PMC:4067558 / 17487-23931 JSONTXT

{"project":"2_test","denotations":[{"id":"24768552-21129364-2047124","span":{"begin":205,"end":207},"obj":"21129364"},{"id":"24768552-21681106-2047125","span":{"begin":865,"end":867},"obj":"21681106"},{"id":"24768552-20004760-2047126","span":{"begin":4721,"end":4723},"obj":"20004760"},{"id":"24768552-23495136-2047127","span":{"begin":6442,"end":6444},"obj":"23495136"}],"text":"CNV Burden in Autosomal-Dominant or X-Linked Genes and Loci Implicated in ASD and/or ID\nAt least 124 genes and 55 genomic loci have been implicated in ASD to date (Tables S6A and S6B; updated from Betancur18), all of which have also been implicated in ID. In addition, we compiled a list of genes and loci that have been implicated in ID, but not yet in ASD (Tables S6C–S6D). When we analyzed samples of inferred European ancestry, we found that 4% (87/2,147) of ASD-affected subjects had CNVs overlapping autosomal-dominant or X-linked genes and loci implicated in ASD and/or ID; this percentage was significantly higher than that in controls (OR = 4.09, 95% confidence interval [CI] = 2.64–6.32, p = 5.7 × 10−12; Figure 1A). We further classified these events into pathogenic, uncertain, or benign according to the American College of Medical Genetics guidelines.32 Pathogenic (or clinically significant) CNVs were identified in 2.8% (60/2,147) of affected subjects (OR = 12.62, 95% CI = 5.44–29.27, p = 2.74 × 10−15), and pathogenic deletions showed a striking estimated OR of 23.13 (95% CI = 5.57–96.08, p = 2.6 × 10−11; Figure 1B). Furthermore, the enrichment of pathogenic CNVs overlapping genes involved in ASD and/or ID was independently observed when the data were broken down by stages: 2.6% (25/979) of affected subjects in stage 1 (OR = 7.61, p = 1.22 × 10−5) carried pathogenic CNVs, whereas 3.0% (35/1,168) in stage 2 (OR = 6.47, p = 2.89 × 10−7) carried pathogenic CNVs. Some of these CNVs (e.g., NRXN1 deletion, 1q21 duplications [MIM 612475], and 16p11.2 duplications) were seen in a small fraction of control subjects, consistent with their variable expressivity and/or incomplete penetrance. Among the affected subjects with pathogenic CNVs, 63% (38/60) carried de novo events (Figure 1C), including two subjects with two pathogenic events each.\nWhen we further considered affected subjects of all ancestries (n = 2,446) and included chromosome abnormalities (\u003e7.5 Mb), select large rare de novo events, and select experimentally validated smaller CNVs (\u003c30 kb), we identified pathogenic CNVs in ∼3.3% of individuals with unexplained ASD (84 pathogenic events in 82/2,446 subjects; Figures 2A and S1A–S1C; Tables S7A and S7B). This most likely represents an underestimate of the true etiologic yield, given that many of the subjects were assessed with clinical diagnostic methods and excluded if positive; similarly, those individuals with known congenital malformations or dysmorphic features were not enrolled. Interestingly, 83% (64/77 [5 without information]) of carriers of pathogenic CNVs were nonsyndromic (i.e., ASD without reported accompanying physical or neurological abnormalities), and 57% (44/77 [5 without information]) had no ID (Figure 2B). The fraction of subjects with ID among carriers of pathogenic CNVs (42%) was not significantly different from the fraction of ID among all affected subjects (46%).\nInheritance data showed that 64% (54/84) of pathogenic CNVs were de novo events (59% were deletions, and 41% were duplications) and that the remaining (36%) were inherited, including seven X-linked CNVs maternally transmitted to males and 23 (13 maternal and 10 paternal [27%]) on autosomes (Figure 2C). Pathogenic deletions tended to be smaller than duplications (Figure 2D). As expected, pathogenic de novo events were on average significantly larger than inherited ones (3.14 Mb—excluding three affected subjects with whole-chromosome aneuploidy—versus 1.44 Mb, respectively). We also observed that the proportion of females was significantly increased among carriers of highly penetrant pathogenic CNVs (male-to-female ratio of 2:1 versus 6:1 among all affected subjects; two-tailed Fisher’s exact test p = 0.017; Figure 2E). In contrast, the male-to-female ratio among individuals with CNVs associated with variable expressivity was 6:1.\nPathogenic CNVs included well-characterized highly penetrant disorders associated with de novo CNVs, such as Phelan-McDermid syndrome (MIM 606232, 22q13.3 deletion including SHANK3 [MIM 606230]), Smith-Magenis syndrome (MIM 182290, 17p11.2 deletion including RAI1 [MIM 607642]), Kleefstra syndrome (MIM 610253, 9q34.3 deletion including EHMT1 [MIM 607001]), Williams syndrome (MIM 194050, 7q11.23 deletion), and large chromosomal abnormalities (Figure 2A; Table S7B). Recurrent deleterious CNVs mediated by segmental duplications affecting 12 distinct regions were identified in 44 individuals. For example, two unrelated males were found to harbor Xq28 duplications (MIM 300815), one de novo and one maternal, corresponding to a ∼0.3 Mb segmental-duplication-mediated gain (153.2–153.5 Mb), which was previously reported in X-linked ID.42 GDI1 (MIM 300104), mutations of which are linked to ID, is the most likely gene involved (Figure S8). Thus, our findings implicate abnormal GDI1 dosage in ASD. Interestingly, one AGP proband with the duplication had autism and a normal IQ, whereas the second had a borderline IQ (72) (see Table S8 for phenotype information of all affected subjects with pathogenic CNVs). Some other findings include a 1.7 Mb de novo deletion encompassing ARID1B (MIM 614556), recently implicated in ID and Coffin-Siris syndrome (MIM 135900), and a small maternally inherited intragenic deletion of HDAC4 (MIM 605314), involved in brachydactyly-mental-retardation syndrome (MIM 600430; Figure S7). Although many 2q37 deletions have been described in ASD, the deletion found in our proband directly implicates HDAC4 haploinsufficiency in autism.\nIn Table S9, we analyzed data across three ASD cohorts, including a total of 5,106 nonoverlapping affected subjects and 3,512 control subjects from the AGP, the Simons Simplex Collection, and the Autism Genetic Resource Exchange (AGRE), for 17 loci and genes commonly reported as implicated in ASD. The most frequent deletions involved 16p11.2 and NRXN1, accounting for 0.31% and 0.32% of affected subjects, respectively. Typical 15q11–q13 duplications of the imprinted PWS-AS critical region were found in 0.25% (13/5,106) of affected subjects, reaffirming this region’s importance in ASD. The majority of these duplications were of maternal origin, but two were paternally derived (one without information; Table S9). Although paternally derived duplications appear to have incomplete penetrance in comparison to maternal ones, there have been several cases reported in subjects with ASD.43"}