ausblenden:
Schlagwörter:
intellectual disability risks, parental consanguinity, whole exome sequencing, parent-patient trios,
impact of inherited and de novo mutations
Zusammenfassung:
In outbred Western populations, most individuals with intellectual disability (ID) are sporadic cases, dominant de novo mutations (DNM) are frequent, and autosomal recessive ID (ARID) is very rare. Due to the high rate of parental consanguinity which raises the risk for ARID and other recessive disorders, the prevalence of ID is significantly higher in Near- and Middle-East countries. Indeed, homozygosity mapping and sequencing in consanguineous families have already identified a plethora of ARID genes, but due to the design of these studies, DNMs could not be systematically assessed, and the proportion of cases that are potentially preventable by avoiding consanguineous marriages or through carrier testing is hitherto unknown. This prompted us to perform whole exome sequencing in 100 sporadic ID patients from Iran and their healthy consanguineous parents. In 61 patients, we identified apparently causative changes in known ID genes. Of these, 44 were homozygous recessive and 17 dominant de novo mutations. Assuming that the DNM rate is stable, these results suggest that parental consanguinity raises the ID risk about 3.6-fold, and about 4.1-4.25-fold for children of first-cousin unions. These results do not rhyme with recent opinions that consanguinity-related health risks are generally small and have been 'overstated' in the past. This article is protected by copyright. All rights reserved.
