Sequencing works in clinical setting to help -- finally -- get a diagnosis

May 8, 2012

Advanced high-speed gene-sequencing has been used in the clinical setting to find diagnoses for seven children out of a dozen who were experiencing developmental delays and congenital abnormalities for mysterious reasons.

"I thought if we could obtain even a couple of relatively secure diagnoses out of the 12 patients, that would prove the value of deploying sequencing approaches systematically in patients with unknown but apparently genetic conditions," said David Goldstein, Ph.D., director of the Duke Center for Human Genome Variation and professor of and microbiology.

"Few sequencing studies have approached the problem as we did, taking a very heterogeneous group of patients," Goldstein said. "Getting a likely diagnosis about half of the time is quite stunning and strongly motivates next-generation sequencing for all patients that fail to get a through traditional testing."

The research team used next-generation sequencing, a new technology that can rapidly read a person's entire genome or just their exome, the sections of DNA that make the proteins, which direct physiological activities. The cost of such sequencing is becoming lower, making it feasible to do the study in a clinical setting.

The work was published online on May 8, in the .

"There are up to 50,000 in America each year with the children having features of , or similar to those we studied," said Vandana Shashi, M.D., co-author and associate professor of pediatrics in the Duke Center for . "Many of these children remain without diagnoses and we could systematically try to help identify a cause."

Shashi said families involved with the study often expressed relief just to have a diagnosis, even when a condition remained difficult or impossible to treat.

"Just knowing what was causing the problem took away the mystery, which gives families some comfort," Shashi said.

Goldstein said that simply studying more patients with sequencing tools would facilitate discovery by searching for similarities among patients that have mutations in the same or similar genes.

With time, this would also reveal more diagnoses, said lead author Anna Need, Ph.D., who works in the Duke Center for Human Genome Variation.

"Despite the fact that we ended up with a short list of gene variants for each person we studied and ran other tests, we had no real evidence of a related disease because there haven't been other reported conditions or people with mutations in those genes," Need said. "Some of the people we had no results for yet may get answers as their variants become associated with diseases through other sequencing."

The results of this study also are important for genetic counseling, Goldstein said.

For example, some of the likely diagnoses are due to new mutations that happened in the children, known as de novo mutations. In these cases, the parents would be less likely to pass it on through a subsequent pregnancy, for example.

Another lesson of the study was that some of these individuals may have multiple genetic conditions. Shashi noted one child received a diagnosis for only one of several conditions she had.

"We may not find all of the genetic causes, but over time the success of this type of testing and the information we learn will only grow," Need said. "Out of the genes we found, two have been found to be associated with disease through recent studies by other researchers."

Goldstein said it is imperative to set up large genetic databases in tertiary medical centers, which have the doctors and scientists who can evaluate who might benefit from next-generation sequencing. They would also have the team to do the genomic sequencing, and then, to follow up with biological tests that show the function of the gene.

Goldstein said that hospitals with the right systems in place can note a patient's clinical features and then examine a patient's cells or do a relatively general protein localization assay in cells to get an idea about gene function.

"This is a generalized follow-up system for any of the candidate genes, and the work can be done at a tertiary hospital center for virtually any candidate gene, but not by the diagnostic companies, which don't do any functional testing," Goldstein said. "That's why I see a role for this effort being grounded in an academic research environment."

Explore further: Mutations in 3 genes linked to autism spectrum disorders

Related Stories

Mutations in 3 genes linked to autism spectrum disorders

April 4, 2012
Mutations in three new genes have been linked to autism, according to new studies including one with investigators at Mount Sinai School of Medicine. All three studies include lead investigators of the Autism Sequencing Consortium ...

Gene discovered for Weaver syndrome

December 15, 2011
Scientists have found a gene that causes Weaver syndrome, a rare genetic disorder that typically causes large size at birth, tall stature, developmental delay during childhood, and intellectual disability. Published today ...

Recommended for you

New comparison chart sheds light on babies' tears

July 10, 2017
A chart that enables parents and clinicians to calculate if a baby is crying more than it should in the first three months of its life has been created by a Kingston University London researcher, following a study of colic ...

Blood of SIDS infants contains high levels of serotonin

July 3, 2017
Blood samples from infants who died of Sudden Infant Death Syndrome (SIDS) had high levels of serotonin, a chemical that carries signals along and between nerves, according to a study funded in part by the National Institutes ...

Is your child's 'penicillin allergy' real?

July 3, 2017
(HealthDay)—Many children suspected of being allergic to the inexpensive, first-line antibiotic penicillin actually aren't, new research indicates.

Probiotic supplements failed to prevent babies' infections

July 3, 2017
(HealthDay)—Probiotic supplements may not protect babies from catching colds or stomach bugs in day care, a new clinical trial suggests.

Starting school young can put child wellbeing at risk

June 22, 2017
New research has shown that the youngest pupils in each school year group could be at risk of worse mental health than their older classmates.

Fidget spinners are the latest toy craze, but the medical benefits are unclear

June 21, 2017
Last week, German customs agents in Frankfurt Airport seized 35 metric tons of an imported plastic device, destroying the shipment for public safety purposes before it could infiltrate the country's marketplaces.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.