Identification and bioinformatics analysis of a novel variant in the HERC2 gene in a patient with intellectual developmental disorder

Abstract

HERC2-associated neurodevelopmental-disorders(NDD) encompass a cluster of medical conditions that arise from genetic mutations occurring within the HERC2 gene. These disorders can manifest a spectrum of symptoms that impact the brain and nervous system, including delayed psychomotor development, severe mental retardation, seizures and autistic features. Whole-Exome-Sequencing(WES) was performed on a ten-year-old male patient referred to the genetic center for genetic analysis. Blood samples were collected from the proband, his parents, and his sister to extract DNA. PCR-Sanger-sequencing was utilized to validate the findings obtained from WES. In order to obtain a more thorough understanding of the impact of the mutation, an extensive analysis was conducted using bioinformatics tools. WES data analysis identified a homozygous single nucleotide change(C > T) at position c14215 located in exon ninety-two of the HERC2 gene (NC_000015.10(NM_004667.6):c.14215C > T). The absence of this mutation among our cohort composed of four hundred normal healthy adults from the same ethnic group, and its absence in any other population database, confirms the pathogenicity of the mutation. This study revealed that the substitution of arginine with a stop codon within the Hect domain caused a premature stop codon at position 4739(p.Arg4739Ter). This mutation significantly results in the production of a truncated HERC2 protein with an incomplete HECT domain. In the final stage of ubiquitin attachment, HECT E3 ubiquitin ligases play a catalytic role by creating a thiolester intermediate using their conserved catalytic cysteine (Cys4762). This intermediate is formed before ubiquitin is transferred to a substrate protein. The truncation of the HERC2 protein is expected to disrupt its ability to perform this function, which could potentially hinder important regulatory processes related to the development and maintenance of synapses. The identification of a novel pathogenic variant, NC_000015.10(NM_004667.6):c.14215C > T, located within the ninety-two exon of the HERC2 gene, is notable for its association with an autosomal recessive inheritance pattern in cases of Intellectual Developmental Disorder(IDD). In the end, this variant could potentially play a part in the underlying mechanisms leading to the onset of intellectual developmental disorder.

Keywords:

• HERC2 gene
• HECT domain
• NC_000015.10 (NM_004667.6):c.14215C > T
• novel variant

Acknowledgement

Authors would like to thank all the participants.

Authors’ contributions

AAS analyzed WES data and contributed in writing the manuscript. NJ designed primers, analyzed Sanger Sequencing, and contributed in writing the manuscript. MB performed clinical data analysis, wrote the manuscript and was a major contributor to designing the project. MKK contributed in designing the project and writing the manuscript. AAS and NJ have contributed equally to this work and shared the first authorship. All authors read and approved the final manuscript.

Consent to participate

Written informed consent was taken from all participants.

Disclosure statement

The authors declare that they have no competing interests.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the University of Tabriz (IR.TABRIZU.REC.1402.160).

Additional information

Funding

There was no funding for the project.