The use of whole-exome sequencing to disentangle complex phenotypes

Hj, Williams; Hurst, John R.; Ocaka, Louise; James, Chela; Pao, C.; Chanudet, Estelle; Lescai, Francesco; Stanescu, Horia; Kleta, Robert; GOSgene,; Rosser, Elisabeth; Bacchelli, Chiara; Beales, Philip L.

doi:10.1038/ejhg.2015.121

Cited by 16 publications

(16 citation statements)

References 15 publications

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“…8 The gene belongs to a family of purinoreceptors for ATP, which function as ligand-gated ion-channels, and seem to have a role in the ATP-induced glutamate transmission in the hippocampus. 48 …”

Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder

Lescai

Als

et al. 2017

Transl Psychiatry

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Bipolar disorder affects about 1% of the world's population, and its estimated heritability is about 75%. Only few whole genome or whole-exome sequencing studies in bipolar disorder have been reported, and no rare coding variants have yet been robustly identified. The use of isolated populations might help finding variants with a recent origin, more likely to have drifted to higher frequency by chance. Following this approach, we investigated 28 bipolar cases and 214 controls from the Faroe Islands by whole exome sequencing, and the results were followed-up in a British sample of 2025 cases and 1358 controls. Seventeen variants in 16 genes in the single-variant analysis, and 3 genes in the gene-based statistics surpassed exome-wide significance in the discovery phase. The discovery findings were supported by enrichment analysis of common variants from genome-wide association studies (GWAS) data and interrogation of protein–protein interaction networks. The replication in the British sample confirmed the association with NOS1 (missense variant rs79487279) and NCL (gene-based test). A number of variants from the discovery set were not present in the replication sample, including a novel PITPNM2 missense variant, which is located in a highly significant schizophrenia GWAS locus. Likewise, PIK3C2A identified in the gene-based analysis is located in a combined bipolar and schizophrenia GWAS locus. Our results show support both for existing findings in the literature, as well as for new risk genes, and identify rare variants that might provide additional information on the underlying biology of bipolar disorder.

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Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder

Lescai

Als

et al. 2017

Transl Psychiatry

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“…Recently, complex disorders have been deciphered by using WES. 19 In the present study, we describe the clinical phenotype of two families with AD-FMD showing incomplete penetrance and variable expressivity. We also report two missense variants in the DPT and SEMA3D genes in FMD, suggesting genetic heterogeneity.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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“…WES continues to be an efficient tool to determine disease-causing variants (Williams et al 2016; Adams & Eng 2018; Suwinski et al 2019), although the monogenic hypothesis in FMD should be reconsidered to achieve results beyond private rare variants for singular families. Thus, the “one variant-one disease” hypothesis, described for classic Mendelian inheritance cannot explain the incomplete penetrance or variable expressivity observed in MD (Martín-Sierra et al 2017) and more complex inheritance models are needed (Cooper et al 2013; Kousi & Katsanis 2015).…”

Section: Introductionmentioning

confidence: 99%

Rare Variants in theOTOGGene Are a Frequent Cause of Familial Meniere’s Disease

Roman‐Naranjo

Gallego‐Martinez

Soto-Varela

et al. 2019

Preprint

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1Objectives: Meniere's disease (MD) is a rare inner ear disorder characterized by 3 2 sensorineural hearing loss, episodic vertigo and tinnitus. Familial MD has been reported 3 3 in 6-9% of sporadic cases, and few genes including FAM136A, DTNA, PRKCB, 3 4 SEMA3D and DPT have been involved in single families, suggesting genetic 3 5 heterogeneity. In this study, the authors recruited 46 families with MD to search for 3 6 relevant candidate genes for hearing loss in familial MD. 3 7 Design: Exome sequencing data from MD patients were analyzed to search for rare 3 8 variants in hearing loss genes in a case-control study. A total of 109 patients with MD 3 9 (73 familial cases and 36 early-onset sporadic patients) diagnosed according to the 4 0 diagnostic criteria defined by the Barany Society were recruited in 11 hospitals. The 4 1 allelic frequencies of rare variants in hearing loss genes were calculated in individuals 4 2 with familial MD. A single rare variant analysis (SRVA) and a gene burden analysis 4 3 (GBA) were conducted in the dataset selecting one patient from each family. Allelic 4 4frequencies from European and Spanish reference datasets were used as controls. 4 5 Results: A total of 5136 single nucleotide variants in hearing loss genes were 4 6 considered for SRVA in familial MD cases, but only one heterozygous variant in the 4 7 OTOG gene (rs552304627) was found in two unrelated families. The GBA found an 4 8 enrichment of rare missense variants in the OTOG gene in familial MD. So, 15/46 4 9 * This novel variant was not included in the gene burden analysis. Abbreviations: MAF FMD, minor allele frequency in familial MD; MAF ALL MD, minor allele frequency in all familial and non-familial MD cases ; NFE, Minor allele frequency in non-Finnish European population; CSVS, Collaborative Spanish Variant Server; Abf, alpha-L-arabinofuranosidase B domain; CADD, Combined Annotation Dependent Depletion Score; CT: cysteine knot domain; vWD, von Willebrand factor type D domain.

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The use of whole-exome sequencing to disentangle complex phenotypes

Cited by 16 publications

References 15 publications

Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder

Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder

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

Rare Variants in theOTOGGene Are a Frequent Cause of Familial Meniere’s Disease

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