Feeding difficulty is the dominant feature in 12 Chinese newborns with CHD7 pathogenic variants

Xiang Chen†,
Kai Yan†,
Yanyan Gao,
Huijun Wang,
Guoqiang Chen,
Bingbing Wu,
Qian QinEmail author,
Lin YangEmail author View ORCID ID profile and
Wenhao Zhou

†Contributed equally

BMC Medical Genetics201920:93

https://doi.org/10.1186/s12881-019-0813-z

Received: 27 December 2018
Accepted: 23 April 2019
Published: 30 May 2019

Open Peer Review reports

Abstract

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 CHD7gene. 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.