학술논문
The added value of WES reanalysis in the field of genetic diagnosis: lessons learned from 200 exomes in the Lebanese population
Whole-exome sequencing
Whole-exome sequencing
Document Type
Report
Author
Jalkh, Nadine; Corbani, Sandra; Haidar, Zahraa; Hamdan, Nadine; Farah, Elias; Abou Ghoch, Joelle; Ghosn, Rouba; Salem, Nabiha; Fawaz, Ali; Djambas Khayat, Claudia; Rajab, Mariam; Mourani, Chebl; Moukarzel, Adib; Rassi, Simon; Gerbaka, Bernard; Mansour, Hicham; Baassiri, Malek; Dagher, Rawane; Breich, David; Mégarbané, André; Desvignes, Jean Pierre; Delague, Valérie; Mehawej, Cybel; Chouery, Eliane
Source
BMC Medical Genomics. January 21, 2019, Vol. 12 Issue 1
Subject
Language
English
ISSN
1755-8794
Abstract
Author(s): Nadine Jalkh[sup.1] , Sandra Corbani[sup.1] , Zahraa Haidar[sup.1] , Nadine Hamdan[sup.1] , Elias Farah[sup.2] , Joelle Abou Ghoch[sup.1] , Rouba Ghosn[sup.1] , Nabiha Salem[sup.1] , Ali Fawaz[sup.3] , Claudia [...]
Background The past few decades have witnessed a tremendous development in the field of genetics. The implementation of next generation sequencing (NGS) technologies revolutionized the field of molecular biology and made the genetic information accessible at a large scale. However, connecting a rare genetic variation to a complex phenotype remains challenging. Indeed, identifying the cause of a genetic disease requires a multidisciplinary approach, starting with the establishment of a clear phenotype with a detailed family history and ending, in some cases, with functional assays that are crucial for the validation of the pathogenicity of a mutation. Methods Two hundred Lebanese patients, presenting a wide spectrum of genetic disorders (neurodevelopmental, neuromuscular or metabolic disorders, etc.), sporadic or inherited, dominant or recessive, were referred, over the last three and a half years, to the Medical Genetics Unit (UGM) of Saint Joseph University (USJ). In order to identify the genetic basis of these diseases, Whole Exome Sequencing (WES), followed by a targeted analysis, was performed for each case. In order to improve the genetic diagnostic yield, WES data, generated during the first 2 years of this study, were reanalyzed for all patients who were left undiagnosed at the genetic level. Reanalysis was based on updated bioinformatics tools and novel gene discoveries. Results Our initial analysis allowed us to identify the specific genetic mutation causing the disease in 49.5% of the cases, in line with other international studies. Repeated WES analysis enabled us to increase the diagnostics yield to 56%. Conclusion The present article reports the detailed results of both analysis and pinpoints the contribution of WES data reanalysis to an efficient genetic diagnosis. Lessons learned from WES reanalysis and interpretation are also shared. Keywords: High throughput sequencing, Exome, NGS, Mutations, Genetic heterogeneity, Genetic diagnostics, Lebanon
Background The past few decades have witnessed a tremendous development in the field of genetics. The implementation of next generation sequencing (NGS) technologies revolutionized the field of molecular biology and made the genetic information accessible at a large scale. However, connecting a rare genetic variation to a complex phenotype remains challenging. Indeed, identifying the cause of a genetic disease requires a multidisciplinary approach, starting with the establishment of a clear phenotype with a detailed family history and ending, in some cases, with functional assays that are crucial for the validation of the pathogenicity of a mutation. Methods Two hundred Lebanese patients, presenting a wide spectrum of genetic disorders (neurodevelopmental, neuromuscular or metabolic disorders, etc.), sporadic or inherited, dominant or recessive, were referred, over the last three and a half years, to the Medical Genetics Unit (UGM) of Saint Joseph University (USJ). In order to identify the genetic basis of these diseases, Whole Exome Sequencing (WES), followed by a targeted analysis, was performed for each case. In order to improve the genetic diagnostic yield, WES data, generated during the first 2 years of this study, were reanalyzed for all patients who were left undiagnosed at the genetic level. Reanalysis was based on updated bioinformatics tools and novel gene discoveries. Results Our initial analysis allowed us to identify the specific genetic mutation causing the disease in 49.5% of the cases, in line with other international studies. Repeated WES analysis enabled us to increase the diagnostics yield to 56%. Conclusion The present article reports the detailed results of both analysis and pinpoints the contribution of WES data reanalysis to an efficient genetic diagnosis. Lessons learned from WES reanalysis and interpretation are also shared. Keywords: High throughput sequencing, Exome, NGS, Mutations, Genetic heterogeneity, Genetic diagnostics, Lebanon