Essays on Science and SocietyGenome-Sequencing Anniversary

A Healthy Son

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Science  25 Feb 2011:
Vol. 331, Issue 6020, pp. 1026
DOI: 10.1126/science.1204088

Gutenberg must have felt like this: the sense of endless possibilities, of infinite applications exploiting the new technology, of the world having changed forever. It seems audacious, but is, I think, correct, to compare his time to ours. I offer a single case study to explain.

K is the youngest of eight siblings. Three of her five brothers were severely developmentally delayed, with cognitive impairment and intractable behavioral disorders. No one else in their large extended family was affected. The most likely explanation for her brothers' condition was X-linked inheritance following a new mutation in their mother. Fragile X was excluded, and the critical gene had eluded detection. The region of the X-chromosome shared by the three affected brothers was 40 megabases, too long to enable prenatal diagnosis.


K despaired of having a healthy son. Then early last spring, targeted X-exome sequencing of constitutional DNA from the affected brothers revealed a nonsense mutation in a gene known to be implicated in mental retardation. The mutation had not been detectable by conventional technologies but was transparent to massively parallel sequencing. K carried the mutant allele. Armed with knowledge of the mutation, K and her husband undertook pregestational diagnosis (PGD), which involves in vitro fertilization of their egg and sperm, then genotyping of embryos via the polar bodies, and implanting a normal embryo in the mother's uterus. In experienced hands, PGD works very well. K and her husband have a healthy newborn son.

Genetics is a way of thinking. Genomics is a set of tools. If we think rigorously about genetics and use these tools well, the resolution of inherited disorders on behalf of our patients will be bounded only by our imaginations. One healthy infant at a time is not a bad way to begin.

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