Transmission disequilibrium analysis of whole genome data in childhood-onset systemic lupus erythematosus

Vazzana, Kathleen M.; Musolf, Anthony M.; Bailey-Wilson, Joan E.; Hiraki, Linda T.; Silverman, Earl D.; Scott, Christiaan; Dalgard, Clifton L.; Deng, Zuoming; Kaplan, Mariana J.; Lewandowski, Laura B.

doi:10.1038/s41435-023-00214-x

Cited by 3 publications

(1 citation statement)

References 78 publications

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“…The Transmission Disequilibrium Test (TDT) stands out as a powerful tool for pinpointing disease-associated loci that exhibit strong genetic in uence in complex disorders, often mirroring the behavior of Mendelian alleles in monogenic conditions within trio family cohorts [20,21]. Diverging from traditional case-focused sequencing strategies that prioritize exons and splice junctions to uncover mutations adhering to classic Mendelian patterns, TDT facilitates the unbiased discovery of disease-related loci throughout the genome, without heavy reliance on presupposed models of inheritance [22][23][24]. Consequently, TDT can enhance existing sequencing methodologies by uncovering signi cant genetic factors that may otherwise remain undetected…”

Section: Introductionmentioning

confidence: 99%

Unveiling Digenic Pathogenic Variants and Mutation Susceptibility in Chinese Patients with Suspected Retinitis Pigmentosa

Ziwei,

Han,

2024

Preprint

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Background Retinitis pigmentosa (RP; MIM: #268000) is a type of inherited retinal dystrophy (IRD) characterized by the progressive loss of retinal photoreceptors. In recent years, the field of bioinformatics has made significant advancements, enabling us to uncover new digenic disease variants associated with RP. Additionally, there is increasing attention given to identifying prevalent founder mutations, as they have the potential to be targeted by mutation-specific therapies that focus on specific regions of the genome. Methods We conducted a retrospective study involving 450 patients who were diagnosed with suspected RP as the study cohort. To serve as a control cohort, we included their family members. In this study, we aimed to establish a genotype-phenotype correlation among all participants. For patients who did not have any identified pathogenic variants, we performed digenic pathogenicity prediction along with Sanger sequencing validation. Furthermore, we conducted transmission linkage disequilibrium analysis to identify susceptibility loci for all patients. Result In our study, we achieved a molecular diagnosis in 67.8% of the patients, with the top 17 genes accounting for 75.63% of the 305 diagnosed cases. We identified a total of 464 known pathogenic loci, consisting of 103 different variants, as well as 73 novel pathogenic loci with 43 different variants. Among these findings, we discovered 12 suspected pathogenic digenic loci pairs, and two of them were successfully validated through Sanger sequencing - PDE6A c.1744C > T/RP1 c.607G > T and CRB1 c.2714G > A/PROM1 c.1438G > A. After applying the Bonferroni correction, we identified eight significant mutations associated with suspected RP. These mutations include MSH2 c.212-16delT, LRP5 c.58-60del, FOXE3 c.211A > G, PRX c.4077-4079del, DMD c.8810A > A, GP1BA c.1322-1344del, SYNE2 c.1170A > C, and SMPD1 c.573T > C. Additionally, our study unveiled 26 combinations of highly correlated susceptible loci involving 31 genes. Among these combinations, MSH2 c.212-16delT and WFS1 c.1832G > A were identified as susceptible interaction hotspots. Conclusion In conclusion, this retrospective study demonstrated that a considerable number of patients achieved a molecular diagnosis. Furthermore, the study aimed to identify novel digenic disease variants in patients with suspected RP utilizing bioinformatics methods. The findings of the study also unveiled significant susceptible mutations associated with suspected RP, shedding light on potential targets for mutation-specific therapy in the future.

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Section: Introductionmentioning

confidence: 99%

Unveiling Digenic Pathogenic Variants and Mutation Susceptibility in Chinese Patients with Suspected Retinitis Pigmentosa

Ziwei,

Han,

2024

Preprint

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Childhood-Onset Systemic Lupus Erythematosus (cSLE): An International Perspective

Aggarwal,

Fernandes,

Migowa

et al. 2024

Curr Allergy Asthma Rep

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Genetic and epigenetic factors shape phenotypes and outcomes in systemic lupus erythematosus – focus on juvenile-onset systemic lupus erythematosus

Charras,

Hiraki,

Lewandowski

et al. 2024

Current Opinion in Rheumatology

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Purpose of review Systemic lupus erythematosus (SLE) is a severe autoimmune/inflammatory disease. Patients with juvenile disease-onset and those of non-European ancestry are most severely affected. While the exact pathophysiology remains unknown, common and rare gene variants in the context of environmental exposure and epigenetic alterations are involved. This manuscript summarizes the current understanding of genetic and epigenetic contributors to SLE risk, manifestations and outcomes. Recent findings Though SLE is a mechanistically complex disease, we are beginning to understand the impact of rare and common gene variants on disease expression and associated outcomes. Recent trans-ancestral and multigenerational studies suggest that differential genetic and environmental impacts shape phenotypic variability between age-groups and ancestries. High genetic burden associates with young age at disease-onset, organ involvement, and severity. Additional epigenetic impact contributes to disease-onset and severity, including SLE-phenotypes caused by rare single gene variants. Studies aiming to identify predictors of organ involvement and disease outcomes promise future patient stratification towards individualized treatment and care. Summary An improved understanding of genetic variation and epigenetic marks explain phenotypic differences between age-groups and ancestries, promising their future exploitation for diagnostic, prognostic and therapeutic considerations.

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Transmission disequilibrium analysis of whole genome data in childhood-onset systemic lupus erythematosus

Cited by 3 publications

References 78 publications

Unveiling Digenic Pathogenic Variants and Mutation Susceptibility in Chinese Patients with Suspected Retinitis Pigmentosa

Unveiling Digenic Pathogenic Variants and Mutation Susceptibility in Chinese Patients with Suspected Retinitis Pigmentosa

Childhood-Onset Systemic Lupus Erythematosus (cSLE): An International Perspective

Genetic and epigenetic factors shape phenotypes and outcomes in systemic lupus erythematosus – focus on juvenile-onset systemic lupus erythematosus

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