Severe intellectual disability occurs in 0.5% of newborns. Over the last years, using microarrays and exome sequencing has aided in the explanation of a big proportion of ID.
Gilissen et al (2014) applied whole-genome sequencing to 50 patients with severe ID (whose extensive genetic work-up, including microarray and exome sequencing, was negative) and their unaffected parents.
84 de novo SNVs affecting the coding region were identified. A statistically significant enrichment of loss-of-function mutations and an enrichment for genes previously implicated in ID-related disorders were noted. Moreover, 8 de novo CNVs were identified, including single-exon deletions, intra-exonic deletions, and interchromosomal duplications affecting known ID genes more frequently than expected.
The authors conclude that their overall diagnostic yield in this extensively studied cohort of severe ID was “42%, and 62% as a cumulative estimate in an unselected cohort”.
Genome sequencing identifies major causes of severe intellectual disability. Gilissen C, Hehir-Kwa JY, Thung DT, van de Vorst M, van Bon BW, Willemsen MH, Kwint M, Janssen IM, Hoischen A, Schenck A, Leach R, Klein R, Tearle R, Bo T, Pfundt R, Yntema HG, de Vries BB, Kleefstra T, Brunner HG, Vissers LE, Veltman JA. Nature. 2014 Jul 17;511(7509):344-7. doi: 10.1038/nature13394. Epub 2014 Jun 4. PMID: 24896178
Posted by Yannis Trakadis, MD