Bruce D. Gelb, MD

An exciting development in birth defects research emerged in 2015! In 2013, Gabriella Miller, a young girl dying from cancer, called upon the U.S. Congress for “less talking, more doing…We need action.” This stimulated Congress to pass the Gabriella Miller Kids First Research Act in 2014, which authorized $12.6 million/year for 10 years toward pediatric research. In implementing this mandate, the National Institutes of Health (NIH) decided to use the 2015 funds for performing whole genome sequencing (WGS) for certain childhood cancers and, of relevance here, for structural birth defects.

Whole genome sequencing, or WGS, refers to sequencing of the entire genome- for humans, 3 billion base pairs of DNA. This includes DNA sequences encoding the instructions for the entire set of proteins that our bodies makes (referred to as the exome) but also all of the controller regions for those genes. Since we already know from scientific studies of children with birth defects that DNA sequencing of exomes can result in the discovery of the underlying cause for 30-40% of cases, it is hoped that WGS can improve that even more. While some proportion of structural birth defects arises from environmental exposures, so that getting to 100% is not possible, the current thinking is that the vast majority of birth defects are attributable primarily to genetic issues. Of note, WGS has only recently become practical for research as remarkable advances in DNA sequencing technology have dropped the price several orders of magnitude, from around $100M after the completion of the Human Genome Project in 2003 to around $1,500 now.

After a robust competition, NIH picked 5 projects concerning structural birth defects for WGS during this first year of the Gabriella Miller program. The defects to be studied are: cleft lip and palate, congenital diaphragmatic hernias, congenital heart defects, disorders of sex development, and eye defects due to abnormal nerve formation. If your birth defect of interest is not on that list, do not despair- there should be competitions in the coming years, which will likely broaden the types being studied.

The NIH will create a common warehouse for these birth defect WGS data, which will be shared widely. The sharing aspect is important for two reasons:

1. Genetic abnormalities underlying one form of birth defect often turn out to be relevant for other types too. The large dataset that will ultimately emerge from the Gabriella Miller program will allow investigators to explore any initial findings in their birth defect of interest more broadly, accelerating discovery.
2. While the data will initially be combed over by the investigators funded for this work, the information will be quickly made available to qualified scientists everywhere. This, too, should maximize their usefulness, speeding discovery.

So, as we ring in a new year and give thanks, let those of us who care about birth defects give special thanks to a brave youngster for bringing a spotlight to the need for more resources for children’s health research, and to Congress for heeding her impassioned call.

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Bruce D. Gelb, MD is the Gogel Family Chair and Director of The Mindich Child Health and Development Institute, Director of the Center for Molecular Cardiology, and Professor of Pediatrics and Genetics & Genomic Sciences.