scholarly journals A novel nonsense variant in SUPT20H gene associated with Rheumatoid Arthritis identified by Whole Exome Sequencing of multiplex families

2018 ◽  
Author(s):  
Maëva Veyssiere ◽  
Javier Perea ◽  
Laetitia Michou ◽  
Anne Boland ◽  
Christophe Caloustian ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
P Value ◽  
Macrophage Differentiation ◽  
Extended Pedigrees ◽  
Whole Exome ◽  
New Variant ◽  
Multiplex Families

AbstractThe triggering and development of Rheumatoid Arthritis (RA) is conditioned by environmental and genetic factors. Despite the identification of more than one hundred genetic variants associated with the disease, not all the cases can be explained. Here, we performed Whole Exome Sequencing in 9 multiplex families (N=30) to identify rare variants susceptible to play a role in the disease pathogenesis. We pre-selected 73 genes which carried rare variants with a complete segregation with RA in the studied families. Follow-up linkage and association analyses with pVAAST highlighted significant RA association of 24 genes (p-value < 0.05 after 106 permutations) and pinpointed their most likely causal variant. We re-sequenced the 10 most significant likely causal variants (p-value ≤ 0.019 after 106 permutations) in the extended pedigrees and 9 additional multiplex families (N=110). Only one SNV in SUPT20H, c.73T>A (p.Lys25*), presented a complete segregation with RA in an extended pedigree with early-onset cases. In summary, we identified in this study a new variant associated with RA in SUPT20H gene. This gene belongs to several biological pathways like macro-autophagy and monocyte/macrophage differentiation, which contribute to RA pathogenesis. In addition, these results showed that analyzing rare variants using a family-based approach is a strategy that allows to identify RA risk loci, even with a small dataset.Author summaryRheumatoid arthritis (RA) is one of the most frequent auto-immune disease in the world. It causes joint swellings and pains which can lead to mobility impairment. To date, the scientific community has identified a hundred genes carrying variants predisposing to RA, in addition to the major gene HLA-DRB1. However, they do not explain all cases of RA. By examining nine families with multiple RA cases, we identified a new rare nonsense variant in SUPT20H gene, c.73T>A (p.Lys25*). This finding is supported by the literature as the SUPT20H gene regulates several biological functions, such as macro-autophagy or monocyte/macrophage differentiation, that contribute to RA pathogenesis.

scholarly journals A novel nonsense variant in SUPT20H gene associated with Rheumatoid Arthritis identified by Whole Exome Sequencing of multiplex families

PLoS ONE ◽  
2019 ◽  
Vol 14 (3) ◽  
pp. e0213387 ◽  
Author(s):  
Maëva Veyssiere ◽  
Javier Perea ◽  
Laetitia Michou ◽  
Anne Boland ◽  
Christophe Caloustian ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Whole Exome ◽  
Multiplex Families

scholarly journals A Rare Novel CLCN2 Variation and Risk of Gilles de la Tourette Syndrome: Whole-Exome Sequencing in a Multiplex Family and a Follow-Up Study in a Chinese Population

2020 ◽  
Vol 11 ◽  
Author(s):  
Aihua Yuan ◽  
Zengge Wang ◽  
Wen Xu ◽  
Qiang Ding ◽  
Ying Zhao ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Tourette Syndrome ◽  
Rare Variants ◽  
Multiplex Family ◽  
Chinese Han ◽  
Genetic Etiology ◽  
Han Population ◽  
Whole Exome ◽  
Multiplex Families

Rare inherited variations in multiplex families with Gilles de la Tourette syndrome (GTS) are suggested to play an important role in the genetic etiology of GTS. In order to explore the rare inherited variations with the risk of GTS, whole-exome sequencing (WES) was performed in a family with three affected patients with GTS. Among the five novel rare variations identified by WES, CLCN2 G161S was presented in three patients, but not in four unaffected individuals, and thus co-segregated with GTS. A validation study was also performed in a cohort of Chinses Han population to further examine the identified rare variants. CLCN2 G161S was genotyped in 207 sporadic patients with tic disorder including 111 patients with GTS and 489 healthy controls. Compared with that in controls [allele frequency (AF) = 0], CLCN2 G161S had higher variant AF in patients with tic (AF = 0.00483) and in patients with GTS (0.00900), respectively. However, this variant was absent from the current 1000 Genome databases, and the variant AF is very low in the current public databases including ExAC (AF = 0.00001) and gnomAD (AF = 0.00003). Our results suggest that CLCN2 G161S might play a major role in the genetic etiology of GTS, at least in a Chinese Han population.

scholarly journals Whole Exome Sequencing of Distant Relatives in Multiplex Families Implicates Rare Variants in Candidate Genes for Oral Clefts

Genetics ◽  
2014 ◽  
Vol 197 (3) ◽  
pp. 1039-1044 ◽  
Author(s):  
Alexandre Bureau ◽  
Margaret M. Parker ◽  
Ingo Ruczinski ◽  
Margaret A. Taub ◽  
Mary L. Marazita ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Candidate Genes ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
Oral Clefts ◽  
Whole Exome ◽  
Multiplex Families

scholarly journals Exome sequencing in paediatric patients with movement disorders

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Anna Ka-Yee Kwong ◽  
Mandy Ho-Yin Tsang ◽  
Jasmine Lee-Fong Fung ◽  
Christopher Chun-Yu Mak ◽  
Kate Lok-San Chan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Movement Disorders ◽  
Rare Variants ◽  
Diagnostic Yield ◽  
Neurological Diseases ◽  
Genetic Diagnosis ◽  
Potential Treatment ◽  
Paediatric Patients ◽  
Whole Exome

Abstract Background Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. Results We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. Conclusions A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management. The study highlights the potential of implementing precision medicine in the patients.

scholarly journals Whole Exome Sequencing of HIV-1 long-term non-progressors identifies rare variants in genes encoding innate immune sensors and signaling molecules

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Sara Konstantin Nissen ◽  
Mette Christiansen ◽  
Marie Helleberg ◽  
Kathrine Kjær ◽  
Sofie Eg Jørgensen ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
Signaling Molecules ◽  
Innate Immune ◽  
Whole Exome ◽  
Genes Encoding ◽  
Hiv 1

scholarly journals Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract

2018 ◽  
Vol 29 (9) ◽  
pp. 2348-2361 ◽  
Author(s):  
Amelie T. van der Ven ◽  
Dervla M. Connaughton ◽  
Hadas Ityel ◽  
Nina Mann ◽  
Makiko Nakayama ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Congenital Anomalies ◽  
Causative Mutation ◽  
Deleterious Mutations ◽  
Whole Exome ◽  
Multiplex Families ◽  
High Fraction ◽  
Etiologic Diagnosis

BackgroundCongenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12% of patients with CAKUT.MethodsWe applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT.ResultsIn 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient’s CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%).ConclusionsWe identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.

Whole‐Exome Sequencing of a Saudi Epilepsy Cohort Reveals Association Signals in Known and Potentially Novel Loci

2021 ◽  
Author(s):  
Amein Kadhem AlAli ◽  
Abdulrahman Al-Enazi ◽  
Ahmed Ammar ◽  
Mahmoud Hajj ◽  
Cyril Cyrus ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
High Rate ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variants ◽  
Unknown Significance ◽  
Rare Genetic Variants

Abstract Background Epilepsy, a serious chronic neurological condition effecting up to 100 million people globally, has clear genetic underpinnings including common and rare variants. In Saudi Arabia the prevalence of epilepsy is high and caused mainly by perinatal and genetic factors. No whole-exome sequencing (WES) studies have been performed to date in Saudi Arabian Epilepsy cohorts. This offers a unique opportunity for the discovery of rare genetic variants impacting this disease as there is a high rate of consanguinity amongst large tribal pedigrees. Results We performed WES on 144 individuals diagnosed with epilepsy, to interrogate known Epilepsy related genes for known and functional novel variants. We also used an American College of Medical Genetics (ACMG) guideline based variant prioritization approach in an attempt to discover putative causative variants. We identified a 32 potentially causative pathogenic variants across 30 different genes in 44/144 (30%) of these Saudi Epilepsy individuals. We also identified 232 variants of unknown significance (VUS) across 101 different genes in 133/144 (92%) subjects. Strong enrichment of variants of likely pathogenicity were observed in previously described epilepsy-associated loci, and a number of putative pathogenic variants in novel loci are also observed. Conclusion Several putative pathogenic variants known to be epilepsy-related loci were identified for the first time in our population, in addition to several potential new loci have been identified which may be prioritized for further investigation.

P2-131: WHOLE-EXOME SEQUENCING OF HISPANIC EARLY-ONSET ALZHEIMER DISEASE FAMILIES IDENTIFIES RARE VARIANTS IN MULTIPLE ALZHEIMER'S-RELATED GENES

2014 ◽  
Vol 10 ◽  
pp. P518-P519
Author(s):  
Margaret Pericak-Vance ◽  
Christiane Reitz ◽  
Brian W. Kunkle ◽  
Badri N. Vardarajan ◽  
Martin A. Kohli ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Early Onset ◽  
Rare Variants ◽  
Whole Exome

scholarly journals Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease

2018 ◽  
Vol 5 (7) ◽  
pp. 832-842 ◽  
Author(s):  
Neha S. Raghavan ◽  
Adam M. Brickman ◽  
Howard Andrews ◽  
Jennifer J. Manly ◽  
Nicole Schupf ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
Whole Exome

scholarly journals Whole-exome sequencing reveals insights into genetic susceptibility to Congenital Zika Syndrome

2021 ◽  
Vol 15 (6) ◽  
pp. e0009507
Author(s):  
Victor Borda ◽  
Ronaldo da Silva Francisco Junior ◽  
Joseane B. Carvalho ◽  
Guilherme L. Morais ◽  
Átila Duque Rossi ◽  
...  
Keyword(s):  
Critical Illness ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Association Analysis ◽  
P Value ◽  
Single Nucleotide Variants ◽  
Zikv Infection ◽  
Whole Exome ◽  
Wide Range ◽  
Congenital Zika Syndrome

Congenital Zika Syndrome (CZS) is a critical illness with a wide range of severity caused by Zika virus (ZIKV) infection during pregnancy. Life-threatening neurodevelopmental dysfunctions are among the most common phenotypes observed in affected newborns. Risk factors that contribute to susceptibility and response to ZIKV infection may be related to the virus itself, the environment, and maternal genetic background. Nevertheless, the newborn’s genetic contribution to the critical illness is still not elucidated. Here, we aimed to identify possible genetic variants as well as relevant biological pathways that might be associated with CZS phenotypes. For this purpose, we performed a whole-exome sequencing in 40 children born to women with confirmed exposure to ZIKV during pregnancy. We investigated the occurrence of rare harmful single-nucleotide variants (SNVs) possibly associated with inborn errors in genes ontologically related to CZS phenotypes. Moreover, an exome-wide association analysis was also performed using a case-control design (29 CZS cases and 11 controls), for both common and rare variants. Five out of the 29 CZS patients harbored known pathogenic variants likely to contribute to mild to severe manifestations observed. Approximately, 30% of affected individuals carried at least one pathogenic or likely pathogenic SNV in genes candidates to play a role in CZS. Our common variant association analysis detected a suggestive protective effect of the rs2076469 in DISP3 gene (p-value: 1.39 x 10−5). The IL12RB2 gene (p-value: 2.18x10-11) also showed an unusual distribution of nonsynonymous rare SNVs in control samples. Finally, genes harboring harmful variants are involved in processes related to CZS phenotypes such as neurological development and immunity. Therefore, both rare and common variations may be likely to contribute as the underlying genetic cause of CZS susceptibility. The variations and pathways identified in this study may also have implications for the development of therapeutic strategies in the future.

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