19 February 2015
By Dan King
When a child is born with abnormal features or fails to develop normally, a harmful genetic mutation is often to blame. Paediatricians and clinical geneticists work together like detectives, using genetic testing to uncover the genetic abnormality causing the child’s disease. Sometimes, the child’s appearance is characteristic of a known disorder and the genetic abnormality is easy to find, as is the case in Down syndrome.
But, when current genetic tests can find no causative mutation in children in UK hospitals, DNA samples from these difficult-to-solve cases are sent to the Wellcome Trust Sanger Institute. Here, we in a study called Deciphering Developmental Disorders harness the latest technologies, statistical methods and computational tools to find the underlying mutation. So far, we are successful about a third of the time.
One of our recent articles describes an unusual and fascinating part of the mutation-puzzle. This publication is entitled ‘Mosaic structural variation in children with developmental disorders’. Both mosaicism and structural variation are genetic features for which our knowledge has been transformed in the past decade.
Mosaicism describes cells from within the same organism with slightly different DNA patterns; corn with different colour kernels and cats with calico fur are familiar examples in non-humans. However, we now know that mosaicism is present in people too and can sometimes be damaging.
Structural variation deals with differences in chromosome shape that are sometimes large enough to be seen by microscope. This occurs when big blocks of DNA (often millions of bases long) are either removed from the chromosome and lead to loss of important genes, or undergo extra copying and overwhelm the chromosome.
So, mosaic structural variation deals with missing or extra blocks of DNA, that are present in some but not all of the cells of a person. Cells can be very sensitive to the amount of protein produced by genes, so having excessive or insufficient gene activity is one way that structural variation can lead to disease.
Unlike most of our DNA, which is inherited from our parents, mosaicism usually arises very early in development, even when the embryo is just a few cells in size – smaller than the eye can see.
In this study, we looked at the DNA of nearly 1,000 children to find out if any of them had mosaic structural abnormalities that might account for their developmental disorders, and we found that nine (0.9 percent) of them did.
The figure above shows a mosaic structural abnormality on the third chromosome of one of these children. On the right side of the figure, the black dots rise, showing an increase in the amount of chromosomal material. The red dots are a measure of the relative balance between the two chromosome copies, one each inherited from mum and dad. Where the black dots rise, the red dots are split, indicating an imbalance of chromosomal material. These features demonstrate extra genetic material across many millions of DNA bases in this chromosome in some cells.
Are mosaic structural abnormalities present in healthy people as well? To find out, we looked for these types of genetic mutations in the DNA of healthy children and found that they were much rarer. This tells us that these unusual abnormalities are likely to be damaging to the cells because they are present in children with disease but not in children without disease.
After we identified these mosaic structural abnormalities, we returned these results to the clinical geneticists and paediatricians who recruited into our study the children with these mutations. These medics could then explain the abnormalities we identified to families. Because these genetic abnormalities arise in children after fertilisation, the parents can be counselled that subsequent children are unlikely to be at increased risk of the same disorder, which can be reassuring for parents who choose to have more children.
We continue to investigate additional examples of unusual genetic abnormalities and explore all the fascinating mysteries present in our genome.
Dan King is a PhD student in Matt Hurles’ group at the Wellcome Trust Sanger Institute. Matt Hurles is a joint leader of the Deciphering Developmental Disorders study, a partnership between the Wellcome Trust Sanger Institute and the Department of Health that aims to advance clinical genetic practice for children with developmental disorders by the systematic application of the latest microarray and sequencing methods.
- King D, et al (2015). Mosaic structural variation in children with developmental disorders. Human Molecular Genetics. DOI:10.1093/hmg/ddv033
- Deciphering Developmental Disorders (2014). Large-scale discovery of novel genetic causes of developmental disorders. Nature. DOI:10.1038/nature14135
- Wright, C et al (2014). Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data. The Lancet. DOI:10.1016/S0140-6736(14)61705-0
- King D, et al (2014).A novel method for detecting uniparental disomy from trio genotypes identifies a significant excess in children with
developmental disorders. Genome Research. DOI:10.1101/gr.160465.113