Genome Sequencing Enhances Diagnostic Yield for Rare Diseases by 8 Percent Over Other Genetic Tests

New York – A recent study reinforces the efficacy of genome sequencing in diagnosing rare, monogenic diseases where other genetic tests, such as exome sequencing, have failed to provide answers.

Published in the New England Journal of Medicine, researchers from Boston Children's Hospital, Harvard Medical School, Dana-Farber Cancer Institute, and other leading institutions analyzed short-read genome sequencing data from 744 families. These families, enrolled through the Broad Center for Mendelian Genomics and the Rare Genomes Project, had previously not received diagnoses from other genetic tests. Remarkably, genome sequencing yielded molecular diagnoses in 218 families.

"We used genome sequencing to identify plausible diagnoses in 29.3 percent of individuals with rare diseases, often after other testing methods had failed," stated Monica Wojcik, the study's first and corresponding author, affiliated with Boston Children's Hospital, Harvard Medical School, and Dana-Farber Cancer Institute.

The research team highlighted that at least 61 families with new molecular diagnoses possessed variants that would have been overlooked by exome sequencing and other approaches. These included complex rearrangements, tandem repeat expansions, structural variants, or copy-neutral inversions.

Among families previously tested with exome sequencing, 148 new diagnoses were made through genome sequencing. Interestingly, 94 of these could have been achieved through reanalysis of existing exome data.

The study emphasized the capability of genome sequencing to uncover pathogenic variations that might evade exome sequencing or other genetic testing methods. These include small or copy-neutral structural variants, deep intronic variants, tandem repeat expansions, and coding variants, especially indels or variants in high GC content regions.

Supporting these findings, a clinical cohort from the Institute of Human Genetics at the University of Leipzig Medical Center included another 78 families with rare, suspected monogenic conditions. Here, genome sequencing resulted in molecular diagnoses in 33 percent of families, with about 8 percent carrying disease-related variants not detectable by more focused sequencing tests.

While many diagnoses were made in families of European descent with neurodevelopmental conditions, the study also achieved molecular diagnoses in cases involving neuromuscular, syndromic, hematologic conditions, and families with diverse ancestries, including African, Ashkenazi Jewish, East Asian, Middle Eastern, South Asian, and admixed ancestry.

"Overall, our findings advocate for genome sequencing as a first-line diagnostic test for rare diseases," the authors concluded. "It has the potential to replace both exome sequencing and chromosomal microarray in a single test, due to its ability to detect multiple types of disease-causing variations and its superior capacity to identify all classes of variations, except for somatic mosaic variants where the lower mean coverage of genome sequencing reduces sensitivity."