Exome sequencing may soon change the future of pediatrics and medicine, and could become the primary tool used by physicians when conducting a differential diagnosis, according to researchers from Baylor College of Medicine‘s departments of molecular and human genetics and pediatrics and the Baylor Human Genome Sequencing Center, as well as the University of Texas Health Science Center at Houston. Nearly a quarter of the 3,386 patients whose DNA was submitted for clinical exome testing in their recent research received a diagnosis related to a known genetic disease, clarifying numerous questions regarding patient health and family health history. The results will be presented on October 21st during the American Society of Human Genetics (ASHG) Annual Meeting in San Diego, California.
Drs. Yaping Yang, laboratory director of the Whole Genome Laboratory at Baylor, and Christine Eng, professor of molecular and human genetics at BCM and senior director of Baylor’s Medical Genetics Laboratories, led the study, which was published in the Journal of the American Medical Association (JAMA). The researchers’ study was spurred on by noting molecular diagnoses (a genetic mutation or variation associated with a disease) in 25 percent of their own patients. As a result, their study confirms a similar finding through the analysis a much larger group of cases, which was published in their initial report (a little more than a year ago) based on 250 patients in the New England Journal of Medicine.
“The findings in this report, I believe, will forever change the future practice of pediatrics and medicine as a whole (…) It is just a matter of time before genomics moves up on the physician’s list of things to do and is ordered before formulating a differential diagnosis. It will be the new ‘family history’ that, better yet, gets you both the important variants inherited from each parent and the new mutations that contribute to disease susceptibility,” said Dr. James R. Lupski, professor of molecular and human genetics and pediatrics at Baylor and a coauthor of the report.
The majority of the diagnoses showed patients carrying mutations that were not present in their parents’ genetics. Therefore, these mutations were determined to have occurred in the egg or sperm. Dr. Richard Gibbs, director of the Baylor College of Medicine Human Genome Sequencing Center and an author of the report, says that this new diagnostic methods and its application not only benefits patients, but also changes the way researchers think about science.
“It has been wonderful to watch this very large team of colleagues bridging from the patient in clinic to the very most cutting edge genomic technology to give families answers where previously there were none,” noted Dr. Arthur Beaudet, professor of molecular and human genetics, chair of the department when the Whole Gene Laboratory was launched, and who founded the Baylor College of Medicine Medical Genetics Laboratories.
This study compared the DNA of each patient to normal reference DNA using new and cutting-edge sequencing technologies. Disease associated mutations were compared with the parent’s DNA to evaluate whether the child inherited genetic characteristics from one or both parents in an effort to better understand the disease. Thanks to this study, new diagnostic methods were developed that can help physicians improve or eliminate negative symptoms of a disease and better inform patients about the possible courses that their condition can take.
Researchers verified that rare genetic events contribute significantly to disease susceptibility. De novo events, in which a single change occurs for the first time when a gene is being made, uniparental disomy, in which a person inherits 2 copies of a mutation from the very same parent, and copy number and mosaicism, when the patient has a small population of cells with a different genetic pattern than most of the cells in the body, were all found to be the three major contributors to the occurrence of disease. Through clinical exome sequencing, many diagnostic dilemmas can be solved by determining the exact disorder of a patient, according to Dr. Lupski, a clinical pediatric geneticist at Texas Children’s Hospital.
“Rare variants and Mendelian disease are important contributors to disease populations. This is in sharp contrast to the thinking of population geneticists who investigate (by genome wide association studies) how common variants contribute to disease susceptibility. We find ‘rare variants’ in aggregate actually contribute to disease susceptibility in a big way. The individual diseases may be rare, but there are thousands of such diseases and many more being defined through genomics,” said Lupski in the press release.
“I expect that in a few years, we will learn of the importance of whole exome sequencing in adult medicine and in fields of pediatrics outside of development (…) we are currently performing an NIH-supported clinical trial of whole exome sequencing in childhood cancer patients to learn of its potential utility for these patients,” said Dr. Sharon Plon, professor of pediatrics and molecular and human genetics at Baylor, and director of the Baylor Cancer Genetics Clinic and a member of the Texas Children’s Cancer Center.
Of 2,000 patients, 504 received a molecular diagnosis, of which 280 had a single gene mutation that caused disease (it was an autosomal dominant), 181 were autosomal recessive (2 genes with mutation), 65 x-linked (mutations on the X chromosome), and 1 inherited through the mitochondria (mitochondrial DNA). 5 situations in which 2 copies of the mutated gene from the same parent (uniparental disomy) were inherited were also found. From the dominant mutations, 208 were de novo mutations (the characteristic didn’t come from the parents), 32 were inherited, and 40 weren’t determined because parental samples could not be analyzed. Among the de novo cases, 5 demonstrated mosaicism suggesting that it occurred after fertilization.
Scientists found 708 presumptive causative variant alleles in the 504 patented studied, and the majority were not previously reported. In 30 percent of the cases, diagnosis occurred in disease genes identified by the scientific community over the last 3 years. 65 cases wouldn’t be found through an available genetic test; an exome sequencing was crucial.
5 percent of the patients had mutations in 2 different genes that could explain several patients’ medical condition. “Doctors generally try to find one diagnosis that explains all the issues a patient may have. We have found that in some cases, a patient may have a blended phenotype of two different conditions (…) that patients may have two different rare genetic diseases to explain their condition was an unexpected finding prior to the use of whole exome sequencing,” explained Eng.
In 2,000 cases, 92 patients could have been diagnosed, screened, or treated earlier. The authors added in the press release: “For the 25 percent of cases that received a molecular diagnosis, this information ended the diagnostic odyssey, provided more informed medical management and allowed for precise determination of reproductive risks, but in relatively few cases, resulted in specific treatment to reverse the condition.”