Can whole-exome sequencing data be used for linkage analysis?

Gazal, Steven; Gosset, Simon; Verdura, Edgard; Bergametti, Françoise; Guey, Stéphanie; Babron, Marie‐Claude; Tournier‐Lasserve, Elisabeth

doi:10.1038/ejhg.2015.143

Cited by 10 publications

(12 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Using real genetic data from three families as an example, Smith et al (35) showed that accurate genetic linkage mapping could be performed with WES SNVs. Gazal et al (36) performed a linkage study of two families with both simulated and real data. They reported similar performances for linkage analyses conducted with GWSA or WES (36).…”

Section: Discussionmentioning

confidence: 99%

“…Obtaining both WES and GWSA data in patients, kindreds, or populations is DNA-, resource-, and time-consuming. Two studies comparing WES and GWSA in linkage analyses based on real data from three families (35) or both simulated and real data from two families (36) showed that the two sets of genetic data defined linkage peaks (35) and excluded genomic regions (36) in a consistent manner. A recent study estimating homozygosity rates with both GWSA and WES data in patients born to consanguineous families provided recommendations for the detection of homozygous regions by WES (37).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Whole-exome sequencing to analyze population structure, parental inbreeding, and familial linkage

Belkadi

Pedergnana

Cobat

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Principal component analysis (PCA), homozygosity rate estimations, and linkage studies in humans are classically conducted through genome-wide single-nucleotide variant arrays (GWSA). We compared whole-exome sequencing (WES) and GWSA for this purpose. We analyzed 110 subjects originating from different regions of the world, including North Africa and the Middle East, which are poorly covered by public databases and have high consanguinity rates. We tested and applied a number of quality control (QC) filters. Compared with GWSA, we found that WES provided an accurate prediction of population substructure using variants with a minor allele frequency > 2% (correlation = 0.89 with the PCA coordinates obtained by GWSA). WES also yielded highly reliable estimates of homozygosity rates using runs of homozygosity with a 1,000-kb window (correlation = 0.94 with the estimates provided by GWSA). Finally, homozygosity mapping analyses in 15 families including a single offspring with high homozygosity rates showed that WES provided 51% less genome-wide linkage information than GWSA overall but 97% more information for the coding regions. At the genome-wide scale, 76.3% of linked regions were found by both GWSA and WES, 17.7% were found by GWSA only, and 6.0% were found by WES only. For coding regions, the corresponding percentages were 83.5%, 7.4%, and 9.1%, respectively. With appropriate QC filters, WES can be used for PCA and adjustment for population substructure, estimating homozygosity rates in individuals, and powerful linkage analyses, particularly in coding regions.exome sequencing | genotyping array | population structure | homozygosity mapping | linkage analysis W hole-exome sequencing (WES) has become the leading strategy for uncovering germ-line exome variants in humans. A number of gene-and variant-level methods have been proposed for the analysis of WES data to select candidate variants in rare Mendelian disorders and more common traits (1-13). These analyses benefit from the use of additional information, such as familial linkage, homozygosity rate, and ethnic background, which are commonly used in the study of inherited diseases (14-17). Genomewide single-nucleotide variant array (GWSAs) are the gold standard method for linkage analysis, because they provide maximal linkage information for the whole genome (18). GWSAs are also classically used to estimate homozygosity rate in patients, confirming or sometimes, revealing parental consanguinity through the inbreeding coefficient parameter F in particular (19,20). Population stratification can be an issue in the analysis of population-based genetic data, including WES, particularly for association studies (21-24). Population structures have been widely determined by GWSA (25, 26) in European (27), African (28, 29), Asian (30), Jewish (31), Mexican (32), and other populations (33). These analyses are mostly based on principal component analysis (PCA) (34), which can also be used to confirm or reveal the ethnicity of an individual patient (or his or her parents).U...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Whole-exome sequencing to analyze population structure, parental inbreeding, and familial linkage

Belkadi

Pedergnana

Cobat

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The analysis strategy to prioritize candidate variants scored them according to their effect on protein structure and phylogenetic conservation by using a seven-point scoring system (Pathogenic Variant or PAVAR 18 To improve the accuracy of the variant prioritization, we combined the previous results with other bioinformatics tools that include phenotype information such as Exomiser v.2, 21 and Variant Annotation Analysis and Search Tool (VAAST)+Phevor that prioritize the variants and the genes affected using a ranking system. 22,23 We used linkage information derived from the WES-common SNVs within each pedigree to reduce the list of candidate variants, according to the method described by Gazal et al 24 Validation by Sanger sequencing …”

Section: Bioinformatics Analysesmentioning

confidence: 99%

Variable expressivity and genetic heterogeneity involving DPT and SEMA3D genes in autosomal dominant familial Meniere’s disease

et al. 2016

View full text Add to dashboard Cite

Autosomal dominant (AD) familial Meniere's disease (FMD) is a rare disorder involving the inner ear defined by sensorineural hearing loss, tinnitus and episodic vertigo. Here, we have identified two novel and rare heterozygous variants in the SEMA3D and DPT genes segregating with the complete phenotype that have variable expressivity in two pedigrees with AD-FMD. A detailed characterization of the phenotype within each family illustrates the clinical heterogeneity in the onset and progression of the disease. We also showed the expression of both genes in the human cochlea and performed in silico analyses of these variants. Three-dimensional protein modelling showed changes in the structure of the protein indicating potential physical interactions. These results confirm a genetic heterogeneity in FMD with incomplete penetrance and variable expressivity.

show abstract

“…Twenty-seven SNVs had been previously annotated and three of them were novel variants. We also used LOD scores derived from WES-common SNVs to reduce the list of candidate variants, as previously described ( Gazal et al, 2016 ), and 10 candidate variants remained (Supplementary Tables S1 , S2 ). The selected candidate variant, a missense heterozygous variant in the coding regions of ELF2 [NM_201999.2], that segregated with the phenotype was validated by Sanger sequencing.…”

Section: Introductionmentioning

confidence: 99%

Clinical and Functional Characterization of a Missense ELF2 Variant in a CANVAS Family

et al. 2018

View full text Add to dashboard Cite

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a rare disorder with an unknown etiology. We present a British family with presumed autosomal dominant CANVAS with incomplete penetrance and variable expressivity. Exome sequencing identified a rare missense variant in the ELF2 gene at chr4:g.140058846 C > T, c.10G > A, p.A4T which segregated in all affected patients. By using transduced BE (2)-M17 cells, we found that the mutated ELF2 (mt-ELF2) gene increased ATXN2 and reduced ELOVL5 gene expression, the causal genes of type 2 and type 38 spinocerebellar ataxias. Both, western blot and confocal microscopy confirmed an increase of ataxin-2 in BE(2)-M17 cells transduced with lentivirus expressing mt-ELF2 (CEE-mt-ELF2), which was not observed in cells transduced with lentivirus expressing wt-ELF2 (CEE-wt-ELF2). Moreover, we observed a significant decrease in the number and size of lipid droplets in the CEE-mt-ELF2-transduced BE (2)-M17 cells, but not in the CEE-wt-ELF2-transduced BE (2)-M17. Furthermore, changes in the expression of ELOVL5 could be related with the reduction of lipid droplets in BE (2)-M17 cells. This work supports that ELF2 gene regulates the expression of ATXN2 and ELOVL5 genes, and defines new molecular links in the pathophysiology of cerebellar ataxias.

show abstract

Can whole-exome sequencing data be used for linkage analysis?

Cited by 10 publications

References 27 publications

Whole-exome sequencing to analyze population structure, parental inbreeding, and familial linkage

Whole-exome sequencing to analyze population structure, parental inbreeding, and familial linkage

Variable expressivity and genetic heterogeneity involving DPT and SEMA3D genes in autosomal dominant familial Meniere’s disease

Clinical and Functional Characterization of a Missense ELF2 Variant in a CANVAS Family

Contact Info

Product

Resources

About