Next-Generation Sequencing Opens Way to Broad-Scale Prenatal and Carrier Testing

Jacquelyn K. Beals, PhD

January 31, 2011

January 31, 2011 — A new study reports the development of a test panel using next-generation sequencing to detect carriers of more than 400 severe recessive childhood diseases. The screening is far less expensive than complete genome sequencing and detects the designated mutations with 95% sensitivity and nearly100% specificity.

Published online January 12 in Science Translational Medicine, this is 1 of several recent studies that employ new genetic technologies to identify a broad spectrum of mutations early; for example, during prenatal development or, for the present study, in carriers before conception occurs.

"Next-generation sequencing is akin to covering the genome by spraying it with tiny fragments ([like] a massive shotgun) — you get everything very inexpensively," explained senior author Stephen F. Kingsmore, MB, ChB, BAO, president and chief executive officer of the National Center for Genome Resources, Santa Fe, New Mexico, and a physician-researcher at Children's Mercy Hospital, Kansas City, Missouri, in an email to Medscape Medical News.

"Traditional sequencing is like a rifle shot with a 'smart' bullet — very precise but very expensive," Dr. Kingsmore added.

Preconception testing for recessive mutations such as the one causing Tay-Sachs disease can decrease incidence of a disease in a generation: 40 years of screening in the North American Ashkenazi Jewish population has decreased the occurrence of Tay-Sachs disease to less than 10% of its prescreening level.

This study, using next-generation sequencing, considered criteria for preconception screening suggested by the American College of Medical Genetics: accuracy and cost of the test, severity of the disease, high penetrance of the recessive disease phenotype, and availability of intervention when mutations are identified.

A cost of less than $1 per test for each condition, along with high accuracy and sensitivity, are also desirable for preconception carrier screening. Screening for a broad spectrum of diseases is thought to improve cost benefits, and covering many mutations is most likely to lower incidence of disease over time.

More than 1100 disorders with probable Mendelian inheritance patterns are a result of recessive mutations, causing about 10% of children's hospitalizations and 20% of infant mortality. The diseases selected for screening are severe enough to influence family planning or infant care. Genes causing mild diseases, disorders with adult onset, or conditions lacking strong evidence for causal mutations were not included. The present study assessed mutations of 437 genes causing 448 recessive diseases.

"We have continued to refine the disease list over the year since the panel [of genes] presented in the manuscript was 'locked down,' " noted Dr. Kingsmore. "As a result, the panel that we have in hand today includes 568 severe childhood recessive diseases. Deriving a comprehensive list of disorders that meet the requirements of the [American College of Medical Genetics] and [Clinical Laboratory Improvement Amendments] is not simple."

"Initially, I had (foolishly) thought that mental retardation did not meet our 'severe' disease criterion," said Dr. Kingsmore. "The later consideration of including them was [a result of] the persuasive evidence presented by our collaborator, Dr. Hilger Ropers of the Max Planck Institute in Berlin, who is a world leader in identification of such genes.... [Dr.] Hilger persuaded me that mental retardation was indeed a severe medical condition with enormous family implications."

The mutations detected with 95% sensitivity and nearly 100% specificity were substitutions, insertions or deletions, splicing, large deletion mutations, and single nucleotide polymorphisms. The study found that DNA samples from 104 individuals carried an average of 2.8 severe recessive mutations (range, 0 - 7) that could cause pediatric disorders.

Clinical Outlook for Preconception Testing

The clinical effect of preconception testing, and of noninvasive prenatal diagnosis using small maternal blood samples to assess the fetal genome, was discussed in a perspective article also published in Science Translation Medicine. The article mentions a current trial by the National Institute of Child Health and Human Development comparing the "accuracy and efficacy of cytogenomic arrays to the standard of microscopic chromosomal karyotype analysis."

The trial includes careful consideration of changes in chromosomal regions associated with disease, as well as 2-year postnatal follow-up of the children. "A similarly cautious approach should be used in applying genome sequencing technology in noninvasive prenatal diagnosis and preconception carrier testing," wrote coauthors Laird Jackson, MD and Reed E. Pyeritz, MD, PhD.

Asked to compare the criteria for carrier, prenatal, or newborn screening, Dr. Jackson, an expert on prenatal genetic tests from the Department of Obstetrics and Gynecology, Drexel University College of Medicine, and Division of Genetics, Children's Hospital of Philadelphia, Pennsylvania, replied via email to Medscape Medical News: "The main difference is that newborn testing is predicated on instituting some modifying management as soon as possible, so that the predicted effects of the gene defect do not occur or are reduced in magnitude. Carrier testing is predicated on the lack of such management for the newborn and developing affected person," said Dr. Jackson. "The matter of pregnancy termination is automatically raised [in prenatal testing,] along with its societal controversy."

Although the perspective article urges caution in applying "rapidly emerging genome sequencing technologies to preconception carrier testing and prenatal genetic diagnosis," Dr. Jackson thinks these technologies will be used clinically in "more than a year or 2, but less than a decade."

"It will obviously depend upon the manner of development. Commercial development will attempt to proceed rapidly and the technologies...and large reference laboratories will join in. But development and implementation of education efforts for both professionals...and the public will require a lot of effort and will be costly in time and dollars," said Dr. Jackson. "Without at least a modicum of discussion and planning, we will continue to have the kind of back and forth that has been seen with 23 and Me."

The study was supported by the Beyond Batten Disease Foundation, National Institutes of Health, Illumina Inc, Life Technologies, and British Airways PLC. At the time of the research, 2 authors were employees of Illumina Inc, and 3 authors are employees of Life Technologies. The other authors, including Dr. Kingsmore, have disclosed no relevant financial relationships.

Sci Transl Med. Published online January 12, 2011.

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