When parents find that a child is not developing as expected, the protracted doctor visits, hospital stays and examinations only add to their distress — especially when no other family member has the condition and the standard tests on the child's blood and genes shed no light on the cause. The uncertainties, costs and anguish can be devastating to families, says Michael Friez, who directs the diagnostic laboratory at the Greenwood Genetic Center in South Carolina, a non-profit organization that analyses patients' genomes for clinicians.
Every clinical geneticist has experienced the inability to identify the cause of a child's neurodevelopmental disorder, adds Roger Stevenson, a clinical geneticist also at the centre. In the early 2000s, he began seeing a family with a toddler that had severe developmental problems, including a smaller-than-average head and intellectual disability.
It was more than a decade after their first visit before sequencing revealed that the boy had a mutation in a gene called DYRK1A, which is thought to have a role in brain development. The finding later helped to diagnose 16 other children in the United States and Europe who had the same symptoms — and although the condition has no cure, Stevenson saw that identifying the gene comforted the boy's parents, as did knowing that there were other children like their son.
New mutations
What was notable about this child's case was that it involved a de novo mutation — one that neither parent carries in their regular complement of DNA. De novo mutations can occur early in the development of the embryo. They can be in parents' gametes. Around 80% of de novo mutations seem to occur in the father's sperm and 20% in the mother's egg, says Joris Veltman, a geneticist at Radboud University Medical Center in Nijmegen, the Netherlands, who in July published a study of de novo mutations in people with intellectual disabilities1.Disorder-causing de novo mutations are hard to detect — they have to be identified among a host of other, innocuous genetic changes. A number of software-based approaches are emerging to sift through sequenced genomes in search of such mutations.
As sequencing instruments and databases of genetic information become increasingly available, tool-builders hope that their software contributions can become part of routine medical care. But sequencing and analysis are different from, say, a blood cholesterol test — samples have to be prepared for the instruments, which churn out the genome sequence in snippets that must be assembled and aligned to a reference genome, such as that curated by the Genome Reference Consortium.
The results are not perfect. A patient's genome sequence can contain errors — caused by the machine misreading a letter of DNA, for example — that must be filtered out computationally. And even then, a huge number of possibilities remains. DNA bases might differ from the reference, sequences can be inserted or deleted and the number of copies of a gene can vary. Of thousands of such changes, only one might have a role in a disorder.
The child's DNA is then compared with that of the parents. Again, not all differences between their genomes connect to the child's disorder. Researchers use software that includes statistical analyses to determine which changes are most likely to have a role. And the tools add information, such as published data about the links between genes and disease. These results help to create lists of genetic changes, or variants, ranked by likelihood of being linked to a disorder. But variant analysis is still an emerging science, and the software tools are still maturing. Despite this, in some cases the approach turns up a specific genetic change that is likely to be the cause of a disorder.
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