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

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 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 ). Electronic supplementary material The online version of this article (10.1186/s12881-019-0813-z) contains supplementary material, which is available to authorized users.

Phenotypic spectrum of typical CHARGE syndrome in a Chinese male neonate: a case report

“…Laryngomalacia and cranial nerve dysfunction are prevalent in patients with CHARGE syndrome and most of them need to be fed by tube at some time (15,16). Chen et al retrospectively analyzed 12 Chinese newborns with CHD7 pathogenic variants and found that feeding difficulty was a dominant clinical feature, which is consistent with the clinical manifestations of our patient (17). In summary, the identification of CHD7 resulted in broadening of the clinical phenotype spectrum of typical CHARGE syndrome in neonatal period.…”

Pervasive cortical and white matter anomalies in a mouse model for CHARGE syndrome

“…Abnormalities in white matter volume and defects in fibre tract integrity have been identified but not studied in CHARGE syndrome (Chen et al, 2019; Gregory et al, 2013; Shiohama et al, 2019). Our results suggest that a substantial proportion of the loss of brain volume identified both within this study and previously may be attributable to a loss of white matter, which was reduced to the same degree as grey matter in Chd7 gt/+ mice.…”

“…However, phenotypes in the central nervous systems of individuals with CHARGE syndrome have been noted. These include: Cranial nerve hypoplasia (Hoch et al, 2017; Lin et al, 1990; Shiohama et al, 2019), cerebellar hypoplasia (Hoch et al, 2017; Shiohama et al, 2019; Sohn et al, 2016; Yu et al, 2013), ventriculomegaly (Hoch et al, 2017), arhinencephaly/holoprosencephaly (Lin et al, 1990), white matter and corpus callosum deficits (Chen et al, 2019; Gregory et al, 2013; Shiohama et al, 2019), decreased basal ganglia volume (Shiohama et al, 2019) and frontal lobe hypoplasia (Gregory et al, 2013). For all the diversity of neuroanatomical phenotypes described, studies are continually emerging noting new observations in the central nervous system of individuals with CHARGE syndrome.…”

Generation and characterization of Chd7‐iCreERT2‐tdTomato mice

“…Indeed, one previous study reveal that the deletion of Chd7 in zebrafish significantly disrupted the normal development process of gut (Cloney et al, 2018). Importantly, gastrointestinal and feeding difficulty is one of leading clinical features of CHARGE syndrome children (Blake & Hudson, 2017; Chen et al, 2019). Thus, it is worth to do more mechanistic study in order to illuminate the function of Chd7 in the gut.…”

“…Indeed, one previous study reveal that the deletion of Chd7 in zebrafish significantly disrupted the normal development process of gut(Cloney et al, 2018). Importantly, gastrointestinal and feeding difficulty is one of leading clinical features of CHARGE syndrome children(Blake & Hudson, 2017;Chen et al, 2019). Thus, it is worth to do more mechanistic study in order to illuminate the function of Chd7 in the gut.In summary, the newly constructed Chd7-CT-tdT mouse line provides a new tool for understanding of the expression and function of CHD7 as well as the pathogenic mechanism of CHARGE syndrome.4 | MATERIALS AND METHODS4.1 | AnimalsAll animal experiments were conducted according to animal welfare regulations and have been approved by responsible authority in Children's Hospital of Fudan University.…”