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Title: Both Rare and De Novo Copy Number Variants Are Prevalent in Agenesis of the Corpus Callosum but Not in Cerebellar Hypoplasia or Polymicrogyria}
Article:
Abstract:
Agenesis of the corpus callosum( ACC), cerebellar hypoplasia( CBLH), and polymicrogyria( PMG) are severe congenital brain malformations with largely undiscovered causes. We conducted a large-scale chromosomal copy number variation( CNV) discovery effort in 255 ACC, 220 CBLH, and 147 PMG patients, and 2, 349 controls. Compared to controls, significantly more ACC, but unexpectedly not CBLH or PMG patients, had rare genic CNVs over one megabase( p = 1. 48×10−3; odds ratio[OR] = 3. 19; 95% confidence interval[CI] = 1. 89–5. 39). Rare genic CNVs were those that impacted at least one gene in less than 1% of the combined population of patients and controls. Compared to controls, significantly more ACC but not CBLH or PMG patients had rare CNVs impacting over 20 genes( p = 0. 01; OR = 2. 95; 95% CI = 1. 69–5. 18). Independent qPCR confirmation showed that 9. 4% of ACC patients had de novo CNVs. These, in comparison to inherited CNVs, preferentially overlapped de novo CNVs previously observed in patients with autism spectrum disorders( p = 3. 06×10−4; OR = 7. 55; 95% CI = 2. 40–23. 72). Interestingly, numerous reports have shown a reduced corpus callosum area in autistic patients, and diminished social and executive function in many ACC patients. We also confirmed and refined previously known CNVs, including significantly narrowing the 8p23. 1-p11. 1 duplication present in 2% of our current ACC cohort. We found six novel CNVs, each in a single patient, that are likely deleterious: deletions of 1p31. 3-p31. 1, 1q31. 2-q31. 3, 5q23. 1, and 15q11. 2-q13. 1; and duplications of 2q11. 2-q13 and 11p14. 3-p14. 2. One ACC patient with microcephaly had a paternally inherited deletion of 16p13. 11 that included NDE1. Exome sequencing identified a recessive maternally inherited nonsense mutation in the non-deleted allele of NDE1, revealing the complexity of ACC genetics. This is the first systematic study of CNVs in congenital brain malformations, and shows a much higher prevalence of large gene-rich CNVs in ACC than in CBLH and PMG.
Introduction:
Agenesis of the corpus callosum( ACC), cerebellar hypoplasia( CBLH), and polymicrogyria( PMG) are a group of complex, severe, and causally heterogeneous brain malformations that result in significant developmental disability and seizures, and sometimes occur together in the same individual. Even individuals with ACC who have intelligent quotients( IQs) in the normal range often have deficits in social and executive functioning and may have an autism spectrum disorder( hereafter autism)[1],[2]. While the incidence of each malformation is low( ∼1/4000 live births, with PMG even less prevalent)[3]–[5], they are nevertheless the most common developmental brain malformations encountered in the clinic and both ACC and CBLH are frequently seen in prenatal brain imaging[6],[7]. Numerous clinical reports or studies focused on individual loci have shown that genomic copy number variants – particularly those that are several megabases in length, affect many genes, and arise de novo – are implicated in the etiology of these three brain malformations. For instance, recurrent CNVs in 1p36, 1q42-43 and 8p23, have been identified in a number of ACC patients, and we recently reviewed more than 40 others mostly detected by karyotype analysis[3],[8]–[14]. Some CNVs resulting in CBLH have been found in 3q22. 3-q25. 2, 6p25. 3, 13q12. 3-q14. 11, 22q13 and Xq28, with the causative genes in 6p25. 3( FOXC1) and 3q22. 3-q25. 2( ZIC1 and ZIC4) having been identified[15]–[20]. CNVs in PMG have been mapped to 1p36. 3, 2p16. 1-p23. 1, 4q21. 21-q22. 1, 6q26-q27, and 22q11. 2, among others[4],[21]–[23]. Most of these studies have used isolated patients or small series, although one study examined rare CNVs in structural brain malformations in 169 patients. However, that study did not distinguish among patients with different classes of malformations( focal cortical dysplasia, microcephaly, lissencephaly, posterior fossa defects, and callosal agenesis, with the latter found in only 18 patients) and focused mostly on pathway analysis[13]. Thus, no studies have assessed the genome-wide burden of rare CNVs or the rate of de novo CNVs in a systematic manner in patients with brain malformations. Overcoming the limitations of prior studies, we analyzed genic CNVs in 545 patients with one or more of these three common brain malformations and in 2, 349 control individuals. We hypothesized that these patients have a higher genome-wide burden of large rare genic CNVs than controls and that a significant percentage of them have large de novo likely pathogenic CNVs including both novel and previously reported intervals. We further anticipated that many of the de novo CNVs would be sub-microscopic[less than 4 megabases( Mb)], demonstrating a larger disease burden for CNVs than previously seen through cytogenetic approaches.
Discussion:
This is the first large-scale CNV analysis involving common brain malformations. Our investigation has demonstrated that large CNVs, particularly deletions, are highly enriched in this well-defined ACC cohort, and our study has led to significant narrowing of critical regions for several ACC chromosomal intervals and discovery of six novel CNVs( five ACC and one CBLH) with high pathogenicity scores. These discoveries will facilitate both the interpretation of CNV results in patients with many developmental disorders and the discovery of the underlying genes and pathways. The genomic burden of large, gene-rich, rare CNVs, particularly deletions, was significantly higher in ACC, ACC-ONLY, and ACC-PLUS patients than controls. Unexpectedly, the burden of rare CNVs was not significantly different in patients with CBLH or PMG( with or without ACC) than in controls. While several causative CNVs have been identified for these malformations[4],[15]–[23], our large-scale study suggests that CNVs may not explain a significant proportion of patients with these malformations. These differences may in part be explained by extrinsic( non-genetic) causes that may be more important for CBLH and PMG than for ACC and other developmental brain disorders[57]–[59]. We also have not addressed( except in the case of NDE1) single gene autosomal recessive models or oligogenic recessive models, which could explain the causes for some or many of the CBLH and PMG cases in our cohort. Therefore, our hypothesis that the genomic burden of rare genic CNVs will be significantly higher in patients compared to controls was supported for ACC but not for the other two malformations, and thus further genetic investigation is warranted for all three groups of disorders. The hypothesis that there would be an enrichment of large de novo CNVs in the patient cohort was also supported for ACC but not CBLH or PMG as we observed that 9. 4% of ACC patients had at least one de novo CNV, with 7. 1% having at least one large de novo CNV≥500 kb. As we had anticipated, almost one-third( 34. 5%) of all de novo CNVs were sub-microscopic( less than 4 Mb). Intriguingly, a significant number of de novo but not inherited CNVs in ACC overlapped de novo CNVs previously observed in patients with autism. One explanation for this is that our ACC cohort was skewed towards patients who had a developmental disability, including autism, since this was the reason why many of these patients were initially ascertained. From Table S7, which lists four features of developmental disability in all of our ACC patients, only 16( 15. 8%) patients( double asterisks) out of the 101 patients( single asterisks) in whom all four features were evaluated had no developmental impairment. None of the CNVs from these 16 patients overlapped de novo CNVs in autism. Thus, because all ACC patients whose de novo CNVs overlapped de novo autism CNVs had some form of developmental disability, their de novo CNVs may contribute less towards ACC and more towards the developmental disability. Another explanation is that the observed overlap points to a shared genetic risk between ACC and autism for the following reasons. First, it has been shown that there is an overlapping genetic risk among divergent neurological disorders indicating that, while there may be some unique variants for each class of disorder, there are many that are also common[60]–[63]. This may be due to these neurological disorders( including ACC and autism) being complex, genetically heterogeneous with variable expressivity, and often caused by disruption of multiple genes each of which has a small to moderate effect. Second, a plethora of studies, including an extensive meta-analysis[64], has demonstrated unequivocally that the corpus callosum area is reduced and that its structure and integrity are compromised in patients with autism[25]–[33]. This is in keeping with findings of under-connectivity of functional brain networks and aberrant interhemispheric information transfer in autism patients[65],[66] and in a mouse model[67]. Third, the vast majority of patients with ACC have disruption of higher order cognition, social intelligence, or both. They have variable deficits in social and executive functioning as shown by several studies of high functioning ACC individuals with IQ in the normal range[1],[2],[68]. While these observations are suggestive, additional studies including single gene analyses will be needed to address more directly whether ACC and autism indeed have a shared genetic basis. Our study demonstrates a prevalence of large gene-rich de novo CNVs in ACC but not in CBLH or PMG. Additional patients with overlapping CNVs as well as mutations in candidate genes identified by deep sequencing will be needed to identify one or more novel causal genes with major effects, which can then be followed up with studies in model organisms. In addition, patients who did not have any likely pathogenic CNVs will have to be subjected to additional analyses such as exome sequencing and assessing non-genic regions that may disrupt the regulation of causative genes.
Here , we systematically test the genetic etiology of three common developmental brain malformations: agenesis of the corpus callosum ( ACC ) , cerebellar hypoplasia ( CBLH ) , and polymicrogyria ( PMG ) by copy number variation ( CNV ) analysis in a large cohort of brain malformation patients and controls . We found significantly more ACC but not CBLH or PMG patients with rare genic CNVs over one megabase and with rare CNVs impacting over 20 genes when compared with controls . De novo CNVs were found in 9 . 4% of ACC patients , and interestingly many such CNVs overlapped with de novo CNVs observed in autism . Notably , numerous studies have demonstrated a reduction in the corpus callosum area in autistic brains . Our analysis also refined previously known large CNVs that cause these malformations , and identified six novel CNVs that are likely deleterious . One ACC patient had inherited a deletion from the father which , through exome sequencing , was found to uncover a recessive nonsense mutation in NDE1 on the non-deleted allele inherited from the mother . Our study is the first to systematically evaluate the burden of rare genic CNVs in congenital brain malformations and shows that large gene-rich CNVs are more common in ACC than in CBLH and PMG .