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Published on: March 11, 2021
Feeding difficulty is the dominant feature in 12 Chinese newborns with CHD7 pathogenic variants
Xiang Chen1, Kai Yan1, Yanyan Gao2
1Departments of Neonatology, Children's Hospital of Fudan University, Shanghai, 201102, China.
Insights
CHARGE syndrome, caused by CHD7 gene variants, often presents with feeding difficulties in newborns. Early suspicion in infants with malformations is crucial for timely diagnosis and intervention.
Area of Science:
- Genetics and Genomics
- Pediatric Medicine
- Medical Diagnostics
Background:
- CHARGE syndrome is a complex genetic disorder with a wide range of congenital anomalies.
- The chromodomain helicase DNA-binding protein 7 (CHD7) gene is the primary genetic cause of CHARGE syndrome.
- The phenotypic spectrum of CHARGE syndrome in neonates is not fully understood.
Purpose of the Study:
- To investigate the phenotype spectrum of neonatal patients with suspected CHARGE syndrome.
- To identify pathogenic or likely pathogenic variants in the CHD7 gene in a neonatal cohort.
- To correlate genetic findings with clinical phenotypes and neuroimaging in neonates.
Main Methods:
- Utilized next-generation sequencing data from the Neonatal Birth Defects Cohort (NBDC).
- Performed bioinformatic and genetic analyses to assess variant pathogenicity.
- Collected clinical information, conducted Sanger sequencing, and analyzed cranial MRI data.
Main Results:
- Identified 12 unrelated patients with CHD7 variants; 8 met CHARGE syndrome diagnostic criteria.
- Feeding difficulty was the predominant feature in the neonatal cohort.
- Discovered six novel CHD7 variants and observed significant brain volume changes in MRI analyses.
Conclusions:
- CHARGE syndrome and CHD7 gene variants should be suspected in newborns presenting with feeding difficulties and malformations.
- This study expands the understanding of the CHARGE syndrome phenotype in neonates.
- Highlights the importance of genetic testing for CHD7 in suspected cases.
Background:
CHARGE syndrome is characterized by coloboma, heart defects, choanal atresia, growth retardation, genitourinary malformation and ear abnormalities. The chromodomain helicase DNA-binding protein 7 (CHD7) gene is the major cause of CHARGE syndrome and is inherited in an autosomal dominant manner. Currently, the phenotype spectrum of CHARGE syndrome in neonatal population remain elusive. We aimed to investigate the phenotype spectrum of neonatal patients suspected to have CHARGE syndrome with pathogenic or likely pathogenic variants in the CHD7 gene.
Methods:
We pooled next-generation sequencing data from the Neonatal Birth Defects Cohort (NBDC, ClinicalTrials.gov Identifier: NCT02551081) in Children's Hospital of Fudan University. The pathogenicity of novel variants was analyzed by bioinformatic and genetic analyses. Clinical information collection, Sanger sequencing and follow-up interviews were performed when possible. Cranial MRI of these patients was performed, the volumes of different regions of the brain were analyzed.
Results:
A total of 12 unrelated patients in our cohort were found with CHD7 variants. Eight patients received a firm clinical diagnosis of CHARGE syndrome (Bergmann criteria, Blake criteria, Verloes criteria and Hale criteria). Three patients did not match any diagnostic criteria, and no patients matched the Verloes criteria. Phenotype spectrum analysis found that feeding difficulty was the dominant feature among this neonatal cohort. Six novel variants in the CHD7 gene (Glu2408*, Lys651*, c.5607 + 1G > T, Leu373Val, Lys2005Asnfs*37 and Gln1991*) were identified, expanding the variant database of the CHD7 gene. Cranial MRI analysis revealed significant volume loss in cingulate gyrus, occipital lobe, and cerebellum and volume gain in the left medial and inferior temporal gyri anterior white matter parts.
Conclusions:
Based on a relatively unbiased neonatal cohort, we concluded that CHARGE syndrome and CHD7 gene variants should be suspected in newborns who have feeding difficulty, and one or more malformations.
Trial Registration:
Neonatal Birth Defects Cohort (NBDC, ClinicalTrials.gov identifier: NCT02551081 ).
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