Exome and Genome Sequencing for the Diagnosis of Rare Diseases

Genetic changes in the germline are the main cause of rare diseases (RD) and represent a significant disease burden in the population. Rapid and comprehensive genetic diagnosis is the key to clinical management.

Whole-genome sequencing was used to diagnose RD in a clinically heterogeneous patient cohort representative of real-world clinical practice. Three subgroups were distinguished based on genetic pre-diagnosis. 963 genomes were sequenced (360 index individuals from different families and 603 family members). The families received genetic counseling and were asked about their acceptance of the diagnostic test.

The diagnosis rate in the overall cohort was 30% (95% confidence interval: [25.3; 34.7%]; 108/360). In 2.2% ([0.7; 3.7%]; 8/360) of cases, variants were found that would not have been detectable in the exome, corresponding to 7.4% ([2.4; 12.4%]; 8/108) among the detected cases in a direct comparison of "exome versus genome." The acceptance of genome sequencing was very high when embedded in human genetic counseling.

Genome sequencing is an effective way to diagnose RD. Genome data provide a comprehensive basis for continuous re-evaluation and are superior to exome data in this respect. The integration of genome sequencing into standard care is now under evaluation as part of the nationwide "Model project genome sequencing" in Germany.