Next-generation sequencing cracks medical mysteries

Rapid, large-scale sequencing of the exome (WES) or whole genome (WGS), known as next-generation sequencing, proves to be a useful tool for diagnosing unknown or rare diseases, which not only has implications for the patients and their treatment but may also impact genetic counselling for the entire family, according to a Singapore study.

In a multiethnic Asian population, genomic sequencing facilitated a diagnosis in about 33–37 percent of individuals with unknown disease as well as led to novel genetic discoveries.

For patients who have waited 5, 10, or more than 20 years before finding an answer, WES or WGS can end the diagnostic odyssey and improve the medical management of their underlying disorder, the investigators said. In addition, the genetic information acquaints the families about the patients’ disorder, its inheritance patterns, and risk of recurrence.

“The diagnostic odyssey, beginning with clinical assessment and comprising a slew of nongenetic and genetic investigations and/or imaging studies and evaluations by multiple specialist physicians over a period of years, creates [an emotional and financial] burden on [the patients and their] families and the healthcare system,” the investigators pointed out.

Thus, receiving a diagnosis and cutting short the years of waiting through genomic sequencing should be a huge boon for patients with unknown conditions, they added.

In the diagnostic study, 196 probands (55 percent male; 74.5 percent Chinese) with suspected genetic disease and their families underwent either WES (n=172) or WGS (n=24) under the Singapore Undiagnosed Diseases Research Endeavour for Kids (SUREKids) programme. These probands were diagnostic ‘unknowns’ who had undergone previous genetic testing without an established diagnosis or whose symptoms were heterogenous and did not appear to fit a well-known Mendelian disorder.

Overall, 73 probands received a molecular diagnosis: 65 via WES (37.8 percent) and eight via WGS (33.3 percent). There were 64 causative variants detected in unique genes, and 61 percent of these were novel. [Arch Dis Child 2020;doi:10.1136/archdischild-2020-319180]

Notably, the diagnostic yield increased nominally when sequencing was conducted on trios or more (40.2 percent), as well as for specific phenotypes (neuromuscular, 54 percent; skeletal dysplasia, 50 percent).

On average, the patients received the molecular diagnosis a full 7.6 years following onset of symptoms (within 1–2 years in 10 patients and >20 years in five), with the median length of diagnostic odyssey being 5 years.

“The time to diagnosis is very obviously impacted by the age of the proband,” the investigators noted. “Those born in the era before the advent of microarray and genomic sequencing will have a longer diagnostic odyssey.”

Ending the diagnostic odyssey altered the treatment and management approach in 27 percent of the patients. As for the families, everybody underwent genetic counselling, and parents of individuals with de novo variants were reassured of the lower recurrence risk.  

“While WES/WGS in patients with rare diseases is increasing, the concern for higher cost, need for bioinformatic resources to process and store large amounts of data, as well as issues regarding reimbursement remain a challenge in the clinical setting,” the investigators acknowledged.

“Lack of regulations protecting individuals from genetic nondiscrimination in most Asian countries can hamper the use of genomic sequencing as a diagnostic tool for these patients … [and] prolong the diagnostic odyssey for [them] and their families,” they added. “Our approach of phenotype-driven genomic sequencing allows clinicians from similar settings to improve diagnostic yield for their patients.”