Both Rare and De Novo Copy Number Variants Are Prevalent in Agenesis of the Corpus Callosum but Not in Cerebellar Hypoplasia or Polymicrogyria

Samin A Sajan,Kathleen J Millen,Susan L Christian,Elliott H Sherr,Hakon Hakonarson,Christopher T Sullivan,Michael J Herriges,Joseph T Glessner,Jyotsna Sudi,Alexander R Paciorkowski,Polina Bukshpun,A James Barkovich,Jean-Baptiste Rivière,Eric Rider,Liliana Fernandez,William B Dobyns,Mari Wakahiro,Sahar Esmaeeli Nieh,Benjamin Michael Neale

doi:10.1371/journal.pgen.1003823

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.

Highlights

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
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

Summary

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]. Numerous clinical reports or studies focused on individual loci have shown that genomic copy number variants – those that are several megabases in length, affect many genes, and arise de novo – are implicated in the etiology of these three brain While the incidence of each malformation is low (,1/4000 live births, with PMG even less prevalent) [3,4,5], they are the most common developmental brain malformations encountered in the clinic and both ACC and CBLH are frequently seen in prenatal brain imaging [6,7].

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