Identification of Novel Pathogenic Genes in Juvenile Systemic Sclerosis

Dr. Kathryn Torok, MD
Pittsburgh Children’s Hospital
Dr. Anne Stevens, MD, PhD
Seattle Children’s Research Institute

Project Overview

Dr. Torok and Dr. Stevens: Systemic sclerosis (SSc) affects about three in a million children, with an age of onset of 8 years. Children thus face a life-long risk for permanent organ damage and death from the inflammation and fibrosis of SSc. Understanding the genetic factors underlying a disease is an important step toward improved therapies and, potentially, a cure.  Genetic background can also determine prognosis, as well as medication response and toxicity, guiding treatment choices. Although the etiology of scleroderma is undoubtedly multifactorial, past studies revealed genes that regulate immunity associated with adult SSc. However, we discovered that some genes associated with juvenile-onset SSc (jSSc) are different, just as a child’s developing immune system is different. Thus, independent genetic studies focused on children with SSc are essential.

This study initiates a collaboration that leverages the extensive genetics experience and pipeline of SRF investigators Dan Kastner and Elaine Remmers at the National Human Genome Research Institute (NHGRI). Patients and their healthy family members are recruited at two of the largest pediatric rheumatology centers in the world (Children’s Hospital of Pittsburgh and Seattle Children’s Hospital).  DNA from these individuals is sent to the NHGRI, where whole genome sequencing is performed with the aim of identifying novel candidate genes. Peripheral blood cells and plasma are also banked for future functional and expression studies that will be guided by the findings of the DNA sequence analysis.

How this work will impact patients

Because causative gene defects usually lead to onset of disease earlier in life, we hypothesize that a whole genome study of early-onset SSc will lead to identification of causative genes that cannot be identified in adult-onset populations.  The results may lead to a better understanding of the molecular mechanisms of all kinds of scleroderma – localized, systemic, juvenile and adult.

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