Diagnostic exome sequencing in persons with severe intellectual disability finds new candidate genes

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 Key study points:

1.  Exome sequencing of patients and their parents can help diagnose the genetic cause of intellectual disability, especially when the cause is a de novo mutation.

 2. Exome sequencing offers a way to identify new candidate intellectual-disability genes.

Primer: The DSM-IV divides intellectual disability (ID) into five categories, but studies often use a simplified system based on IQ: severe (IQ<50) and mild (IQ 50-70) ID. Genetic abnormalities may be present in 25 – 50% of ID cases. Some genetic causes of ID are well-recognized, like Trisomy 21. Other genetic causes of ID are just coming to light, like pathogenic copy number variants, and single gene causes of ID.

Identification of the cause of ID is particularly challenging when the ID is non-syndromic, that is, when it does not present with any other clinical features or comorbidities that might suggest a known cause of ID. In some study populations, up to 60% of ID cases have no identified cause, even after extensive workups including clinical examination and genetic testing.

From a genetic and evolutionary perspective, the paradox of severe ID is that although affected individuals rarely reproduce, the prevalence of severe ID in the population is relatively stable. One hypothesis put forward to explain this is that de novo point mutations are an important cause of severe ID. The reasoning is that since many genes can affect intellectual development, a low rate of spontaneous mutation across all these genes could produce the incidence rate seen in the general population.

Background reading:

1.  Vissers, L. E. L. M. et al. A de novo paradigm for mental retardation. Nat. Genet. 42, 1109–1112 (2010).

 2. Kaufman, L., Ayub, M. & Vincent, J. B. The genetic basis of non-syndromic intellectual disability: a review. J Neurodev Disord 2, 182–209 (2010).

This [gene sequencing] study: 100 patients with unexplained intellectual disability (IQ <50), along with their unaffected parents, were enrolled in this Dutch study. Exome sequencing was performed for all parents and patients. De novo, recessive and X-linked mutations were identified from this sequencing data. The authors were able to diagnose the cause of ID in 16 patients: 10 had de novo mutations in known ID genes, 3 had maternally-inherited mutations in X-linked ID genes and 3 had de novo mutations in novel ID genes identified in this study.

The novel ID genes were first identified as candidate genes that had de novo mutations, but were not known to be involved in ID. The authors then resequenced these candidate genes in a series of 765 individuals with ID. They found de novo mutations in the same genes in this confirmatory series, and assigned a causal function to these genes.

In sum: The application of exome sequencing for diagnosis of severe ID is novel. Though only 16 patients were diagnosed, these were all patients who could not previously be diagnosed with other genetic tests. Cost may be a concern since the patient as well as both parents must be sequenced.

Exome sequencing also enabled the identification of new candidate genes that may be involved in ID. The authors even assigned a causative role in ID to three novel genes. However, this causative role is based on phenotypic similarity between individuals with loss-of-function mutations in the same gene. An animal model or a plausible molecular pathway that could be tested would provide better proof of causation.

The identification of new ID genes and new candidate ID genes is important as it will enable more diagnoses to be made in the future. Thus, this study highlights a new method to both diagnose patients and to increase our understanding of the genetic causes of ID.

 Click to read the study in NEJM

 Written by [TJ] and [MP]

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