基因外显子组测序,临床疾病 z-bo 2020-09-21 335

　　The latest report by researchers from the Department of Molecular and Human Genetics Pediatrics, the Human Genome Sequencing Center, and the University of Texas Health Sciences Center at Baylor College of Medicine reported that several key mutated genes have been discovered in patients with familial Parkinson’s disease, including TNK2 and TNR have rare mutations. In 12 families, these two genes have 9 mutation sites. This study provides a basis for in-depth study of the pathogenic genes of Parkinson's disease.

　　In fact, Dr. James R. Lupski, Professor of Molecular and Human Genetics and Pediatrics at Baylor College of Medicine, has conducted related research on a large number of diseases, including sudden cardiac death, Contiguous Gene Duplication Syndrome, Meier-Gorlin Syndrome, etc. He even believes that clinical exome sequencing can diagnose 25% of diseases.

　　Clinical exome sequencing can diagnose 25% of diseases

　　A few years ago, Dr. James R. Lupski was diagnosed with a known genetic disease (a genetic mutation or disease-related mutation) among the 3386 patients who underwent the whole exome test. It further validated their diagnosis rate of 250 initial reports published in the New England Journal of Medicine a year ago.

　　Christine Eng will also submit the current results to the American Society of Human Genetics Annual Meeting in San Diego on October 21, 2014.

　　In this article, Dr. James R. Lupski, Professor of Molecular and Human Genetics and Pediatrics at Baylor College of Medicine pointed out: "The results of this report will, in general, change the future of pediatrics and medical practice forever. Elevating genomics to what doctors do Before being on the list, it is only a matter of time. This will be a new'family history', allowing you to acquire important mutations inherited from each patient and new mutations that cause disease susceptibility."

　　In fact, most of the diagnosis is made in patients who inherit a new mutation (in the egg or sperm) that has not been seen in their parents before.

　　Using a new sequencing technology (called next-generation sequencing) to measure the patient’s DNA and compare the results with normal references. Then, any disease-related mutations are also compared with the patient’s DNA to determine whether the child has inherited the mutation from their parents to better understand the cause of the disease. In this study, whole-exome sequencing also identified ways that doctors can clinically intervene to alleviate or eliminate negative symptoms, allowing families to obtain more information about the possible course of the disease.

　　In addition to demonstrating a 25% diagnosis rate in a larger patient group, this latest study also shows that rare genetic events can trigger disease susceptibility on a large scale.

　　The main causes of the disease include neonatal events in the patient-a single change (called Mendelian mutation) that first occurred in the gene, uniparental disomy (the patient inherited two copies of a mutation from the same parent), Chimera and copy number.

　　Lupski, a clinical pediatric geneticist at Texas Children’s Hospital, points out: “Clinical exome sequencing can assist in the diagnosis of various difficult-to-diagnose diseases.” Many patients in this study were obtained from Texas Children’s Hospital and other US Medical center.

　　Lupski said: "Rare variants and Mendelian diseases are important factors in the disease population. This is in sharp contrast to the thinking of population geneticists, who use genome-wide association studies to investigate how common mutations trigger disease susceptibility. We It was discovered that the aggregation of'rare variants' can actually cause disease susceptibility on a large scale. Individual diseases may be rare, but there are thousands of such diseases, which are more determined by the genome."

　　Dr. Sharon Plon, Professor of Pediatrics and Molecular Human Genetics at Baylor College of Medicine, Director of the Cancer Genetics Clinic at Baylor College of Medicine, and a member of the Cancer Center at Texas Children’s Hospital, noted: “I expect that in the next few years, we will understand the The importance of subgroup sequencing outside the fields of adult medicine and pediatrics. A clinical trial supported by NIH is currently being implemented to perform whole-exome sequencing in children with cancer to understand the effects of whole-exome sequencing on these patients Potential effectiveness."

　　In a detailed study of 2000 patients, 504 patients underwent molecular diagnosis, of which 280 patients had a disease-causing single gene mutation (autosomal dominant), and 181 patients were euchromatic recessive (two mutant genes) ), 65 patients have X chromosome (X chromosome mutation), and 1 patient is assumed to have mitochondrial inheritance. In 5 cases, the patient inherited two copies of the mutant gene from the same parent (uniparental disomy). Among the dominant mutations, 208 are new mutations that are not inherited from their parents, 32 are hereditary, and 40 are uncertain because their parents' samples cannot be used for laboratory analysis.

　　Among the new mutations, there are 5 proven chimeras, indicating that the mutations occurred after fertilization. Chimerism means that the patient has a small cell population with a different genetic pattern than most cells in the body.

　　Researchers found 708 putative pathogenic variant alleles in 504 cases, most of which are new and have not been reported before. It is worth noting that nearly 30% of diagnoses occurred in disease genes identified by researchers in the past 3 years. In 65 cases, apart from exome sequencing, no genetic testing was available to find the mutated gene at that time.

　　Eng said: “Doctors usually try to find a diagnosis to explain all the problems that a patient may have. We have found that in some cases, the patient may have a mixed phenotype of two different diseases. This patient There may be two different rare genetic diseases to explain that their disease was an accidental discovery before the use of whole exome sequencing."