ★★☆☆ | not provided |
c.1808_1811del | p.Asn603fs | Pathogenic | ★★☆☆ | not provided |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the CHD7 gene are most notably associated with CHARGE syndrome, an acronym for a constellation of features including coloboma, heart defects, choanal atresia, growth retardation, genital abnormalities, and ear abnormalities. This gene is also implicated in Kallmann syndrome, which involves hypogonadotropic hypogonadism and an impaired sense of smell. Beyond these, CHD7 variants may contribute to conditions such as anophthalmia/microphthalmia and isolated coloboma.
UK clinical status
The CHD7 gene is included in several clinical diagnostic panels within the NHS Genomic Medicine Service, reflecting its established role in various inherited conditions. It is part of panels for conditions such as CAKUT, Choanal atresia, Clefting, Deafness and congenital structural abnormalities, and Differences in sex development (R146). Further panels include Foetal anomalies (R21), Hypogonadotropic hypogonadism (R148), Intellectual disability (R29), Monogenic hearing loss (R67), Ocular coloboma, Pituitary hormone deficiency (R159), and several for kidney-related conditions, among others.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
For individuals with conditions linked to CHD7 variants, general healthy lifestyle practices are encouraged. Maintaining a balanced diet, engaging in regular physical activity, and avoiding exposure to environmental toxins are universally beneficial for overall well-being. Regular medical oversight and adherence to specific management plans tailored to the individual's condition are paramount. While lifestyle choices can support general health, they are not a substitute for clinical care or treatments for genetic conditions.
Supplement considerations
There is no conclusive scientific evidence to suggest that specific supplements can prevent or treat conditions associated with CHD7 gene variants. Individuals considering any supplements should consult with a healthcare professional, as some supplements may interact with medications or not be appropriate for all health conditions. Adherence to medical advice and prescribed treatments remains the cornerstone of managing genetic conditions.
Frequently asked questions
What is the primary function of the CHD7 gene?
The CHD7 gene provides instructions for making a protein that plays a key role in chromatin remodelling. This process regulates gene expression by altering how DNA is packaged, influencing various developmental processes throughout the body.
Which conditions are most commonly associated with CHD7 variants?
CHD7 variants are most commonly associated with CHARGE syndrome, a complex disorder characterised by multiple congenital anomalies. They are also linked to Kallmann syndrome, which involves impaired sexual development and smell.
Where is the CHD7 gene located in the human genome?
The CHD7 gene is located on the long arm of chromosome 8, specifically at position 8q12.2. This location helps scientists and clinicians identify and study genetic changes within the gene.
Can lifestyle or diet influence CHARGE syndrome?
While a healthy lifestyle, including a balanced diet and regular activity, is beneficial for general health, there is no evidence that it can prevent or treat CHARGE syndrome. Management of the condition relies on medical interventions and supportive care.
Why is the CHD7 gene included in so many NHS diagnostic panels?
The CHD7 gene's inclusion in numerous NHS diagnostic panels, such as those for congenital anomalies, intellectual disability, and hearing loss, reflects its critical role in a wide range of developmental processes and its association with several well-defined clinical conditions.
References
- Schulz Y, Wehner P, Opitz L. CHD7, the gene mutated in CHARGE syndrome, regulates genes involved in neural crest cell guidance. Human genetics. 2014. PMID: 24728844
- Marcos S, Sarfati J, Leroy C. The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients. The Journal of clinical endocrinology and metabolism. 2014. PMID: 25077900
- Balasubramanian R, Choi JH, Francescatto L. Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency. Proceedings of the National Academy of Sciences of the United States of America. 2014. PMID: 25472840
- Bergman JE, de Ronde W, Jongmans MC. The results of CHD7 analysis in clinically well-characterized patients with Kallmann syndrome. The Journal of clinical endocrinology and metabolism. 2012. PMID: 22399515
- Bouazoune K, Kingston RE. Chromatin remodeling by the CHD7 protein is impaired by mutations that cause human developmental disorders. Proceedings of the National Academy of Sciences of the United States of America. 2012. PMID: 23134727
- Bergman JE, Janssen N, Hoefsloot LH. CHD7 mutations and CHARGE syndrome: the clinical implications of an expanding phenotype. Journal of medical genetics. 2011. PMID: 21378379
- Jongmans MC, van Ravenswaaij-Arts CM, Pitteloud N. CHD7 mutations in patients initially diagnosed with Kallmann syndrome--the clinical overlap with CHARGE syndrome. Clinical genetics. 2009. PMID: 19021638
- Kim HG, Kurth I, Lan F. Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. American journal of human genetics. 2008. PMID: 18834967
- Lalani SR, Safiullah AM, Fernbach SD. Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation. American journal of human genetics. 2006. PMID: 16400610
- Vissers LE, van Ravenswaaij CM, Admiraal R. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nature genetics. 2004. PMID: 15300250
- Adam MP, Bick S, Mirzaa GM. CHD7 Disorder. 1993. PMID: 20301296
- Adam MP, Bick S, Mirzaa GM. Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency. 1993. PMID: 20301509