Genetic Diagnosis of Intellectual Disability

Identification: Brunner, Han


Genetic Diagnosis of Intellectual Disability
Han G. Brunner
Radboud UMC, Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Nijmegen,The Netherlands; Maastricht University Medical Center, GROW School for Oncology and Developmental Biology, Maastricht, The Netherlands
Severe intellectual disability with an IQ of less than 50 affects approximately 1 in 200 newborns.
Recent technological advances have clarified the genetics of ID: There are at least 1000 genes involved in causing ID. While autosomal recessive ID predominates in inbred populations, new mutations are by far the most common cause of ID in outbred populations. Whole exome trio sequencing and array analysis for structural variants can clarify up to 60% of all cases of severe ID in the Dutch population, with the majority being due to de novo events. This has implications for our ability to predict and prevent such events.  Studies of spontaneous new mutations in humans show that paternal mutations predominate by about 4:1. There is an increase in mutations with age, which is most marked in males. Also, the types of mutations that occur are slightly different between males and females. There is a large contrast with consanguineous populations where homozygosity for recessive variants predominates. The total number of known recessive and dominant ID genes is similar. Collectively more than 1000 ID genes are known, suggesting that a significant fraction of all human genes are relevant and necessary for optimal brain function. Since most ID genes are now known, and since most disruptive events affect the coding sequence, whole genome and whole exome sequencing coupled with microarrays for detection of copy number variations can conclusively diagnose a large proportion of patients. Progress will rely on better technology, more accurate calling and interpretation of genomic variants, and the development and application of more complex inheritance schemes, notably autosomal dominant inheritance with reduced penetrance, and polygenic scenarios.


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