Dataset Information

Identification of a novel EXT2 frameshift mutation in a family with hereditary multiple exostoses by whole-exome sequencing.

ABSTRACT:

Background

Hereditary multiple exostoses (HME), also referred to as multiple osteochondromas, is an autosomal dominant skeletal disease characterized by the development of multiple overgrown benign bony tumors capped by cartilage and is associated with bone deformity, joint limitation, and short stature. Mutations in exostosin glycosyltransferase (EXT)1 and EXT2 genes, which are located on chromosomes 8q24.1 and 11p13, contribute to the pathogenesis of HME.

Methods

In the present study, a genetic analysis of a four-generation Chinese family with HME was conducted using whole-exome sequencing (WES), followed by validation using Sanger sequencing.

Results

A novel heterozygous frameshift mutation in exon 5 of EXT2 (c.944dupT, p.Leu316fs) was identified in all affected individuals but was not detected in any unaffected individuals. This mutation results in a frameshift that introduces a premature termination codon at position 318 (p.Leu316fs) with the ability to produce a truncated EXT2 protein that lacks the last 433 amino acids at its C-terminal to indicate a defective exostosin domain and the absence of the glycosyltransferase family 64 domain, or to lead to the degradation of mRNAs by nonsense-mediated mRNA decay, which is critical for the function of EXT2.

Conclusion

Our results indicate that WES is effective in extending the EXT mutational spectra and is advantageous for genetic counseling and the subsequent prenatal diagnosis.

SUBMITTER: Yang M

PROVIDER: S-EPMC8418499 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RationaleGenetic elucidation of cone-dominated retinal dystrophies in Indian subcontinent is much needed to identify and catalog underlying genetic defects. In this context, the present study recruited a consanguineous Indian family affected with autosomal recessive cone dystrophy (CD). Considering the huge genetic heterogeneity and recessive inheritance of the disease, we chose to dissect out causal variant in this family by whole exome sequencing (WES).Patient concernsIn the recruited family, three of the six siblings had complaints of poor visual acuity, photophobia, and disturbed colour vision since early childhood. Fundus examination disclosed vascular attenuation and macular retinal pigment epithelium (RPE) changes in all the affected siblings, signifying degeneration of photoreceptor cells.DiagnosisComplete clinical investigation and electroretinography studies led to the diagnosis of cone dystrophy in three siblings of the family.InterventionsDetailed ophthalmic examination, including family history, visual function testing, and retinal imaging, was performed. We captured and sequenced exomes of 2 affected siblings and their mother using SureSelect Human All Exon V5 Kit on Illumina HiSeq 2000/2500 platform with 100 bp paired-end sequencing method. Candidates after data analysis were screened by segregation analysis and Sanger sequencing. Considering recessive inheritance and consanguinity in the pedigree, we attempted to map large loci homozygous by descent in the genome of patients using exome sequencing variants. Extensive protein modeling was carried out to assess possible consequences of the identified variant on the 3-dimensional structure of the protein.OutcomesWES generated more than 65,000 variants for each individual. Assuming recessive inheritance, 13,026 variants were selected. Further filtering on the basis of their position in gene, class, and minor allele frequency constricted the huge list to 12 rare variants. Finally, we ascertained a single base deletion c.1148delC (p.Thr383fs) in the gene CNGB3 as the causal variant. This is a recurrent frameshift mutation resulting in truncated CNGB3 protein. We mapped a large 15-Mb stretch of homozygous markers spanning the causal variant in the proband. The gene CNGB3 encodes modulatory subunit of cyclic nucleotide-gated channels in cone photoreceptors. Protein modeling reveals loss of 2 transmembrane helices and conserved CAP_ED domain in truncated CNGB3, which eventually is predicted to form nonfunctional channels and hamper phototransduction.LessonsWe have identified a recurrent mutation c.1148delC (p.Thr383fs) in CNGB3 for autosomal recessive CD. The present report provides the first description of CNGB3 mutation from India. It is also the foremost investigation of familial CD in Indian patients; therefore, it presents the primary genetic etiology of CD in India.