Discovery of Novel Variants on the CHD7 Gene: A Case Series of CHARGE Syndrome

Abstract

Background: CHARGE syndrome (CS) is a single-gene genetic disorder with multiple organ malformations caused by a variant of the chromodomain helicase DNA-binding protein 7 (CHD7) gene on chromosome 8q12.1. In this study, we aimed to investigate new variants that have emerged in these cases compared with typical CS and the relationship between the genes and phenotypes.Methods: Patients with suspected genetic diseases were subjected to Whole Exome Sequencing (WES) at a genetics laboratory in Guangzhou. The average sequencing coverage depth was >200 ×, and 96% was >20 ×. The variant interpretation was manipulated according to the American College of Medical Genetics (ACMG) guidelines. Molecular data on databases for ClinVar and CHD7 were also collected and collated. We reviewed the currently described CHD7 variants and analyzed the genetic variation and phenotypic heterogeneity.Results: Data of 12 patients with CS from four hospitals in China were collected. According to gestational age, most of them (8/12) were near-term babies with a lower birth weight than their peers, averaging 2.62 kg. In this study, the most common phenotypes were respiratory tract malformations (11/12), heart malformations (10/12), and central nervous system malformations (9/12). Two fetuses were confirmed to have brain or heart abnormalities during prenatal testing, while 10/12 were found to have abnormalities during prenatal testing. The maximum Acute Physiology and Chronic Health Evaluation (APACHE II) score at admission was 19, and the average was 11.58. Five variants in the CHD7 gene c.7012C > T (p.Q2338*), c.7868delC (p.P2623Rfs*16), c.5405-3C > G, c.6936 + 2T > C, and c.8077-2A > G) were novel and were located in exons 33, 36, and introns 25, 32, and 37, respectively. There may be a positive correlation between exon location and phenotype.Conclusion: Five novel variants were discovered. These expanded the mutational spectrum of the CHD7 gene and the phenotype of CS. There may be a correlation between the new mutation sites and the phenotype, which has some reference value for the evaluation of mutation sites.

Digenic CHD7 and SMCHD1 inheritance Unveils phenotypic variability in a family mainly presenting with hypogonadotropic hypogonadism

“…Of note, deleterious loss-of function CHD7 mutations interrupt the regulation of gene expression and result in disordered neural crest development [ 41 ]. CHD7 gene mutations are considered to be the genetic cause of over 90 % of patients with typical CHARGE syndrome [ [42] , [43] , [44] ]. Therefore, identifying each novel pathogenic mutation of CHD7 gene, expanding the mutational spectrum, and incorporating it into the database is beneficial for the diagnosis of CHARGE syndrome and estimating the prevalence of the disease [ 45 , 46 ].…”

Ocular manifestations of CHARGE syndrome in a pediatric cohort with genotype/phenotype analysis

“…Frameshift and nonsense variants in CHD7 are most commonly identified in CHARGE syndrome, accounting for more than 63% of reported variants between 2004 and 2015 (Alazami et al, 2008; Aramaki et al, 2006; Delahaye et al, 2007; Jongmans et al, 2006; Jyonouchi et al, 2009; Lalani et al, 2006; Legendre et al, 2017; McMain et al, 2008; Tellier et al, 1998; Wincent et al, 2009; Zentner et al, 2010). Similarly, the ClinVar and CHD7 gene databases (http://www.chd7.org) shows that 75% of the 1054 pathogenic and likely pathogenic variants are frameshift (44%) or nonsense (31%) (Wu et al, 2022). Our combined rate of 59% of frameshift (37%) and nonsense (22%) variants was lower than the previously published studies as well as the gene databases.…”

“…CHD7.org) shows that 75% of the 1054 pathogenic and likely pathogenic variants are frameshift (44%) or nonsense (31%) (Wu et al, 2022).…”

Naturally occurring genetic diseases caused by de novo variants in domestic animals

“…The CHD7 gene encodes an ATP‐dependent chromodomain helicase DNA‐binding (CHD) protein that plays a significant role in cell proliferation and neuronal differentiation (Cardoso et al., 2021). In humans, many disease‐associated variants have been discovered in this gene associated with CHARGE syndrome and most of them arose de novo (van Ravenswaaij‐Arts & Martin, 2017; Wu et al., 2022). In addition, other studies, also in humans, have shown that de novo variants in the CHD7 gene are associated with congenital heart disease, the most common type of congenital defect (Homsy et al., 2015; Ji et al., 2020; Patt et al., 2023; Sevim et al., 2020).…”