NDLI: Relevance of next generation sequencing (NGS) data re-analysis in the diagnosis of monogenic diseases leading to organ failure

Content Provider	Springer Nature : BioMed Central
Author	Saglia, Claudia Bracciamà, Valeria Trotta, Luca Mioli, Fiorenza Faini, Angelo Corso Brach Del Prever, Giulia Margherita Kalantari, Silvia Luca, Maria Romeo, Carmelo Maria Scolari, Caterina Peruzzi, Licia Calvo, Pier Luigi Mussa, Alessandro Fenoglio, Roberta Roccatello, Dario Alberti, Claudio Carli, Diana Amoroso, Antonio Deaglio, Silvia Vaisitti, Tiziana
Abstract	Background In 2018, our center started a program to offer genetic diagnosis to patients with kidney and liver monogenic rare conditions, potentially eligible for organ transplantation. We exploited a clinical exome sequencing approach, followed by analyses of in silico gene panels tailored to clinical suspicions, obtaining detection rates in line with what reported in literature. However, a percentage of patients remains without a definitive genetic diagnosis. This work aims to evaluate the utility of NGS data re-analysis for those patients with an inconclusive or negative genetic test at the time of first analysis considering that (i) the advance of alignment and variant calling processes progressively improve the detection rate, limiting false positives and false negatives; (ii) gene panels are periodically updated and (iii) variant annotation may change over time. Methods 114 patients, recruited between 2018 and 2020, with an inconclusive or negative NGS report at the time of first analysis, were included in the study. Re-alignment and variant calling of previously generated sequencing raw data were performed using the GenomSys Variant Analyzer software. Results 21 previously not reported potentially causative variants were identified in 20 patients. In most cases (n = 19), causal variants were retrieved out of the re-classification from likely benign to variants of unknown significance (VUS). In one case, the variant was included because of inclusion in the analysis of a newly disease-associated gene, not present in the original gene panel, and in another one due to the improved data alignment process. Whenever possible, variants were validated with Sanger sequencing and family segregation studies. As of now, 16 out of 20 patients have been analyzed and variants confirmed in 8 patients. Specifically, in two pediatric patients, causative variants were de novo mutations while in the others, the variant was present also in other affected relatives. In the remaining patients, variants were present also in non-affected parents, raising questions on their re-classification. Conclusions Overall, these data indicate that periodic and systematic re-analysis of negative or inconclusive NGS data reports can lead to new variant identification or reclassification in a small but significant proportion of cases, with benefits for patients’ management.
Related Links	https://bmcmedgenomics.biomedcentral.com/counter/pdf/10.1186/s12920-023-01747-w.pdf
Ending Page	13
Page Count	13
Starting Page	1
File Format	HTM / HTML
ISSN	17558794
DOI	10.1186/s12920-023-01747-w
Journal	BMC Medical Genomics
Issue Number	1
Volume Number	16
Language	English
Publisher	BioMed Central
Publisher Date	2023-11-27
Access Restriction	Open
Subject Keyword	Human Genetics Microarrays Gene Expression Clinical exome sequencing Next-generation sequencing Kidney Diseases Liver Diseases Genetic re-analysis Variant re-classification Re-alignment
Content Type	Text
Resource Type	Article
Subject	Genetics (clinical) Genetics
Journal Impact Factor	2.1/2023
5-Year Journal Impact Factor	2.5/2023

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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