A study led by Indian scientist Dr. Saumya Jamuar, researcher at Harvard Medical School and Boston Children's Hospital, co-founder of Global Gene Corp, and Prof. Christopher Walsh, MD, PhD, chief of Genetics and Genomics at Boston Children’s Hospital, opened up new possibilities for finding genetic causes for previously mysterious neurologic and psychiatric conditions. As per the August 21st issue of The New England Journal of Medicine Dr. Jamuar led this study along with Prof. Christopher Walsh, MD, PhD, chief of Genetics and Genomics at Boston Children’s Hospital using a technique called “ targeted high-coverage sequencing ” technique and was able to identify subtle somatic mutations—those affecting just a percentage of cells—in patients with brain disorders.
Dr. Jamuar along with Prof. Christopher Walsh led this study and used a technique called “targeted high-coverage sequencing” to find mutations in 158 patients with brain malformations of unknown genetic cause, who had symptoms such as seizures, intellectual disability and speech and language impairments.
Rather than analyzing the whole genome or exome (protein-coding regions of genes), the investigators focused on a panel of known or suspected genes, but drilled deeper than the traditional genomic sequencing technique. Whole genome or exome sequencing typically breaks the DNA into little fragments, each of which is read multiple times—typically 30—to find the disease-causing mutation. But 30 reads aren’t statistically enough to catch mutations that only occur in 15 to 20 percent of our cells—especially given that mutations may affect just one of our two copies of a gene. So Walsh, Jamuar and colleagues scaled up the number of reads, sequencing each candidate gene not 30 but greater than 200 times. This enabled them to find mutations in 27 of the 158 patients (17 percent). Of these, 8 mutations (30 percent) occurred in only a proportion of the blood cells (so-called mosaic mutations)— 5 of these 8 were missed by traditional genomic sequencing, and one was missed on a previous whole exome sequencing.
Commenting on the new study, Dr. Jamuar said, "This new approach enhances whole-genome and whole-exome sequencing. We found that ~30% of patients with an identified mutation had a somatic mutation, 63% of which would have been missed on traditional testing. This has huge implications for researchers studying similar disease conditions such as autism, schizophrenia, etc. It changes the way we think about genetic diseases and lastly, translates into clinically relevant diagnostic tool that can help reach a patient's diagnosis. With increasing diagnosis and awareness of these mutations, the hope is that it would lead to identification of a potential target for mediation and cure."
Traditionally, we are taught that we inherit our genes from our parents and each cell of our body has the same genetic make up. Variations in our genes, also known as mutations, disrupt the function of the gene and lead to a disease. These mutations can be inherited from the parents or can arise spontaneously when the egg or the sperm is being formed (also known as de novo mutations). In these cases, all cells of the body will carry the mutation.
However, more recently, researchers are realizing that an individual can have two or more different genetic make up - one normal and other abnormal, a process known as somatic mosaicism. In this scenario, the mutation develops after fertilization (when the sperm and egg have come together to form the embryo) and hence, only affects some cells but not the others. It is estimated that each one of us carries at least one such mutation in our body but the relevance of somatic mosaicism to human disease has not been well studied.
Traditional methods of genetic testing are unable to detect these (somatic) mutations and hence, the true prevalence of somatic mosaicism in relation to human disease has never been quantified previously. Not every cell in the body is the same genetically, and disease-causing mutations don’t necessarily affect every cell—making these mutations easy to miss even with next-generation genomic sequencing.
Dr. Jamuar along with Prof. Christopher Walsh led this study and used a technique called “targeted high-coverage sequencing” to find mutations in 158 patients with brain malformations of unknown genetic cause, who had symptoms such as seizures, intellectual disability and speech and language impairments.
Rather than analyzing the whole genome or exome (protein-coding regions of genes), the investigators focused on a panel of known or suspected genes, but drilled deeper than the traditional genomic sequencing technique. Whole genome or exome sequencing typically breaks the DNA into little fragments, each of which is read multiple times—typically 30—to find the disease-causing mutation. But 30 reads aren’t statistically enough to catch mutations that only occur in 15 to 20 percent of our cells—especially given that mutations may affect just one of our two copies of a gene. So Walsh, Jamuar and colleagues scaled up the number of reads, sequencing each candidate gene not 30 but greater than 200 times. This enabled them to find mutations in 27 of the 158 patients (17 percent). Of these, 8 mutations (30 percent) occurred in only a proportion of the blood cells (so-called mosaic mutations)— 5 of these 8 were missed by traditional genomic sequencing, and one was missed on a previous whole exome sequencing.
Commenting on the new study, Dr. Jamuar said, "This new approach enhances whole-genome and whole-exome sequencing. We found that ~30% of patients with an identified mutation had a somatic mutation, 63% of which would have been missed on traditional testing. This has huge implications for researchers studying similar disease conditions such as autism, schizophrenia, etc. It changes the way we think about genetic diseases and lastly, translates into clinically relevant diagnostic tool that can help reach a patient's diagnosis. With increasing diagnosis and awareness of these mutations, the hope is that it would lead to identification of a potential target for mediation and cure."
Traditionally, we are taught that we inherit our genes from our parents and each cell of our body has the same genetic make up. Variations in our genes, also known as mutations, disrupt the function of the gene and lead to a disease. These mutations can be inherited from the parents or can arise spontaneously when the egg or the sperm is being formed (also known as de novo mutations). In these cases, all cells of the body will carry the mutation.
However, more recently, researchers are realizing that an individual can have two or more different genetic make up - one normal and other abnormal, a process known as somatic mosaicism. In this scenario, the mutation develops after fertilization (when the sperm and egg have come together to form the embryo) and hence, only affects some cells but not the others. It is estimated that each one of us carries at least one such mutation in our body but the relevance of somatic mosaicism to human disease has not been well studied.
Traditional methods of genetic testing are unable to detect these (somatic) mutations and hence, the true prevalence of somatic mosaicism in relation to human disease has never been quantified previously. Not every cell in the body is the same genetically, and disease-causing mutations don’t necessarily affect every cell—making these mutations easy to miss even with next-generation genomic sequencing.
