Whole-Exome Sequencing of 2,000 Danish Individuals and the Role of Rare Coding Variants in Type 2 Diabetes

Lohmueller, Kirk E.; Sparsø, Thomas; Li, Qibin; Andersson, Ehm A.; Korneliussen, Thorfinn Sand; Albrechtsen, Anders; Banasik, Karina; Grarup, Niels; Hallgrímsdóttir, Ingileif B.; Kiil, Kristoffer; Kilpeläinen, Tuomas O.; Krarup, Nikolaj T.; Pers, Tune H.; Sánchez, Gastón; Hu, Youna; DeGiorgio, Michael; Jørgensen, Torben; Sandbæk, Annelli; Lauritzen, Torsten; Brunak, Søren; Kristiansen, Karsten; Li, Yingrui; Hansen, Torben; Wang, Jun; Nielsen, Rasmus; Pedersen, Oluf

doi:10.1016/j.ajhg.2013.11.005

Cited by 123 publications

(84 citation statements)

References 84 publications

(110 reference statements)

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“…For further comparison with psychiatric and non-psychiatric diseases, SNVs described in exome studies of schizophrenia [Need et al, 2012;Xu et al, 2012a, b;Timms et al, 2013;Fromer et al, 2014;Guipponi et al, 2014;McCarthy et al, 2014;Ambalavanan et al, 2015;Kranz et al, 2015] and type 2 diabetes (T2D; [Lohmueller et al, 2013;Estrada et al, 2014;Steinthorsdottir et al, 2014]) were also included in the analyses. A total of 154 SNVs in 136 proteins were retrieved from schizophrenia exome studies.…”

Section: Methods Datasetsmentioning

confidence: 99%

The contribution of protein intrinsic disorder to understand the role of genetic variants uncovered by autism spectrum disorders exome studies

Schuch

Paixão‐Côrtes

Friedrich

et al. 2016

American J of Med Genetics Pt B

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Several autism spectrum disorders (ASD) exome studies suggest that coding single nucleotide variants (SNVs) play an important role on ASD etiology. Usually, the pathogenic effect of missense mutations is estimated through predictors that lose accuracy for those SNVs placed in intrinsically disordered regions of protein. Here, we used bioinformatics tools to investigate the effect of mutations described in ASD published exome studies (549 mutations) in protein disorder, considering post-translational modification, PEST and Molecular Recognition Features (MoRFs) motifs. Schizophrenia and type 2 diabetes (T2D) datasets were created for comparison purposes. The frequency of mutations predicted as disordered was comparable among the three datasets (38.1% in ASD, 35.7% in schizophrenia, 46.4% in T2D). However, the frequency of SNVs predicted to lead a gain or loss of functional sites or change intrinsic disorder tendencies was higher in ASD and schizophrenia than T2D (46.9%, 36.4%, and 23.1%, respectively). The results obtained by SIFT and PolyPhen-2 indicated that 38.9% and 34.4% of the mutations predicted, respectively, as tolerated and benign showed functional alterations in disorder properties. Given the frequency of mutations placed in IDRs and their functional impact, this study suggests that alterations in intrinsic disorder properties might play a role in ASD and schizophrenia etiologies. They should be taken into consideration when researching the pathogenicity of mutations in neurodevelopmental and psychiatric diseases. Finally, mutations with functional alterations in disorder properties must be potential targets for in vitro and in vivo functional studies.

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Section: Methods Datasetsmentioning

confidence: 99%

The contribution of protein intrinsic disorder to understand the role of genetic variants uncovered by autism spectrum disorders exome studies

Schuch

Paixão‐Côrtes

Friedrich

et al. 2016

American J of Med Genetics Pt B

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“…The mutation was not found in the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) [17], where only one individual has been reported with a pathogenetic mutation (p.Arg8*) in the RAD51B gene out of 13,006 alleles. One germline RAD51B mutation (Trp359*) was found in 2 out of 3,930 Danish alleles [18].…”

Section: Resultsmentioning

confidence: 99%

Germline RAD51B truncating mutation in a family with cutaneous melanoma

et al. 2015

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Known melanoma predisposition genes only account for around 40% of high-density melanoma families. Other rare mutations are likely to play a role in melanoma predisposition. RAD51B plays an important role in DNA repair through homologous recombination, and inactivation of RAD51B has been implicated in tumorigenesis. Thus RAD51B is a good candidate melanoma susceptibility gene, and previously, a germline splicing mutation in RAD51B has been identified in a family with early-onset breast cancer. In order to find genetic variants associated with melanoma predisposition, whole-exome sequencing was carried out on blood samples from a three-case cutaneous melanoma family. We identified a novel germline RAD51B nonsense mutation, and we demonstrate reduced expression of RAD51B in melanoma cells indicating inactivation of RAD51B. This is only the second report of a germline truncating RAD51B mutation. While this case report is consistent with melanoma being part of the RAD51B cancer spectrum further population-based screening of large case-control sample series will be needed to definitively establish if this is the case.

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“…In the gnomAD database, Gln530* is present in 7 of 55 818 non‐Finnish European individuals, but absent from all other populations. The variant is also absent from SweGen, 2000 Danes, 1000 genomes Norway, and the Telemark database, which together contain 8000 alleles 15, 16, 23. This supports that the variant is associated with a significant increase in QTc and with an increased risk of cardiac events, although this risk is reported to be lower than for KCNQ1 missense variants 24…”

Section: Discussionmentioning

confidence: 99%

“…Additional databases of allele frequencies, such as gnomAD,14 SweGen,15 2000 Danes,16 and the in‐house Telemark database with ≈1000 exomes, were consulted when manually reviewing the variants that remained after filtering. Sequence variants that were synonymous (predicting no change in amino acids), intronic (outside splice sites), or in untranslated regions were discarded, unless they had previously been reported as pathogenic or likely pathogenic.…”

Section: Methodsmentioning

confidence: 99%

Genetic and Phenotypic Characterization of Community Hospital Patients With QT Prolongation

Gibbs

Thalamus

Tveten

et al. 2018

JAHA

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BackgroundCongenital long‐QT syndrome (LQTS) is a genetic disorder characterized by prolongation of the corrected QT interval (QTc) on an ECG. The aim of the present study was to estimate the prevalence of pathogenic and likely pathogenic sequence variants in patients who had at least 1 ECG with a QTc ≥500 ms.Methods and ResultsTelemark Hospital Trust is a community hospital within the Norwegian national health system, serving ≈173 000 inhabitants. We searched the ECG database at Telemark Hospital Trust, Norway, from January 2004 to December 2014, and identified 1531 patients with at least 1 ECG with a QTc ≥500 ms. At the time of inclusion in this study (2015), 766 patients were alive. A total of 733 patients were invited to participate, and 475 accepted. The 17 genes that have been reported to cause monogenic LQTS were sequenced among the patients. Pro‐QTc score was calculated for each patient. A molecular genetic cause of LQTS was detected in 31 (6.5%) of 475 patients. These patients had a lower pro‐QTc score than those without pathogenic or likely pathogenic variants (1.7±1.0 versus 2.8±1.6; P<0.001).ConclusionsCompared with the general population, hospitalized patients with a QTc ≥500 ms in at least 1 ECG recording had an increased likelihood for pathogenic and likely pathogenic variants in LQTS genes. We recommend increased awareness of the possibility of LQTS in patients with at least 1 ECG with a QTc ≥500 ms.

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Whole-Exome Sequencing of 2,000 Danish Individuals and the Role of Rare Coding Variants in Type 2 Diabetes

Cited by 123 publications

References 84 publications

The contribution of protein intrinsic disorder to understand the role of genetic variants uncovered by autism spectrum disorders exome studies

The contribution of protein intrinsic disorder to understand the role of genetic variants uncovered by autism spectrum disorders exome studies

Germline RAD51B truncating mutation in a family with cutaneous melanoma

Genetic and Phenotypic Characterization of Community Hospital Patients With QT Prolongation

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