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Array-Based Comparative Genomic Hybridization Analysis of Recurrent Chromosome 15Q Rearrangements Trilochan Sahoo,1* Chad A

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Array-Based Comparative Genomic Hybridization Analysis of Recurrent Chromosome 15Q Rearrangements Trilochan Sahoo,1* Chad A American Journal of Medical Genetics 139A:106–113 (2005) Array-Based Comparative Genomic Hybridization Analysis of Recurrent Chromosome 15q Rearrangements Trilochan Sahoo,1* Chad A. Shaw,1 Andrew S. Young,1 Nathan L. Whitehouse,1 Richard J. Schroer,2 Roger E. Stevenson,2 and Arthur L. Beaudet1 1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 2J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina Genomic rearrangements of chromosome 15q11- KEY WORDS: Angelman syndrome; autism; chro- q13 cause diverse phenotypes including autism, mosome 15; comparative genomic Prader–Willi syndrome (PWS), and Angelman hybridization; isodicentric 15; syndrome (AS). This region is subject to genomic Prader–Willi syndrome imprinting and characterized by complex combi- nations of low copy repeat elements. Prader–Willi and Angelman syndrome are caused primarily by INTRODUCTION 15q11-13 deletions of paternal and maternal ori- The chromosome 15q11-q13 interval is complex, having low gin, respectively. Autism is seen with maternal, copy repeat sequences, a high frequency of rearrangements, but not paternal, interstitial duplications. Isodi- and the presence of imprinted genes. Phenotypes associated centric 15q, most often of maternal origin, is with rearrangements of 15q11-q13 include autism, Prader– associated with a complex phenotype often Willi syndrome (PWS), and Angelman syndrome (AS). Autism including autistic features. Limitations of con- is a neurodevelopmental disorder of early childhood character- ventional cytogenetic tests preclude a detailed ized by social and communicative impairments and unusual analysis in most patients with 15q rearrange- patterns of stereotypical–repetitive behaviors [Bailey et al., ments. We have developed a microarray for 1996; Filipek et al., 2000]. Autism overlaps clinically with comparative genomic hybridization utilizing 106 several neurodevelopmental disorders (e.g., AS, fragile X genomic clones from chromosome 15q to charac- syndrome, Rett syndrome) [Barton and Volkmar, 1998; terize this region. The array accurately localized Folstein and Rosen-Sheidley, 2001; Peters et al., 2004; all breakpoints associated with gains or losses on Trillingsgaard and Ostergaard, 2004; Veltman et al., 2004]. 15q. The results confirmed the location of the Numerous cytogenetic abnormalities have been detected in common breakpoints associated with interstitial patients with autism, including segmental aneuploidies and deletions and duplications. The majority of translocations involving most chromosomes. The frequency of idic(15q) chromosomes are comprised of symme- 15q11-q13 abnormalities is 0.5 to 3% making them the most trical arms with four copies of the breakpoint 1 to common autosomal cytogenetic abnormality in autistic dis- breakpoint 5 region. Patients with less common order [Browne et al., 1997; Cook et al., 1997; Schroer et al., breakpoints that are not distinguished by routine 1998; Bolton et al., 2001; Borgatti et al., 2001; Roberts et al., cytogenetic methods were more accurately char- 2002, 2003; Thomas et al., 2002]. Most of these abnormalities acterized by array analysis. This microarray are of maternal origin suggesting that an imprinted gene in the provides a detailed characterization for chromo- region plays a role [Cook et al., 1997; Schroer et al., 1998; somal abnormalities involving 15q11-q14 and is Bolton et al., 2001]. The 15q11-q13 aberrations in autism useful for more precise genotype–phenotype cor- overlap the PWS and AS critical region, and both syndromes relations for autism, PWS, AS, and idic(15) syn- have phenotypic overlap with autism [Peters et al., 2004; drome. ß 2005 Wiley-Liss, Inc. Trillingsgaard and Ostergaard, 2004; Veltman et al., 2004]. Additionally, there are suggestions that the variable beha- vioral problems, including autism, in patients with AS/PWS, might be correlated with the nature and size of the 15q rearrangements [Butler et al., 2004; Varela et al., 2004]. This article contains supplementary material, which may be Despite the high frequency of 15q11-q13 aberrations in autism, viewed at the American Journal of Medical Genetics website evidence for linkage to this region in multiplex autism families at http://www.interscience.wiley.com/jpages/1552-4825/suppmat/ has been weak [Cook et al., 1998; Salmon et al., 1999; Liu et al., index.html. 2001; Nurmi et al., 2001; Shao et al., 2003]. The weak genetic Grant sponsor: March of Dimes Birth Defects Foundation linkage or association might be compatible with a major de funding (to ALB); Grant number: MOD 12-FY03-43; Grant novo component in the etiology as we have suggested in a mixed sponsor: NIH grants (to ALB); Grant numbers: NIH HD37283, genetic and epigenetic model for autism [Jiang et al., 2004]. NIH HD24064; Grant sponsor: National Association for Autism The existence of large low-copy-repeats (LCRs) in the Research pilot research award (to TS); Grant number: NAAR 704/ vicinity of the three common PWS/AS chromosomal break- TS/01-201-004-00-00. points (BP) and also telomeric to the PWS/AS critical region is *Correspondence to: Trilochan Sahoo, Department of Molecular suggested to be responsible for the recurrent deletion/duplica- and Human Genetics, Baylor College of Medicine, One Baylor tion events involving 15q11-q13 [Christian et al., 1995, 1999; Plaza, Rm. T619, Houston, Texas 77030. Fantes et al., 2002; Pujana et al., 2002; Ritchie et al., 1998]. E-mail: [email protected] Recent findings suggest that many chromosomal rearrange- Received 1 February 2005; Accepted 14 September 2005 ments, including translocations, inversions, isochromosomes, DOI 10.1002/ajmg.a.31000 and small marker chromosomes, may involve susceptibility to ß 2005 Wiley-Liss, Inc. American Journal of Medical Genetics: DOI 10.1002/ajmg.a Chromosome 15 CGH Microarray 107 rearrangement related to the presence of LCRs [Lupski, 1998; others. Genomic DNA from whole blood and lymphoblast cell Ji et al., 2000; Stankiewicz and Lupski, 2002; Shaw and lines was made using the PureGene kit (Gentra Systems, Lupski, 2004]. Minneapolis, MN) as per manufacturer’s protocol. Microarray-based comparative genomic hybridization (CGH) using large-insert clones is useful for detecting Array Design and Production deletions or duplications that are greater than about 10 kb Chromosome 15 is 100 Mb and can be covered by but below the level of detection by karyotype analysis. approximately 700 minimally overlapping BAC or PAC (P1 Microarray CGH enables assessment of hundreds or even artificial chromosome) clones. Clone selection was based on the thousands of sites in a single hybridization thus providing a information from public databases (Fig. 1; http://genome.ucsc. whole-genome scan for rearrangements [Pinkel et al., 1998; edu; http://www.ensembl.org/Homo_sapiens/mapview) both of Pollack et al., 1999]. Array CGH has been used for the detection which use the July 2003 freeze of the draft genome sequence. of constitutional chromosomal abnormalities [Shaw-Smith The array included 106 clones with a variable distribution et al., 2004; Vissers et al., 2004]. Recent studies utilizing across 15q (Fig. 1; supplementary data). The highest density of chromosome 15-specific bacterial artificial chromosome (BAC) clones is in the 10-Mb 15q11-q14 interval encompassing the microarrays of varying resolution have provided more detailed PWS/AS critical region and the common deletion/duplication molecular characterization of chromosome 15 rearrangements breakpoints. A resolution of greater than one clone per mega- [Locke et al., 2004; Wang et al., 2004]. base for 15q11-q13 and less than one clone per megabase for We present here the development of a high-resolution 15q14-qter was achieved. We included 38 clones specific for the chromosome 15 array and its use in further characterizing subtelomeric region of chromosomes 1–22, 12 clones for cytogenetic abnormalities of 15q11-q13. chromosome X, and six clones for the Y chromosome. Chromo- some- and locus-specificity of all selected clones was verified by MATERIALS AND METHODS FISH and end-sequencing. A few clones at the pericentromeric region of 15q cross-hybridize with other regions due to pseudo- Patient Samples gene sequences representing intra- and interchromosomal Samples were obtained from the South Carolina Autism duplicons. Project (SCAP, Greenwood Genetics Center, Greenwood, SC), the Autism Genetic Resource Exchange (AGRE), the NIGMS BAC/PAC DNA Preparation and Array Printing Human Genetic Cell Repository (GM numbers, Coriell Insti- Preparation of DNA from BACs/PACs and chemical cross- tute, Camden, NJ), or Baylor College of Medicine (BCM) as linking of DNA was performed as described previously with indicated in Tables I and II. All patients including those from minor modifications [Cai et al., 2002; Yu et al., 2003]. AGRE (http://www.agre.org/) and from the SCAP were diag- nosed using the Autism Diagnostic Interview-Revised (ADI-R). Genomic DNA Labeling and Hybridization The ADI-R is a semi-structured diagnostic interview for use with patients suspected of having a pervasive developmental Patient and reference genomic DNAs were labeled by ran- disorder. It was developed for research purposes, but can also dom priming using a BioPrime DNA labeling kit (Invitrogen, be used for clinical diagnoses. Samples were obtained at BCM Carlsbad, CA) as described [Cai et al., 2002; Yu et al., 2003]. All and the Greenwood Genetic Center under protocols approved experiments included
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