As part of the NHGRI-funded Clinical Sequencing Exploratory Research (CSER1) consortium, HudsonAlpha Institute for Biotechnology in collaboration with the University of Alabama at Birmingham (UAB) completed whole exome or genome sequencing for over 500 children affected by global developmental delay and intellectual disability (DD/ID). Parent-proband trio sequencing was conducted when biological parents were available to aid in identification of disease causal genetic variation in the child. Through this study, almost 150 children were found to harbor a genetic variant explaining at least part of their condition. Identification of genetic causes often leads to more precise clinical diagnoses, more accurate prognostic information, and can end the costly and challenging medical “odysseys” in which numerous but ultimately futile tests are performed.
In addition to genetically diagnosing children with rare disease, the CSER1 project, through major data sharing efforts, contributed to the identification of new genetic insights, including five publications describing new disease genes and ongoing collaborations related to other potential DD/ID genes. The CSER1 study also has demonstrated the benefits of reanalysis for individuals in which no genetic cause was determined at time of initial analysis. Reanalysis efforts in CSER1 resulted in a genetic diagnosis for 23 children in which a causal variant was not initially identified.
Another focus of the CSER1 study was to identify secondary findings (pathogenic genetic variation not related to the child’s DD/ID, but with the potential to impact health) in enrolled parents, and return these findings only to participants at their discretion. Secondary genetic variation was identified in 9% of the 819 parent participants, affecting genes associated with a variety of different diseases including, breast and ovarian cancer, colorectal cancer, cardiomyopathy, long QT syndrome and Charcot-Marie-Tooth disease. Interestingly, an overwhelming number of CSER1 parent participants chose to receive secondary findings, with over 95% requesting receipt.
Building upon the infrastructure, expertise, and experience gained through the CSER1 study, HudsonAlpha and UAB have initiated a new clinical research collaboration with investigators at the University of Mississippi Medical Center (UMMC) to provide genetic diagnoses for newborns with symptoms suggestive of a rare genetic disease. This team will be part of CSER2 (Clinical Sequencing Evidence-generating Research), a large collaborative NHGRI-funded project aimed at continuing and extending the work started by the original CSER consortium.
The CSER2 collaboration between HudsonAlpha, UAB, and UMMC will focus on sequencing for newborns from neonatal intensive care units (NICUs) in the Southeast United States. The SouthSeq project will conduct whole genome sequencing (WGS) for approximately 1,500 newborns with signs that are suggestive of a genetic disorder. The goals of SouthSeq are to discover genetic variation associated with a rare disorder as early as possible in a child’s life and determine to what extent such information improves clinical outcomes. Moreover, SouthSeq aims to enroll newborns at hospitals where minorities and individuals from rural areas are highly represented. Enriching for patients in these areas is designed to help expand the reach of genomic medicine and ensure that broad and diverse segments of the population derive benefit, including those who suffer from health outcome disparities and who have historically been under-represented in genetic and clinical research efforts. Finally, SouthSeq aims to implement and test methods for genetic result return that do not depend on genetic counselors or medical geneticists, in the hopes of expanding access to genomic testing beyond that which can be supported by current medical genetic infrastructure.
SouthSeq is an ambitious project that aims to make new discoveries about how genetics affects our lives, develop new approaches to communicate genetic information to patients, and expand the boundaries of genomic medicine to impact the health of some of the most vulnerable members of society.
Research reported in this publication was supported by the National Human Genome Research Institute and the National Cancer Institute of the National Institutes of Health under Award Number U01HG007301. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.