PMC:4067558 / 14685-16939 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4067558","sourcedb":"PMC","sourceid":"4067558","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4067558","text":"Array- and exome-based studies have revealed a substantial contribution of de novo variation to ASD risk,19 prompting us to assess this further. After screening 2,096 trios (of all ancestries), we found 102 rare de novo CNVs in 99 affected subjects (three of whom had two events; Table S4). Overall, 4.7% of trios had at least one de novo CNV, whereas control subjects had a frequency of 1%–2%.4,31,38 The average length of de novo events in our affected subjects (1.17 Mb) was larger than that of de novo CNVs in unaffected siblings from the Simons Simplex Collection (0.67 Mb, p = 0.01)4 and in control trios (0.55 Mb, p = 0.01).31 The average size of de novo CNVs was also larger than the size of all rare CNVs in our affected (188 kb) and control (159 kb) subjects. De novo CNVs affected 3.8-fold more genes in affected subjects than in control subjects4,31 (2.6-fold for deletions and 6.1-fold for duplications). Even after controlling for the difference in CNV size by proportionally scaling the number of intersected genes in each group, we observed a 1.77-fold difference (1.2-fold for deletions and 2.8-fold for duplications, p = 0.02). Furthermore, de novo CNVs in simplex families intersected 4.0-fold more genes than did CNVs in controls4,31 (1.8-fold after size correction, p = 0.01). There were no significant differences between subjects from simplex families and those from multiplex families in the frequency (5% and 4.2%, respectively) or gene content (n = 18.7 and 18.8, respectively) of de novo CNVs. Similarly, no significant difference was found between males and females in the size (1.17 and 1.2 Mb, respectively) or gene content (n = 18 and 17.3, respectively) of de novo CNVs. For 85 of 102 de novo events, it was possible to determine the parent of origin, and roughly equal numbers of events originated on the paternal allele (n = 45) and the maternal allele (n = 40) (Tables S5A–S5H). Taken together, our data indicate that there is an increased burden of de novo events in ASD-affected subjects. The clinical relevance of de novo CNVs in ASD is confirmed by the fact that among 102 such events identified, half (n = 46) are considered etiologically relevant, including 40 loci known to be involved in ASD and ID (see below).","tracks":[{"project":"2_test","denotations":[{"id":"24768552-23259942-2047115","span":{"begin":105,"end":107},"obj":"23259942"},{"id":"24768552-21658581-2047116","span":{"begin":399,"end":401},"obj":"21658581"},{"id":"24768552-22083728-2047116","span":{"begin":399,"end":401},"obj":"22083728"},{"id":"24768552-22196331-2047116","span":{"begin":399,"end":401},"obj":"22196331"},{"id":"24768552-21658581-2047117","span":{"begin":588,"end":589},"obj":"21658581"},{"id":"24768552-22083728-2047118","span":{"begin":631,"end":633},"obj":"22083728"},{"id":"24768552-21658581-2047119","span":{"begin":859,"end":861},"obj":"21658581"},{"id":"24768552-22083728-2047119","span":{"begin":859,"end":861},"obj":"22083728"},{"id":"24768552-21658581-2047120","span":{"begin":1251,"end":1253},"obj":"21658581"},{"id":"24768552-22083728-2047120","span":{"begin":1251,"end":1253},"obj":"22083728"}],"attributes":[{"subj":"24768552-23259942-2047115","pred":"source","obj":"2_test"},{"subj":"24768552-21658581-2047116","pred":"source","obj":"2_test"},{"subj":"24768552-22083728-2047116","pred":"source","obj":"2_test"},{"subj":"24768552-22196331-2047116","pred":"source","obj":"2_test"},{"subj":"24768552-21658581-2047117","pred":"source","obj":"2_test"},{"subj":"24768552-22083728-2047118","pred":"source","obj":"2_test"},{"subj":"24768552-21658581-2047119","pred":"source","obj":"2_test"},{"subj":"24768552-22083728-2047119","pred":"source","obj":"2_test"},{"subj":"24768552-21658581-2047120","pred":"source","obj":"2_test"},{"subj":"24768552-22083728-2047120","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#ec93a9","default":true}]}]}}