Dataset Information

Whole-exome sequencing to identify a novel LMNA gene mutation associated with inherited cardiac conduction disease.

ABSTRACT:

Background

Inherited cardiac conduction diseases (CCD) are rare but are caused by mutations in a myriad of genes. Recently, whole-exome sequencing has successfully led to the identification of causal mutations for rare monogenic Mendelian diseases.

Objective

To investigate the genetic background of a family affected by inherited CCD.

Methods and results

We used whole-exome sequencing to study a Chinese family with multiple family members affected by CCD. Using the pedigree information, we proposed a heterozygous missense mutation (c.G695T, Gly232Val) in the lamin A/C (LMNA) gene as a candidate mutation for susceptibility to CCD in this family. The mutation is novel and is expected to affect the conformation of the coiled-coil rod domain of LMNA according to a structural model prediction. Its pathogenicity in lamina instability was further verified by expressing the mutation in a cellular model.

Conclusions

Our results suggest that whole-exome sequencing is a feasible approach to identifying the candidate genes underlying inherited conduction diseases.

SUBMITTER: Lai CC

PROVIDER: S-EPMC3861486 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Whole-exome sequencing to identify a novel LMNA gene mutation associated with inherited cardiac conduction disease.

Lai Chun-Chi CC Yeh Yung-Hsin YH Hsieh Wen-Ping WP Kuo Chi-Tai CT Wang Wen-Ching WC Chu Chia-Han CH Hung Chiu-Lien CL Cheng Chia-Yang CY Tsai Hsin-Yi HY Lee Jia-Lin JL Tang Chuan-Yi CY Hsu Lung-An LA

PloS one 20131212 12

<h4>Background</h4>Inherited cardiac conduction diseases (CCD) are rare but are caused by mutations in a myriad of genes. Recently, whole-exome sequencing has successfully led to the identification of causal mutations for rare monogenic Mendelian diseases.<h4>Objective</h4>To investigate the genetic background of a family affected by inherited CCD.<h4>Methods and results</h4>We used whole-exome sequencing to study a Chinese family with multiple family members affected by CCD. Using the pedigree ...[more]

PMID: 24349489

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Project description:Inherited peripheral neuropathies (IPNs) are a group of related diseases primarily affecting the peripheral motor and sensory neurons. They include the hereditary sensory neuropathies (HSN), hereditary motor neuropathies (HMN), and Charcot-Marie-Tooth disease (CMT). Using whole-exome sequencing (WES) to achieve a genetic diagnosis is particularly suited to IPNs, where over 80 genes are involved with weak genotype-phenotype correlations beyond the most common genes. We performed WES for 110 index patients with IPN where the genetic cause was undetermined after previous screening for mutations in common genes selected by phenotype and mode of inheritance. We identified 41 missense sequence variants in the known IPN genes in our cohort of 110 index patients. Nine variants (8%), identified in the genes MFN2, GJB1, BSCL2, and SETX, are previously reported mutations and considered to be pathogenic in these families. Twelve novel variants (11%) in the genes NEFL, TRPV4, KIF1B, BICD2, and SETX are implicated in the disease but require further evidence of pathogenicity. The remaining 20 variants were confirmed as polymorphisms (not causing the disease) and are detailed here to help interpret sequence variants identified in other family studies. Validation using segregation, normal controls, and bioinformatics tools was valuable as supporting evidence for sequence variants implicated in disease. In addition, we identified one SETX sequence variant (c.7640T>C), previously reported as a putative mutation, which we have confirmed as a nonpathogenic rare polymorphism. This study highlights the advantage of using WES for genetic diagnosis in highly heterogeneous diseases such as IPNs and has been particularly powerful in this cohort where genetic diagnosis could not be achieved due to phenotype and mode of inheritance not being previously obvious. However, first tier testing for common genes in clinically well-defined cases remains important and will account for most positive results.

Dataset Information

Whole-exome sequencing to identify a novel LMNA gene mutation associated with inherited cardiac conduction disease.

Background

Objective

Methods and results

Conclusions

Publications

Whole-exome sequencing to identify a novel LMNA gene mutation associated with inherited cardiac conduction disease.

Similar Datasets

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