A novel CHD7 variant disrupting acceptor splice site in a patient with mild features of CHARGE syndrome: a case report.
BMC Med Genet
; 20(1): 127, 2019 07 17.
Article
em En
| MEDLINE
| ID: mdl-31315586
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
DNA Helicases
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Predisposição Genética para Doença
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Sítios de Splice de RNA
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Proteínas de Ligação a DNA
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Síndrome CHARGE
Tipo de estudo:
Prognostic_studies
Limite:
Adolescent
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Female
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Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article