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

Xiang Chen,Guoqiang Chen,Lin Yang,Wenhao Zhou,Huijun Wang,Yanyan Gao,Kai Yan,Bingbing Wu,Qian Qin

doi:10.1186/s12881-019-0813-z

Abstract

BackgroundCHARGE 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.MethodsWe 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.ResultsA 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.ConclusionsBased 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 registrationNeonatal Birth Defects Cohort (NBDC, ClinicalTrials.gov identifier: NCT02551081).

Highlights

CHARGE syndrome is characterized by coloboma, heart defects, choanal atresia, growth retardation, genitourinary malformation and ear abnormalities
Bergmann et al reported that a large number of patients with a chromodomain helicase DNA-binding protein 7 (CHD7) variant do not fulfill the clinical criteria of CHARGE syndrome
Clinical diagnosis A total of 12 pathogenic/likely pathogenic variants in the CHD7 gene were identified by generation sequencing in 12 unrelated newborns

Summary

Introduction

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. 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. CHARGE syndrome ([MIM:214800]) is a rare disease with a prevalence between 1:15,000 and 1:17,000 This syndrome is mainly characterized by coloboma, heart defects, choanal atresia, growth retardation, genitourinary malformation and ear abnormalities [1]. We describe the phenotype spectrum of 12 neonatal patients carrying CHD7 variants This is the largest sample size with a focus on CHARGE syndrome in the Chinses Han population

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