Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing

• Published in: European journal of human genetics : EJHG Vol. 27; no. 10; pp. 1519 - 1531
• Main Authors: Bruel, Ange-Line, Nambot, Sophie, Quéré, Virginie, Vitobello, Antonio, Thevenon, Julien, Assoum, Mirna, Moutton, Sébastien, Houcinat, Nada, Lehalle, Daphné, Jean-Marçais, Nolwenn, Chevarin, Martin, Jouan, Thibaud, Poë, Charlotte, Callier, Patrick, Tisserand, Emilie, Philippe, Christophe, Them, Frédéric Tran Mau, Duffourd, Yannis, Faivre, Laurence, Thauvin-Robinet, Christel
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.10.2019; Nature Publishing Group
• Subjects: 45/23; 631/208/514/1948; 631/208/514/2254; Adolescent; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Child; Child, Preschool; Computational Biology - methods; Congenital defects; Cytogenetics; Disease; Female; Gene Expression; Genetic Association Studies; Genetic Predisposition to Disease; Genetics; Genomics; Genomics - methods; Human Genetics; Human health and pathology; Humans; Intellectual disabilities; Life Sciences; Male; Molecular Diagnostic Techniques; Phenotypes; Polymorphism, Single Nucleotide; Rare diseases; Sequence Analysis, DNA; Whole Exome Sequencing - methods; Whole genome sequencing; Genetics; Clinical Exome Sequencing (cES); Congenitals anomalies; DNA Sequencing; Next Generation Sequencing
• ISSN: 1018-4813; 1476-5438; 1476-5438
• DOI: 10.1038/s41431-019-0442-1

In clinical exome sequencing (cES), the American College of Medical Genetics and Genomics recommends limiting variant interpretation to established human-disease genes. The diagnostic yield of cES in intellectual disability and/or multiple congenital anomalies (ID/MCA) is currently about 30%. Though the results may seem acceptable for rare diseases, they mean that 70% of affected individuals remain genetically undiagnosed. Further analysis extended to all mutated genes in a research environment is a valuable strategy for improving diagnostic yields. This study presents the results of systematic research reanalysis of negative cES in a cohort of 313 individuals with ID/MCA. We identified 17 new genes not related to human disease, implicated 22 non-OMIM disease-causing genes recently or previously rarely related to disease, and described 1 new phenotype associated with a known gene. Twenty-six candidate genes were identified and are waiting for future recurrence. Overall, we diagnose 15% of the individuals with initial negative cES, increasing the diagnostic yield from 30% to more than 40% (or 46% if strong candidate genes are considered). This study demonstrates the power of such extended research reanalysis to increase scientific knowledge of rare diseases. These novel findings can then be applied in the field of diagnostics.