Research ArticleHuman Genomics

Carrier Testing for Severe Childhood Recessive Diseases by Next-Generation Sequencing

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Science Translational Medicine  12 Jan 2011:
Vol. 3, Issue 65, pp. 65ra4
DOI: 10.1126/scitranslmed.3001756

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Shining a Light on Comprehensive Carrier Screening

Although diseases inherited in a Mendelian fashion are rare, together they account for about 20% of deaths in infancy. For Mendelian diseases that are recessive (of which there are more than 1000), screening before pregnancy (preconception screening) together with genetic counseling of those carrying a mutant allele could reduce the incidence of these diseases and the suffering that they incur. In the case of Tay-Sachs disease, an incurable neurodegenerative disease of infancy, preconception screening for disease gene mutations and genetic counseling among individuals of Ashkenazi descent has reduced the incidence of this tragic disease by 90%. However, simultaneous testing for many recessive childhood diseases is costly, so, to date, screening has included just a few diseases such as Tay-Sachs disease, cystic fibrosis, and familial dysautonomia.

In a new study, Kingsmore and his colleagues have combined target gene capture and enrichment, next-generation sequencing, and sophisticated bioinformatic analysis to develop a platform capable of screening several hundred DNA samples simultaneously for 448 severe recessive diseases of childhood. They demonstrate that their method is sensitive, specific, and scalable in a research setting and that it should be straightforward to automate the process. The authors report that individuals in the general population carry an average of three recessive childhood disease mutations. They also discovered that about 10% of disease mutations in commonly used databases are incorrect, suggesting that disease mutation annotations in such databases should be carefully scrutinized. The authors predict that their screening test could be made faster and more cost-effective with the advent of microdroplet polymerase chain reaction and third-generation sequencing technologies. Their study provides a proof of concept that it should be possible to introduce preconception carrier screening for many recessive pediatric disease mutations as long as the disease genes are known. Many social, legal, and societal issues need to be addressed before preconception carrier screening can be made available for the general population, and cost is still a big consideration. However, this methodology could also be applied for comprehensive screening of newborns and would allow early diagnosis and intervention for a variety of Mendelian diseases. Although it may be some time before preconception carrier testing enters the community setting, physicians, patients, parents, and genetic counselors need to discuss the impact and implications of this new technology.


  • * These authors contributed equally to this work.

  • Citation: C. J. Bell, D. L. Dinwiddie, N. A. Miller, S. L. Hateley, E. E. Ganusova, J. Mudge, R. J. Langley, L. Zhang, C. C. Lee, F. D. Schilkey, V. Sheth, J. E. Woodward, H. E. Peckham, G. P. Schroth, R. W. Kim, S. F. Kingsmore, Carrier Testing for Severe Childhood Recessive Diseases by Next-Generation Sequencing. Sci. Transl. Med. 3, 65ra4 (2011).