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Susan D. Thompson, PhD

Exome Sequencing Studies in Juvenile Idiopathic Arthritis | Cincinnati Children's Hospital Medical Center | Award Period: March 2013-February 2015

The Researcher’s Summary:

Idiopathic Arthritis (JIA) is the major autoimmune arthritis of childhood, and there are about 50,000 children in the U.S. with JIA. Causes of this disease are not well understood, but include a genetic component. New technologies, such as “Next Generation” DNA sequencing, may now make it possible to refine our understanding of JIA. JIA most often occurs as sporadic cases, with no history of disease in the family. While we know of many genes that each contribute a small amount to disease, there are still missing pieces.

One possible contributor might be a new or “de novo” mutation, which occurs when the DNA replication machinery makes an error during the formation of the gametes in a parent. These errors, depending on their location in the gene, may alter the function of the protein encoded by that gene. This advanced sequencing approach, focusing on the expressed portion of the genome, termed the “exome,” provides an unbiased way to discover new mutations that directly alter protein function.

We will use DNA samples that have been collected from children with JIA and their parents. More than 500 of these trios are in the freezer. This large collection gives us the opportunity to select patients who were at a very young age at disease onset, and have severe disease to maximize our chances for success. The de novo sequence mutations will be found by comparing the DNA code of the JIA child to both parents. Advanced bioinformatics approaches will help us determine whether the predicted changes in the coded protein are important for JIA.

We will also study the exome sequence for a small number of families where there are strong patterns of disease inheritance. This type of inheritance pattern is not seen often in JIA families, but we are fortunate to have nine such pedigrees, where there are three or more related people with JIA, represented in our DNA collections. Each of these families has the potential to provide new information about a gene or biological pathway important in disease.

We expect to find very rare DNA sequence variants in one or both parents that explain the pattern of inheritance. In this case the important DNA sequences will be identified by determining what the affected family members share in their exome that is different from the unaffected members. Our DNA collection also includes five monozygotic (identical) twinsets, where only one twin has JIA. One possible explanation for this is a DNA mutation occurred after fertilization and the twinning. Thus, a mutation that accounts for disease could be present in one twin but not the other. There is precedent for this mechanism in other diseases.

Together, the rapidly evolving exome sequencing methodologies and the unique and extensive JIA DNA collection on hand will most likely lead to the identification of new genes and pathways related to JIA susceptibility. This information could lead to earlier and more definitive diagnoses, as well as suggest new drug targets.

 

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Susan D. Thompson, PhD

Exome Sequencing Studies in Juvenile Idiopathic Arthritis | Cincinnati Children's Hospital Medical Center | Award Period: March 2013-February 2015


The Researcher’s Summary:

Idiopathic Arthritis (JIA) is the major autoimmune arthritis of childhood, and there are about 50,000 children in the U.S. with JIA. Causes of this disease are not well understood, but include a genetic component. New technologies, such as “Next Generation” DNA sequencing, may now make it possible to refine our understanding of JIA. JIA most often occurs as sporadic cases, with no history of disease in the family. While we know of many genes that each contribute a small amount to disease, there are still missing pieces.

One possible contributor might be a new or “de novo” mutation, which occurs when the DNA replication machinery makes an error during the formation of the gametes in a parent. These errors, depending on their location in the gene, may alter the function of the protein encoded by that gene. This advanced sequencing approach, focusing on the expressed portion of the genome, termed the “exome,” provides an unbiased way to discover new mutations that directly alter protein function.

We will use DNA samples that have been collected from children with JIA and their parents. More than 500 of these trios are in the freezer. This large collection gives us the opportunity to select patients who were at a very young age at disease onset, and have severe disease to maximize our chances for success. The de novo sequence mutations will be found by comparing the DNA code of the JIA child to both parents. Advanced bioinformatics approaches will help us determine whether the predicted changes in the coded protein are important for JIA.

We will also study the exome sequence for a small number of families where there are strong patterns of disease inheritance. This type of inheritance pattern is not seen often in JIA families, but we are fortunate to have nine such pedigrees, where there are three or more related people with JIA, represented in our DNA collections. Each of these families has the potential to provide new information about a gene or biological pathway important in disease.

We expect to find very rare DNA sequence variants in one or both parents that explain the pattern of inheritance. In this case the important DNA sequences will be identified by determining what the affected family members share in their exome that is different from the unaffected members. Our DNA collection also includes five monozygotic (identical) twinsets, where only one twin has JIA. One possible explanation for this is a DNA mutation occurred after fertilization and the twinning. Thus, a mutation that accounts for disease could be present in one twin but not the other. There is precedent for this mechanism in other diseases.

Together, the rapidly evolving exome sequencing methodologies and the unique and extensive JIA DNA collection on hand will most likely lead to the identification of new genes and pathways related to JIA susceptibility. This information could lead to earlier and more definitive diagnoses, as well as suggest new drug targets.