Whole Genome Sequencing Increased Discovery of Rare Disorders by 31% in UK Study

The authors backed plans for the United Kingdom to establish a national diagnostic program based on whole genome sequencing (WGS) to speed the time to diagnosis.

A report published this week in the BMJ said that whole genome sequencing (WGS) was able to make a diagnosis of 31% additional rare disorders in patients in the National Health System.

In the study, the authors backed plans for the United Kingdom to establish a national diagnostic program based on WGS to speed the time to diagnosis.

The study, led by researchers from the MRC Mitochondrial Biology Unit and Departments of Clinical Neuroscience and Medical Genetics at the University of Cambridge, involved 319 families with suspected mitochondrial disease recruited through the 100,000 Genomes Project.

The project was created to embed genomic testing in the NHS, discover new disease genes, and make genetic diagnosis available for more patients. Current genetic testing regimes fail to diagnose around 40% of patients.

In total, 345 participants (aged 0 to 92 with a median age of 25 years) had their whole genome sequenced. Through different analyses, the researchers found that they could make a definite or probable genetic diagnosis for 98 families (31%). Standard tests, which are often more invasive, failed to reach these diagnoses.

Six possible diagnoses (2% of the 98 families) were made. A total of 95 different genes were implicated.

Surprisingly, 62.5% of the diagnoses were nonmitochondrial disorders, with some having specific treatments. This happened because so many different diseases resemble mitochondrial disorders, making it very difficult to know which are which.

"We recommend that whole genome sequencing should be offered early in the diagnostic pathway in a patient’s local secondary or tertiary care centre and before invasive tests such as a muscle biopsy," wrote the authors.

Mitochondrial disorders affect around 1 in 4300 people and cause progressive, incurable diseases. Although they are among the most common inherited diseases, diagnosis is difficult. The impairment of mitochondrial function tends to affect tissues with high energy demand such as the brain, the peripheral nerves, the eye, the heart and the peripheral muscles.


Schon KR, Horvath R, Wei W, et al., Use of whole genome sequencing to determine the genetic basis of suspected mitochondrial disorders: A cohort study. BMJ. Published online Novemver 4, 2021. doi: 10.1136/ bmj-2021-066288