Copy number variants contribute to a serious birth defect

Almost all people have two copies each of 22 chromosomes and one pair of sex chromosomes. It therefore follows that we have two copies of each gene on each non-sex chromosome, one from each parent. But that isn’t always the case. Research over the past 15 years has shown that all of us have large segments of DNA duplicated and deleted in many places in the genome. Sometimes these segments contain entire genes, introducing what’s known as a copy number variant (CNV). As a result, there may be one copy of some genes, or three or four, or even more.

Interestingly, even healthy people have been found to have many CNVs in their genomes. But they are also increasingly implicated in disease. Now recent findings show that they are an important contributor to congenital diaphragmatic hernia (CDH), a severe birth defect. In a paper published in Proceedings of the National Academy of Sciences, a research team led by Jackson Laboratory Professor  Charles Lee, Ph.D., FACMGThe study of structural genomic variation in human biology, evolution and disease.Charles Lee, Ph.D., FACMG, and Associate Research Scientist Qihui Zhu, Ph.D., identified six significant CNVs that were unique to CDH patients or enriched in them compared with healthy controls. The research was conducted in collaboration with a group from Harvard Medical School and Massachusetts General Hospital led by Patricia Donahoe, M.D.

Congenital diaphragmatic hernia (CDH) occurs when the diaphragm, a thin muscle that separates the chest from the abdomen, does not form properly during prenatal development, and the contents from the abdominal cavity (stomach, spleen, intestines and/or liver) migrate into the chest. About 1,600 babies are born with CDH every year in the U.S., or 1 in every ~3,000 live births. CDH is one of the most common and severe birth defects, and it is associated with high morbidity and mortality rates. Currently little is known about why CDH occurs.

Previous studies had shown that some single nucleotide variants (SNVs) contribute to CDH, but CNVs had not yet been studied on a large scale. The paper, “Systemic analysis of copy number variation associated with congenital diaphragmatic hernia,” describes the results of a large-scale case control analysis of CNVs in 196 patients with CDH, 109 unaffected parents and 987 healthy population-matched controls. The CNV regions identified validate several hypothesized CDH candidate genes and identify additional genes and pathways that may contribute to the pathogenesis of CDH. The six CNVs most significantly associated with CDH involve genes that are involved with DNA binding/transcription regulation and embryonic organ development.

The results underscore the importance of CNVs in CDH and indicate that they may contribute to other birth defects as well. Moving forward, the researchers plan to work with additional groups of CDH patients to validate the CNVs identified in the paper and continue to look for additional ones. In addition, functional studies of the CDH candidate genes identified in the paper will provide more insight into CDH pathology and reveal targets for potential therapeutics.