A novel cardiomyopathy phenotype linked to a CHD7 missense variant
Abstract Loss of function in the chromatin remodeler CHD7 causes CHARGE syndrome, characterized by variable penetrance and diverse abnormalities. However, establishing genotype-phenotype correlations has been challenging, as most CHD7 inactivating mutations are null alleles. Through CHD7 missense va...
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Nature Portfolio
2025-06-01
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| author | In Young Park Chih-Wei Hsu Karim Bouazoune Christina E. Espindola Madeline Hannah McLaughlin Armond Cristian Coarfa Sandra L. Grimm James F. Martin Donna M. Martin Cheryl Lyn Walker |
| author_facet | In Young Park Chih-Wei Hsu Karim Bouazoune Christina E. Espindola Madeline Hannah McLaughlin Armond Cristian Coarfa Sandra L. Grimm James F. Martin Donna M. Martin Cheryl Lyn Walker |
| author_sort | In Young Park |
| collection | DOAJ |
| description | Abstract Loss of function in the chromatin remodeler CHD7 causes CHARGE syndrome, characterized by variable penetrance and diverse abnormalities. However, establishing genotype-phenotype correlations has been challenging, as most CHD7 inactivating mutations are null alleles. Through CHD7 missense variant analysis at potential phosphorylation sites, we identified T730 (T720 in mice) as a critical residue associated with pathogenesis. Using a CHD7 T730 missense variant (Chd7 T720A) and a frameshift null allele (Chd7 fs) in a mouse model, we found that Chd7 fs/fs mice were non-viable, while Chd7 fs/+ mice exhibited haploinsufficiency-related circling behavior. Notably, Chd7 fs/T720A mice died before postnatal day 2, indicating the Chd7 T720A allele is hypomorphic. Micro-CT analysis at E18.5 revealed that heterozygous mice primarily exhibited hypertrophic cardiomyopathy (HCM), while homozygous mice developed both HCM and dilated cardiomyopathy (DCM). RNA-seq analysis of neonatal Chd7 T720A/T720A hearts revealed a disrupted transcriptome, which in males and females was characterized by downregulation of mitochondrial energy metabolism genes and enrichment of ETS family transcription factor targets. We further identified GSK3β, GSK3α, HIPK1, and DYRK2 as candidate kinases for this site, suggesting a regulatory role in CHD7. This missense variant causing developmental heart abnormalities establishes the first genotype-phenotype correlation for CHD7, and offers new insights into CHARGE syndrome pathogenesis. |
| format | Article |
| id | doaj-art-cd98beec3cbf41c5b21f6ccaade7f822 |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-cd98beec3cbf41c5b21f6ccaade7f8222025-08-20T03:10:35ZengNature PortfolioScientific Reports2045-23222025-06-0115111610.1038/s41598-025-00606-1A novel cardiomyopathy phenotype linked to a CHD7 missense variantIn Young Park0Chih-Wei Hsu1Karim Bouazoune2Christina E. Espindola3Madeline Hannah McLaughlin Armond4Cristian Coarfa5Sandra L. Grimm6James F. Martin7Donna M. Martin8Cheryl Lyn Walker9Center for Precision Environmental Health, Baylor College of MedicineDepartment of Integrative Physiology, Baylor College of MedicineCenter for Precision Environmental Health, Baylor College of MedicineCenter for Precision Environmental Health, Baylor College of MedicineCenter for Precision Environmental Health, Baylor College of MedicineDepartment of Duncan Cancer Center-Biostatistics, Baylor College of MedicineDepartment of Duncan Cancer Center-Biostatistics, Baylor College of MedicineDepartment of Integrative Physiology, Baylor College of MedicineDepartment of Pediatrics, University of Michigan Medical SchoolCenter for Precision Environmental Health, Baylor College of MedicineAbstract Loss of function in the chromatin remodeler CHD7 causes CHARGE syndrome, characterized by variable penetrance and diverse abnormalities. However, establishing genotype-phenotype correlations has been challenging, as most CHD7 inactivating mutations are null alleles. Through CHD7 missense variant analysis at potential phosphorylation sites, we identified T730 (T720 in mice) as a critical residue associated with pathogenesis. Using a CHD7 T730 missense variant (Chd7 T720A) and a frameshift null allele (Chd7 fs) in a mouse model, we found that Chd7 fs/fs mice were non-viable, while Chd7 fs/+ mice exhibited haploinsufficiency-related circling behavior. Notably, Chd7 fs/T720A mice died before postnatal day 2, indicating the Chd7 T720A allele is hypomorphic. Micro-CT analysis at E18.5 revealed that heterozygous mice primarily exhibited hypertrophic cardiomyopathy (HCM), while homozygous mice developed both HCM and dilated cardiomyopathy (DCM). RNA-seq analysis of neonatal Chd7 T720A/T720A hearts revealed a disrupted transcriptome, which in males and females was characterized by downregulation of mitochondrial energy metabolism genes and enrichment of ETS family transcription factor targets. We further identified GSK3β, GSK3α, HIPK1, and DYRK2 as candidate kinases for this site, suggesting a regulatory role in CHD7. This missense variant causing developmental heart abnormalities establishes the first genotype-phenotype correlation for CHD7, and offers new insights into CHARGE syndrome pathogenesis.https://doi.org/10.1038/s41598-025-00606-1CHARGE syndromeCHD7T730 phosphorylationCardiomyopathyGSK3 |
| spellingShingle | In Young Park Chih-Wei Hsu Karim Bouazoune Christina E. Espindola Madeline Hannah McLaughlin Armond Cristian Coarfa Sandra L. Grimm James F. Martin Donna M. Martin Cheryl Lyn Walker A novel cardiomyopathy phenotype linked to a CHD7 missense variant Scientific Reports CHARGE syndrome CHD7 T730 phosphorylation Cardiomyopathy GSK3 |
| title | A novel cardiomyopathy phenotype linked to a CHD7 missense variant |
| title_full | A novel cardiomyopathy phenotype linked to a CHD7 missense variant |
| title_fullStr | A novel cardiomyopathy phenotype linked to a CHD7 missense variant |
| title_full_unstemmed | A novel cardiomyopathy phenotype linked to a CHD7 missense variant |
| title_short | A novel cardiomyopathy phenotype linked to a CHD7 missense variant |
| title_sort | novel cardiomyopathy phenotype linked to a chd7 missense variant |
| topic | CHARGE syndrome CHD7 T730 phosphorylation Cardiomyopathy GSK3 |
| url | https://doi.org/10.1038/s41598-025-00606-1 |
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