developmental disorders / Human genetics

A striking number of genetic changes can occur early in human development

Dr. Pengfei Liu has a challenging job.  As the assistant laboratory director of Baylor Genetics and assistant professor of molecular and human genetics at Baylor College of Medicine, he is part of a team of researchers that evaluates young patients with a variety of developmental issues in order to determine the posibility of a genetic diagnosis of their condition. About one of their studies, Liu said, “we performed clinical genomic studies and analyzed the genetic material of more than 60,000 individuals. Of these samples, five had extreme numbers of genetic changes that could not be explained by random events alone.”

Dr. Pengfei Liu

The genetic material of an organism encodes the instructions that guide its development. These codes are not written in stone; they can change or mutate any time during the life of the organism. Single changes in the code can occur spontaneously, as a mutation, causing developmental problems. Others, as Liu and his colleagues have discovered, are too numerous to be explained by random mutation processes present in the general population. Studying such multiple genetic changes occurring before or early after conception may inform scientists about the fundamental basis of many diseases.

The researchers looked at a type of genetic change called copy number variants, which refers to the number of copies of genes in human DNA. Normally we each have two copies of each gene located on a pair of homologous chromosomes.

The human genome is compared to an encyclopedia that has two copies of each volume. Courtesy of Dr. J.R. Lupski

“Copy number variants in human DNA can be compared to repeated or missing paragraphs or pages of text in a book,” said Dr. James R. Lupski, Cullen Professor of Molecular and Human Genetics at Baylor. “For instance, if one or two pages are duplicated in a book it could be explained by random mistakes. On the other hand, if 10 different pages are duplicated, you have to suspect that it did not happen by chance. We want to understand the basic mechanism underlying these multiple new copy number variant mutations in the human genome.”

Copy number variants in human DNA can be compared to repeated or missing paragraphs or pages of text in the ‘encyclopedia of life.’ Courtesy of Dr. J.R. Lupski.

A rare, early and transitory phenomenon that can affect human development

The researchers call this phenomenon multiple de novo copy number variants. As the name indicates, the copy number variants are many and new (de novo). The latter means that the patients carrying the genetic changes did not inherit them from their parents because neither the mother nor the father carries the changes.

In this rare phenomenon, the copy number variants are predominantly gains – duplications and triplications – rather than losses of genetic material, and are present in all the cells of the child. The last piece of evidence, together with the fact that the parents do not carry the alterations, suggests that the extra copies of genes may have occurred either in the sperm or the egg, the parent’s germ cells, and before or very early after fertilization.

“This burst of genetic changes happens only during the early stages of embryonic development and then it stops,” Liu said. “Interestingly, despite having a large number of mutations, the young patients present with relatively mild neurological problems.”

The researchers are analyzing more patient samples looking for additional cases of multiple copy number variants to continue their investigation of what may trigger this rare phenomenon.

“We hope that as more researchers around the world learn about this and confirm it, the number of cases will increase,” Liu said. “This will improve our understanding of the underlying mechanism and of why and how pathogenic copy number variants can arise not only in developmental disorders but in cancers.”

A new era of clinical genomics-supported medicine and research

This discovery has been possible in great measure thanks to the breadth of genetic testing performed and genomic data available at Baylor Genetics laboratory.

Dr. James R. Lupski

“The diagnostics lab Baylor Genetics is one of the pioneers in this new era of clinical genomics-supported medical practice and disease gene discovery research,” Lupski said. “They are developing the clinical genomics necessary to foster and support the Precision Medicine Initiative of the National Institutes of Health, and generating the genomics data that further drives human genome research.”

Using state-of-the art technologies and highly-trained personnel, Baylor Genetics analyzes hundreds of samples daily for genetic evaluation of patients with conditions suspected to have underlying genetic factors potentially contributing to their disease. Having this wealth of information and insight into the genetic mechanisms of disease offers now the possibility of advancing medicine and basic research in ways that were not available before.

“There is so much that both clinicians and researchers can learn from the data generated in diagnostic labs,” Liu said. “Clinicians receive genomic information that can aid in diagnosis and treatment of their patients, and researchers gather data that can help them unveil the mechanisms underlying the biological perturbations resulting in the patients’ conditions.”

Read all the details of this research in Cell.

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Other contributors to this work include Bo Yuan, Claudia M.B. Carvalho, Arthur Wuster, Klaudia Walter, Ling Zhang, Tomasz Gambin, Zechen Chong, Ian M. Campbell, Zeynep Coban  Akdemir, Violet Gelowani, Karin Writzl, Carlos A. Bacino, Sarah J. Lindsay, Marjorie Withers, Claudia Gonzaga-Jauregui, Joanna Wiszniewska, Jennifer Scull, Pawel Stankiewicz, Shalini N. Jhangiani, Donna M. Muzny, Feng Zhang, Ken Chen, Richard A. Gibbs, Bernd Rautenstrauss, Sau Wai Cheung, Janice Smith, Amy Breman, Chad A. Shaw, Ankita Patel and Matthew E. Hurles. The researchers are affiliated with one of more of the following institutions Baylor, Wellcome Trust Sanger Institute in the U.K., Fudan University in China, the University of Texas MD Anderson Cancer Center Houston, the Clinical Institute of Medical Genetics in Slovenia and the Medical Genetics Center in Germany.

This work was supported in part by grants from the US National Institute of Neurological Disorders and Stroke (R01NS058529), the National Human Genome Research Institute (U54HG003273), a joint NHGRI/National Heart Blood and Lung Institute grant (U54HG006542) to the Baylor Hopkins Center for Mendelian Genomics, and the BCM Intellectual and Developmental Disabilities Research Center, IDDRC Grant Number 5P30HD024064-23, from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The work was also partially supported by the Wellcome Trust (WT098051).

Ana María S. Rodríguez, Ph.D.

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