Exploration of Tools for the Interpretation of Human Non-Coding Variants

Tabarini, Nicole; Biagi, Elena; Uva, Paolo; Iovino, Emanuela; Pippucci, Tommaso; Seri, Marco; Cavalli, Andrea; Ceccherini, Isabella; Rusmini, Marta; Viti, Federica

doi:10.3390/ijms232112977

Cited by 10 publications

(7 citation statements)

References 95 publications

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“…For example, only 25% to 50% of patients have a molecular diagnosis by WES depending on the disease, leaving many cases still unsolved [24]. WGS is now largely used with the advantage of covering the non-coding part of the human genome [25] but requires careful analysis [26] and novel tools [27].…”

Section: Discussionmentioning

confidence: 99%

WGS Revealed Novel BBS5 Pathogenic Variants, Missed by WES, Causing Ciliary Structure and Function Defects

Karam,

Delvallée,

Estrada-Cuzcano

et al. 2023

IJMS

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Bardet–Biedl syndrome (BBS) is an autosomal recessive ciliopathy that affects multiple organs, leading to retinitis pigmentosa, polydactyly, obesity, renal anomalies, cognitive impairment, and hypogonadism. Until now, biallelic pathogenic variants have been identified in at least 24 genes delineating the genetic heterogeneity of BBS. Among those, BBS5 is a minor contributor to the mutation load and is one of the eight subunits forming the BBSome, a protein complex implied in protein trafficking within the cilia. This study reports on a European BBS5 patient with a severe BBS phenotype. Genetic analysis was performed using multiple next-generation sequencing (NGS) tests (targeted exome, TES and whole exome, WES), and biallelic pathogenic variants could only be identified using whole-genome sequencing (WGS), including a previously missed large deletion of the first exons. Despite the absence of family samples, the biallelic status of the variants was confirmed. The BBS5 protein’s impact was confirmed on the patient’s cells (presence/absence and size of the cilium) and ciliary function (Sonic Hedgehog pathway). This study highlights the importance of WGS and the challenge of reliable structural variant detection in patients’ genetic explorations as well as functional tests to assess a variant’s pathogenicity.

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Section: Discussionmentioning

confidence: 99%

WGS Revealed Novel BBS5 Pathogenic Variants, Missed by WES, Causing Ciliary Structure and Function Defects

Karam,

Delvallée,

Estrada-Cuzcano

et al. 2023

IJMS

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“…104,106,107 The ongoing development of genomic technologies and new bioinformatic tools will gradually improve our capacity to understand noncoding variants and boost the diagnostic capabilities of GS. 104,105,108 Kidney genomics is also extending beyond monogenic conditions to multifactorial (polygenic) disorders. Genome-wide association studies enable the calculation of so-called polygenic risk scores (PRSs).…”

Section: Future Outlookmentioning

confidence: 99%

The Role of Genetic Testing in Adult CKD

Knoers,

van Eerde

2024

JASN

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Mounting evidence indicates that monogenic disorders are the underlying cause in a significant proportion of chronic kidney disease patients. In recent years, the diagnostic yield of genetic testing in these patients has increased significantly as a result of revolutionary developments in genetic sequencing techniques and sequencing data analysis. Identification of disease-causing genetic variant(s) in chronic kidney disease patients may facilitate prognostication and personalized management, including nephroprotection and decisions around kidney transplantation, and is crucial for genetic counseling and reproductive family planning. A genetic diagnosis in a chronic kidney disease patient allows for screening of at-risk family members, which is also important for determining their eligibility as kidney transplant donors. Despite evidence for clinical utility, increased availability, and data supporting the cost-effectiveness of genetic testing in chronic kidney disease, especially when applied early in the diagnostic process, many nephrologists do not use genetic testing to its full potential because of multiple perceived barriers. Our aim in this paper is to empower nephrologists to (further) implement genetic testing as a diagnostic means in their clinical practice, based on the most recent insights and exemplified by patient vignettes. We stress why genetic testing is of significant clinical benefit to many chronic kidney disease patients, provide recommendations for which patients to test and which test(s) to order, give guidance about interpretation of genetic testing results, and highlight the necessity for and essential components of pre- and post-test genetic counseling.

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“…Subsequent efforts and developments in the field produced last-generation methods, using one of three general strategies: i) prediction of the likelihood of a missense mutation for causing pathogenic changes in a protein ( Sim et al, 2012 ; Adzhubei et al, 2013 ; Carter et al, 2013 ; Katsonis et al, 2014 ; Niroula et al, 2015 ; Capriotti et al, 2017 ; Raimondi et al, 2017 ; Rentzsch et al, 2019 ; Pejaver et al, 2020 ; Manfredi et al, 2022 ; Quinodoz et al, 2022 ); ii) evolutionary conservation analysis of the mutated sites; iii) methods combining different strategies ( Stein et al, 2019 ; Petrosino et al, 2021 ). More recently, several methods have been developed to also predict the impact of variants in noncoding regions ( Rojano et al, 2019 ; Katsonis et al, 2022 ; Tabarini et al, 2022 ). These methods include generic tools, which predict single-nucleotide pathogenic variants across the entire genome ( Quang et al, 2015 ; Shihab et al, 2015 ; Zhou and Troyanskaya, 2015 ; Capriotti and Fariselli, 2017 ; Rentzsch et al, 2019 ) and more specific algorithms, which predict the impact of splicing variants ( Desmet et al, 2009 ; Cheng et al, 2019 ; Jaganathan et al, 2019 ; Rentzsch et al, 2021 ).…”

Section: Tools For Rare Disease Genome Interpretationmentioning

confidence: 99%

Resources and tools for rare disease variant interpretation

Licata

Via

Turina

et al. 2023

Front. Mol. Biosci.

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Collectively, rare genetic disorders affect a substantial portion of the world’s population. In most cases, those affected face difficulties in receiving a clinical diagnosis and genetic characterization. The understanding of the molecular mechanisms of these diseases and the development of therapeutic treatments for patients are also challenging. However, the application of recent advancements in genome sequencing/analysis technologies and computer-aided tools for predicting phenotype-genotype associations can bring significant benefits to this field. In this review, we highlight the most relevant online resources and computational tools for genome interpretation that can enhance the diagnosis, clinical management, and development of treatments for rare disorders. Our focus is on resources for interpreting single nucleotide variants. Additionally, we present use cases for interpreting genetic variants in clinical settings and review the limitations of these results and prediction tools. Finally, we have compiled a curated set of core resources and tools for analyzing rare disease genomes. Such resources and tools can be utilized to develop standardized protocols that will enhance the accuracy and effectiveness of rare disease diagnosis.

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Exploration of Tools for the Interpretation of Human Non-Coding Variants

Cited by 10 publications

References 95 publications

WGS Revealed Novel BBS5 Pathogenic Variants, Missed by WES, Causing Ciliary Structure and Function Defects

WGS Revealed Novel BBS5 Pathogenic Variants, Missed by WES, Causing Ciliary Structure and Function Defects

The Role of Genetic Testing in Adult CKD

Resources and tools for rare disease variant interpretation

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