<i>De Novo</i> Mutations in Moderate or Severe Intellectual Disability

<div><p>Genetics is believed to have an important role in intellectual disability (ID). Recent studies have emphasized the involvement of <i>de novo</i> mutations (DNMs) in ID but the extent to which they contribute to its pathogenesis and the identity of the corresponding genes remain largely unknown. Here, we report a screen for DNMs in subjects with moderate or severe ID. We sequenced the exomes of 41 probands and their parents, and confirmed 81 DNMs affecting the coding sequence or consensus splice sites (1.98 DNMs/proband). We observed a significant excess of <i>de novo</i> single nucleotide substitutions and loss-of-function mutations in these cases compared to control subjects, suggesting that at least a subset of these variations are pathogenic. A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (<i>ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45</i>), resulting in a diagnostic yield of ∼29%. We also identified 12 possibly pathogenic DNMs in genes (<i>HNRNPU, WAC</i>, <i>RYR2, SET, EGR1, MYH10</i>, <i>EIF2C1</i>, <i>COL4A3BP, CHMP2A, PPP1CB, VPS4A, PPP2R2B</i>) that have not previously been causally linked to ID. Interestingly, no case was explained by inherited mutations. Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID. We conclude that DNMs represent a major cause of moderate or severe ID.</p></div

Distribution of the DNMs identified in this study and in controls.

<p>*canonical splice site variants not included.</p><p>**Consensus splice site variant not included.</p><p>NA, not applicable. LoF SNVs, nonsense and canonical splice site. Nominally significant <i>P</i> values (<0.05) calculated using an <i>R</i> exact binomial test.</p><p>Distribution of the DNMs identified in this study and in controls.</p

Number of DNMs per affected individual in each trio.

<p>Number of DNMs per affected individual in each trio.</p

Physical protein-protein interaction network generated by GeneMANIA (http://www.GeneMANIA.org/; Gene Ontology molecular function based weighting).

<p>The Query genes included those listed in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004772#pgen-1004772-t003" target="_blank">Table 3</a> from this study (in bold) and known and candidate ID genes reported with predicted-damaging DNMs from other studies (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004772#pgen.1004772.s003" target="_blank">Table S2</a>). Known ID genes are in red. The resulting network of 38 interconnected proteins was found to be enriched for proteins whose Gene Ontology molecular functions are implicated in the glutamate receptor signalling pathway (GRIN1, GRIN2A, GRIN2B, GRIA1, CACNG2, SHANK3; <i>FDR q</i>-value = 7.04e-6).</p

Top risk DNMs identified in this study.

<p>AA, total amino acids. All predictions by SIFT (<a href="http://sift.jcvi.org/" target="_blank">http://sift.jcvi.org/</a>), PFF2 (PolyPhen-2; <a href="http://genetics.bwh.harvard.edu/pph2/" target="_blank">http://genetics.bwh.harvard.edu/pph2/</a>) and PROVEAN (PVN; (<a href="http://provean.jcvi.org/genome_submit.php" target="_blank">http://provean.jcvi.org/genome_submit.php</a>) were damaging (scores indicated in parenthesis). CSS, Canonical splice site.</p><p>Top risk DNMs identified in this study.</p