A novel CHD7 variant disrupting acceptor splice site in a patient with mild features of CHARGE syndrome: a case report

Abstract

Background CHARGE syndrome (MIM# 214800)—which is characterised by a number of congenital anomalies including coloboma, ear anomalies, deafness, facial anomalies, heart defects, atresia choanae, genital hypoplasia, growth retardation, and developmental delay—is caused by a heterozygous variant in the CHD7 (MIM# 608892) gene located on chromosome 8q12. We report the identification of a novel c.5535-1G > A variant in CHD7 and provide the evaluation of its effect on pre-mRNA splicing. Case presentation In this study, we report on a female presenting features of CHARGE syndrome. A novel heterozygous CHD7 variant c.5535-1G > A located in the acceptor splice site of intron 26 was identified in the proband’s DNA sample after analysis of whole exome sequencing data. In silico predictions indicating that the variant is probably pathogenic by affecting pre-mRNA splicing were verified by genetic analysis based on reverse transcription of the patient’s RNA followed by PCR amplifications performed on synthesised cDNA and Sanger sequencing. Sanger sequencing of cDNA revealed that the c.5535-1G > A variant disrupts the original acceptor splice site and activates a cryptic splice site only one nucleotide downstream of the pathogenic variant site. This change causes the omission of the first nucleotide of exon 27, leading to a frameshift in the mRNA of the CHD7 gene. Our results suggest that the alteration induces the premature truncation of the CHD7 protein (UniProtKB: Q9P2D1), thus resulting in CHARGE syndrome. Conclusion Genetic analysis of novel splice site variant underlines its importance for studying the pathogenic splicing mechanism as well as for confirming a diagnosis. Electronic supplementary material The online version of this article (10.1186/s12881-019-0859-y) contains supplementary material, which is available to authorized users.

Clustering of Juvenile Canavan disease in an Indian community due to population bottleneck and isolation: genomic signatures of a founder event

“…This non-classical splicing defect due to an exonic mutation has been classi ed as type IV splicing defect [29]. Such examples have been reported previously [27,30,31]. This is in line with the reported literature that, a milder missense variant and another pathogenic LOF variant often leads to M/JCD.…”

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

“…As a member of the chromosomal domain helicase family, CHD7 is an ATP-dependent chromatin remodeling enzyme that regulates DNA accessibility in a tissue-specific manner. The CHD7 protein belongs to a member of CHD7 family which contains four major domains: two chromodomains, an SNF2 family N-terminal domain, a helicase ATP binding domain, and two BRK do-mains [ 37 ]. CHD7 has been shown to play a critical role in chromatin remodeling, apoptosis, cell cycle regulation, transcription, and embryonic stem cell differentiation [ 38 , 39 ].…”

De novo Splice Site Mutation of the <b><i>CHD7</i></b> Gene in a Chinese Patient with Typical CHARGE Syndrome

“…Including sensorineural hearing loss, CS is a rare autosomal dominant multisystem disorder that usually results from alterations in one allele of the CHD7 gene. As CS has a close resemblance to several other genetic disorders, genetic testing should be an important tool for patients with clinical suspicion [17]. CHD7 (OMIM: 608892) encodes CHD7 on chromosome 8q12, which is a kind of ATP-dependent chromatin remodeling enzyme.…”