Almost 1 in 200 children has a severe intellectual disability, marked by delayed development of language, memory, problem-solving, and social skills. While intellectual disabilities are largely assumed to be genetic in origin, often caused by gene copy number variations (CNV) and single nucleotide polymorphisms (SNPs, pronounced "snip"), the exact cause can be difficult to detect.
Molecular diagnosis of intellectual disability is complicated because it is difficult to find the exact location of these DNA variations, and the smaller-scale diagnostic tools, like microarray detection of CNV or exome sequencing, are not as effective as we would like. A joint Dutch-American study, recently published in Nature, found that the diagnosis of severe intellectual disability is greatly improved with the use of whole genome sequencing. According to researcher Han Brunner, whole genome sequencing produces 100 times more data than exome sequencing, making it a huge step forward as a diagnostic tool.
The authors, led by Christian Gilissen, used whole genome sequencing on 50 patients with severe intellectual disabilities, who had not received a positive molecular diagnosis after extensive screening using conventional methods. They found 84 new SNPs causing loss-of-function mutations in certain genes and enhancement of other genes previously implicated with intellectual disability. The substitution rate of these SNPs detected using whole genome sequencing was significantly higher than any previously reported using other diagnostic tools. The authors also found 8 new CNVs, which included single-exon and intra-exonic deletions, and duplications of sections of DNA within chromosomes, all of which significantly affected genes implicated with intellectual disability.
Ultimately, the authors were able to give a molecular diagnosis to 42% of their patients using whole genome sequencing, while microarray and exome sequencing diagnosed 12% and 27% of patients, respectively. They also found that spontaneous mutation is responsible for up to 60% of cases of intellectual disability, and heritability accounts for only 2% of cases. With the decreasing cost of whole genome sequencing (see right), $100 000 000 to a few thousand dollars in 10 years, the authors are confident that this tool will continue to be useful in diagnosing not only intellectual disability, but other disorders with a genetic origin (i.e. cancer) as well.