Researchers Pinpoint Genetic Causes of Mental Disability

Laird Harrison

October 21, 2014

SAN DIEGO — Whole-genome sequencing can identify the genetic variations responsible for a large proportion of severe intellectual disabilities, a new study shows.

The technique can uncover mutations and adds to the information that has been available from genomic microarrays and exome sequencing, said lead investigator Christian Gilissen, PhD, a bioinformatician at the Radboud University Medical Center in Nijmegen, the Netherlands.

"Based on clinical diagnostic criteria, we can provide a genetic diagnosis for the majority of severe intellectual disability cases," said Dr Gilissen, who presented the study here at the American Society of Human Genetics 2014 Annual Meeting.

About 0.5% of newborns have a severe intellectual disability, and researchers have attributed these disorders to genetic causes. But a wide range of genetic anomalies can trigger these disorders, making it difficult to identify the exact cause of a patient's disability.

Previous microarray studies and exome sequencing have shown that de novo copy number variations (CNVs) and single-nucleotide variations (SNVs) are factors in intellectual disability.

Finding out what's going on helps stop the odyssey.

Still, most cases of intellectual disability remain undiagnosed. Dr Gilissen explained that analyzing single genes could uncover the cause of severe intellectual disability in about 1.5% of the cases.

Genomic microarrays could find about 12% of causes, whereas exome sequencing could cover 27%, he said.

To find out if whole-genome sequencing could add to what these techniques provide, Dr Gilissen and his team applied it to 50 patients with severe intellectual disability and their unaffected parents.

Previous genetic prescreening, including microarray-based CNV studies and exome sequencing, failed to identify the cause of the disabilities in these patients.

But the whole-genome sequencing revealed de novo SNVs — new mutations — that provided a conclusive genetic cause in 13 patients and a possible cause in another eight patients.

Together, these approaches yielded a 42% rate of diagnosis, said Dr Gilissen. And combining this with the other methods, the investigators were able to diagnose a majority of the patients.

The sequencing technique identified seven clinically relevant de novo CNVs and one recessively inherited compound heterozygous CNV. These CNVs included single-exon and intraexonic deletions of known intellectual disability genes, as well as interchromosomal duplications.

The investigators were able to map most of these CNVs at the single-nucleotide resolution level and find positional information for duplicated sequences. "You can find really small deletions very accurately," Dr Gilissen explained.

These results show that de novo mutations and CNVs affecting the coding region are the major cause of severe intellectual disability, he reported.

The use of whole-genome sequencing is an important step forward in finding the causes of severe intellectual disability, said session moderator Thomas Meitinger, MD, professor of human genetics at Munich Technical University in Germany.

Although it could be a long time before treatments can be developed on the basis of these findings, they can provide some relief to parents searching for causes, Dr Meitinger told Medscape Medical News. "Finding out what's going on helps stop the odyssey," he said.

Knowing the diagnosis can also help physicians compare patients with the same genetic diagnosis, and learn from the therapies their colleagues have tried, Dr Meitinger noted.

Dr Gilissen and Dr Meitinger have disclosed no relevant financial relationships.

American Society of Human Genetics (ASHG) 2014 Annual Meeting: Abstract 49. Presented October 19, 2014.


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