Intellectual Disability Likely Not Inherited

Deborah Brauser

September 28, 2012

September 28, 2012 — Parents have a low risk of passing on severe intellectual disability to their offspring, new research suggests.

Using exome sequencing, investigators looked for newly formed mutations in 51 children with unexplained severe nonsyndromic intellectual disability; they also looked for mutations in their unaffected parents, as well as in 20 children without the disorder.

Results showed that the children with the disability had more disease-causing mutations in their genomes compared with their healthy peers. In addition, new mutations in 16 known and 6 novel genes appeared to cause the disorder in up to 55% of the cases studied.

"Although believed to be relatively common in intellectual disability, these results suggest that only a small proportion of cases...are likely to be inherited in autosomal recessive fashion (affected children inherit 1 copy of the faulty gene mutation from each parent)," said André Reis, MD, from the Institute of Human Genetics at the University of Erlangen-Nuremberg in Germany, in a release.

The investigators recommend that "large-scale sequencing should become a first-tier clinical diagnostic test for patients without a recognizable condition."

In addition, combining further genotype-phenotype studies with disease mechanism studies "should lead to improved patient care and novel treatment strategies," they write.

The study was published online September 27 in the Lancet.

Cause Unclear

According to the researchers, intellectual disability affects 1% to 2% of all children worldwide. It is defined as "substantial impairment of cognitive and adaptive functions that has onset in childhood."

"The genetic cause of intellectual disability in most patients is unclear because of the absence of morphological clues, information about the position of such genes, and suitable screening methods," they write.

Exome sequencing can examine thousands of genes while reading "only the parts of the human genome that encode proteins, where most of the disease-causing mutations are found," notes the release.

For this study, the investigators enrolled 51 children (62% girls) with severe nonsyndromic intellectual disability who participated in the German Mental Retardation Network and their nonaffected parents, and 20 children and parents from the KORA Augsburg Diabetes Family Study (healthy control participants).

DNA was extracted from peripheral blood leuckocyte samples from all participants. Enriched exomes were then assessed and sequenced.

First-Line Diagnostic Tool?

Results showed that significantly more of the children with intellectual disability had loss-of-function gene variants than did the healthy control participants (40% vs 10%, P = .02), "suggesting their contribution to disease development."

"After exclusion of copy-number variants, de-novo point mutations and small indels are associated with severe, sporadic non-syndromic intellectual disability, accounting for 45-55% of patients with high locus heterogeneity," write the researchers.

"Autosomal recessive inheritance seems to contribute little in the outbred population investigated," they add.

However, they also note that because several of the participants "did not meet the expected syndromic manifestation," a strong bias could have been present in the clinical syndrome descriptions.

"To fully exploit the diagnostic potential of exome sequencing, more knowledge about the frequency and pathogenicity of sequence variants is needed," write the investigators.

"Copy number variant profiling and whole-exome sequencing should resolve most...cases of severe intellectual disability," write Jozef Gecz, PhD, and Eric Haan, MBBS, from the School of Pediatrics and Reproductive Health at the University of Adelaide in Australia and from the Women's and Children's Hospital of North Adelaide, in an accompanying editorial.

They note that the remaining cases "might be more complex" and caused by other contributors, such as multiple genes, noncoding region mutations, and environmental factors.

The editorialists write that sequencing is both a powerful and cost-effective tool.

"Whole-genome sequencing technology has the potential to become the first-line diagnostic test for many disorders, and particularly intellectual disability, if it is able to identify copy number variants and triplet repeat disorders (eg, fragile X syndrome) as well as single nucleotide variants," they write.

"Families and patients can look forward to the benefits of a clear diagnosis."

The study was supported by the German Ministry of Education and Research, the European Commission 7th Framework Program, and the Swiss National Science Foundation. The study authors and the editorialists have disclosed no relevant financial relationships.

Lancet. Published online September 27, 2012. Abstract