The added value of WES reanalysis in the field of genetic diagnosis: lessons learned from 200 exomes in the Lebanese population.

Jalkh N1, Corbani S1, Haidar Z1, Hamdan N1, Farah E2, Abou Ghoch J1, Ghosn R1, Salem N1, Fawaz A3, Djambas Khayat C4,5, Rajab M6, Mourani C4,5, Moukarzel A4,5, Rassi S7, Gerbaka B4,5, Mansour H8, Baassiri M9, Dagher R10, Breich D11, Mégarbané A12,13, Desvignes JP14, Delague V14, Mehawej C1, Chouery E15.

Author information

Abstract

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.