RESEARCH ARTICLE Identification of Genomic Loci Contributing to Agenesis of the Corpus Callosum Mary C. O’Driscoll,1* Graeme C. M. Black,1 Jill Clayton-Smith,1 Elliott H. Sherr,2 and William B. Dobyns3 1University of Manchester, Manchester Academic Health Sciences Centre, Central Manchester Foundation Trust, Hathersage Road, Manchester, M13 9WL, United Kingdom 2Department of Neurology, University of California-San Francisco, San Francisco, California 3Department of Human Genetics, University of Chicago, Chicago, Illinois Received 9 August 2009; Accepted 24 May 2010 Agenesis of the corpus callosum (ACC) is a common brain malformation of variable clinical expression that is seen in many How to Cite this Article: syndromes of various etiologies. Although ACC is predominant- O’Driscoll M, Black G, Clayton-Smith J, Sherr ly genetic, few genes have as yet been identified. We have EH, Dobyns WB. 2010. Identification of constructed and analyzed a comprehensive map of ACC loci genomic loci contributing to agenesis of the across the human genome using data generated from 374 patients corpus callosum. with ACC and structural chromosome rearrangements, most Am J Med Genet Part A 152A:2145–2159. having heterozygous loss or gain of genomic sequence and a few carrying apparently balanced rearrangements hypothesized to disrupt key functional genes. This cohort includes more than 100 previously unpublished patients. The subjects were ascertained et al., 2008], the underlying genetic causes remain elusive. Recent from several large research databases as well as the published improvements inmolecular and cytogenetictechnology have led toa literature over the last 35 years. We identified 12 genomic loci rapid increase in the number and definition of copy number variants that are consistently associated with ACC, and at least 30 other (CNVs) [de Smith et al., 2007; Perry et al., 2008] and to a broadening recurrent loci that may also contain genes that cause or contrib- in our understanding of the many chromosomal regions and ute to ACC. Our data also support the hypothesis that many ACC syndromes associated with ACC. We therefore present and analyze loci confer susceptibility to other brain malformations as well as a comprehensive map of ACC loci in the human genome using data ACC, such as cerebellar hypoplasia, microcephaly, and polymi- generated from 374 patients with ACC and structural chromosome crogyria. The database presented here provides a valuable re- rearrangements, including at least 101 previously unpublished cases. source for diagnosis and management of individuals with ACC The subjects were ascertained from large research databases main- and individuals with chromosome rearrangements in whom tained by the authors (WBD, EHS), the Californian Birth Defects ACC should be suspected, and of course for identifying ACC Monitoring Program (CBDMP—see the Methods Section), three causal and contributory genes. Well-defined diagnostic criteria, online databases of patients with chromosome rearrangements improved scanning techniques, and increased recognition of (DECIPHER, ECARUCA, DGAP—see the Methods Section), and associated abnormalities will further facilitate gene mapping a comprehensive literature review. and allow definition of distinct syndromes within this heteroge- Using these combined strategies we identified 12 loci with 6 or neous group of patients. Ó 2010 Wiley-Liss, Inc. more subjects with ACC, and another 18 loci with 3–5 patients with ACC. We also found many other possible loci (17) described in Key words: corpus callosum; corpus callosum agenesis; corpus small numbers of patients with ACC, which may represent either callosum hypoplasia; magnetic resonance imaging; chromosome; copy number variant; brain malformation Additional supporting information may be found in the online version of this article. Grant sponsor: NIH; Grant numbers: 1R01-NS058721, 4 K02-NS052192; INTRODUCTION Grant sponsor: NIHR/Manchester Biomedical Research Centre. The corpus callosum (CC) is the largest of three forebrain com- *Correspondence to: Mary C. O’Driscoll, Genetic Medicine, St Mary’s Hospital, Manchester missures in humans, and originates from themost rostral segment of Academic Health Sciences Centre, University of Manchester, M13 9WL, the developing forebrain.Agenesis of thecorpus callosum (ACC) is a United Kingdom. E-mail: [email protected] common brain malformation with significant variability in expres- Published online 3 August 2010 in Wiley Online Library sion [Glass et al., 2008] (Fig. 1). Although ACC is commonly (wileyonlinelibrary.com). associated with genetic disorders [Dobyns, 1996; Schell-Apacik DOI 10.1002/ajmg.a.33558 Ó 2010 Wiley-Liss, Inc. 2145 2146 AMERICAN JOURNAL OF MEDICAL GENETICS PART A FIG. 1. Agenesis or hypogenesis of the corpus callosum in six patients with various chromosome deletions on T1-weighted midline sagittal magnetic resonance images. A,B: The normal shape of the corpus callosum is shown in two individuals with arrows pointing to the rostrum (r), genu (g), body (b), and splenium (s). C: Agenesis or complete absence of the corpus callosum in a girl with deletion 1q44 (LR05-202). D: Hypogenesis of the corpus callosum with absent rostrum, thin and short body and absent splenium in a boy with deletion 1q44 (LR06-076). E: Severe hypogenesis in a girl with deletion 6q26-q27 (LR06-191). F: Mild hypogenesis with a short, comma-shaped corpus callosum in a boy with deletion 6q26-q27 (LR00-183). G: Hypogenesis in a girl with interstitial deletion 6q25 (LR00-226). H: Mild hypogenesis with a short, comma-shaped corpus callosum in a girl with interstitial deletion 14q13 (LR01-197). low penetrance ACC loci or incidental findings (Fig. 2 and see are also used [Barkovich, 2002; Hetts et al., 2006; Schell-Apacik supporting information Table I which may be found in the online et al., 2008]. Hypoplasia of the CC describes a thin CC where all version of this article). Many of the latter had poorly defined critical the segments are present but abnormally thin, and has sometimes regions, other incidental chromosome abnormalities unrelated to been used when the CC appears short but otherwise normally the ACC phenotype, or an incorrect diagnosis of ACC. From our formed, as well as thin. analysis of these data, we hypothesize that the human genome contains over 30 loci in which heterozygous loss or gain of gene products causes or contributes to ACC. Furthermore, some of the Sources of Data higher penetrance loci contain two (or more) ACC causative genes, We retrieved data from our own, largely unpublished, research and several ACC loci also confer susceptibility to other brain databases (sources (1) and (2) below) and supplemented this with malformations such as cerebellar hypoplasia, microcephaly, and data from several appropriate online databases. We also consulted polymicrogyria. These data provide information that will assist in all available reports of CC anomalies associated with cytogenetic the interpretation of abnormal karyotypes and microarray results in abnormalities in the published medical literature from 1965, with a pre- and postnatal medical and research settings and direct genetic particular emphasis on reports since the last review in 1996 investigation in patients with brain imaging abnormalities involv- [Dobyns, 1996]. Our primary sources included: ing the CC. It also has the potential to contribute to our knowledge of the genes and gene pathways involved in normal and abnormal (1) Lisdb: This is a large database of 5,400 patients ascertained brain development. based on birth defects of the brain and other neurodevelop- mental disabilities collected and maintained by WBD. Of these METHODS 409 are recorded to have a callosal disorder documented by brain imaging studies, some of which have been the subject of The CC is the principal connection between the right and left previous publications. cerebral hemispheres. Four contiguous segments can be seen on (2) Brain Development Research Program (BDRP): This is a study MRI brain imaging: the rostrum, genu, body, and splenium (Fig. of cortical malformations lead by EHS, with a focus on callosal 1A,B). Several different terms have been used in the literature to anomalies that includes 456 patients with ACC as detected by describe callosal malformations. Complete absence is referred to MRI. Only clinically confirmed cytogenetic data are included as ACC. Partial absence, typically involving the anterior rostrum from this cohort. and posterior body and splenium, is preferentially described as (3) California Birth Defects Monitoring Program (CBDMP) hypogenesis although the terms partial agenesis and dysgenesis Database (www.cbdmp.org): This is a database maintained by O’DRISCOLL ET AL. 2147 the State of California Department of Public Health and the of other brain malformations. Several different terms were used March of Dimes Foundation that identifies children with birth to describe CC abnormalities without any obvious consensus. defects including ACC. From a review of data between 1993 and These included ‘‘absent,’’ ‘‘agenesis,’’ ‘‘dysgenesis,’’ ‘‘hypogenesis,’’ 2003, 645 cases of ACC were identified. However, brain imaging ‘‘hypoplasia,’’ ‘‘thin,’’ and ‘‘partial agenesis.’’ For this reason, we studies were not available for children listed in this database. have used ACC as an umbrella term to cover all of these descriptions. (4) European Cytogeneticists Association Register of Unbalanced We identified many patients from literature reports or online Chromosome Abberations (ECARUCA;