RESEARCH REVIEW Genomic and Clinical Characteristics of Microduplications in Chromosome 17 Oleg A. Shchelochkov,1,2 S.W. Cheung,1 and J.R. Lupski1,2,3* 1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 2Division of Genetics, Department of Pediatrics, University of Iowa, Iowa City, Iowa 3Department of Pediatrics, Baylor College of Medicine, Houston, Texas Received 2 August 2009; Accepted 13 November 2009 Genomic disorders have been increasingly recognized as a sig- nificant source of clinically relevant phenotypes largely fostered How to Cite this Article: by advances in technologies for genome-wide analyses. Molecu- Shchelochkov OA, Cheung SW, Lupski JR. lar and clinical studies of copy number variants involving 2010. Genomic and clinical characteristics of chromosome 17 began with locus-specific studies of Charcot- microduplications in chromosome 17. –Marie–Tooth disease type 1A (CMT1A, OMIM #118220) and Am J Med Genet Part A 152A:1101–1110. hereditary neuropathy with liability to pressure palsies (HNPP, OMIM #162500), which laid the foundation for the paradigm of duplication/deletion and gene-dosage for our understanding of genomic disorders. With the clinical introduction of high-reso- conditions caused by genomic rearrangements are collectively lution array comparative genomic hybridization (aCGH) the defined as genomic disorders [Lupski, 1998, 2009]. Due to the number of recognized genomic disorders including microdupli- limited resolution of conventional cytogenetic techniques, the cations has been increasing rapidly. A relatively high proportion majority of genomic disorders were missed in the past, because of disease-associated copy number variants map to chromosome the genomic rearrangements were not cytogenetically visible. How- 17. This may result from its unique structural features, such as ever, high-resolution array comparative genomic hybridization relative abundance of segmental duplications and interspersed (aCGH) techniques have revolutionized the approach to diagnosis repetitive elements, high gene content, and the presence of of genomic disorders, and enabled the screen of the entire human dosage-sensitive genes. These genomic rearrangements are me- genome for CNVs. Improved detection of various CNVs, both gains diated by diverse mechanisms including Non-Allelic Homolo- and losses, sometimes presents a challenge to determine their gous Recombination (NAHR), Non-Homologous End-Joining potential role in human diseases. (NHEJ), and Fork Stalling and Template Switching (FoSTeS). We Duplications or deletions of regions on chromosome 17 have provide specific examples of chromosome 17 microduplications been implicated in a number of genomic disorders in humans with the emphasis on their phenotype, specific clinical features [Lupski and Stankiewicz, 2005]. Genomic studies have provided us aiding in their diagnosis, and counseling. Ó 2010 Wiley-Liss, Inc. with insight into the complex genomic structure of chromosome 17. This elucidated the framework for our understanding of the Key words: chromosome 17; microduplication; genomotype; mechanisms underlying genomic rearrangements in chromosome NAHR; NJEH; FoSTeS; MMBIR; mechanisms of rearrangement; 17 and their contribution to the clinical phenotypes. This article Potocki–Lupski syndrome; 17p13.3 duplication syndrome reviews (1) clinically relevant microduplications in chromosome 17, (2) discusses the genomic architecture predisposing chromo- some 17 to recurrent and non-recurrent rearrangements, (3) describes Charcot–Marie–Tooth syndrome type 1a (CMT1A) and INTRODUCTION hereditary neuropathy with liability to pressure palsies (HNPP) as a Genomic rearrangements describe mutational changes that alter paradigm for reciprocal rearrangement mechanisms, and (4) pro- genome structure (e.g., duplication, deletion, insertion, and inversion). Theseare different fromthe traditional mutation caused by Watson–Crick base pair alterations. Each of these rearrange- *Correspondence to: J.R. Lupski, M.D., Ph.D., CullenProfessor and Vice Chairman, Department ments, excepting inversions, result in copy number variation of Molecular and Human Genetics, Baylor College of Medicine, One Baylor (CNV) or change from the usual copy number of two for a given Plaza, Houston, TX 77050. E-mail: [email protected] genomic segment or genetic locus of our diploid genome. Genomic Published online 7 April 2010 in Wiley InterScience rearrangements can represent polymorphisms that are neutral in (www.interscience.wiley.com) function, or may produce abnormal phenotypes. The pathological DOI 10.1002/ajmg.a.33248 Ó 2010 Wiley-Liss, Inc. 1101 1102 AMERICAN JOURNAL OF MEDICAL GENETICS PART A vides specific examples of microduplications with the emphasis on NAHR resulting in non-recurrent rearrangements can be medi- their genomotype–phenotype correlations. ated by areas of homology between repetitive elements such as For the purpose of this manuscript, we will be using the term LINEs and SINEs. LINEs are a class of transposable genomic ‘‘genomotype’’ as opposed to ‘‘genotype,’’ to emphasize that a elements of approximately 6 kb in size. They are abundantly present genomic change may convey phenotype irrespective of its gene in chromosome 17 constituting approximately 14% of its final content through either position effects or a regulatory region (e.g., a sequence [Zody et al., 2006]. The most abundant form of LINE, conserved non-coding sequence) encompassed by CNV. Further- retrotransposition-competent L1 contains a 50-UTR segment with more, the phenotypic consequences may relate to the copy number promoter activity, two open reading frames, and a 30-UTR ending change of more than one gene in cis position contained within or with a poly(A). The open reading frames encode proteins with flanking the CNV (i.e., ‘‘cis-genetics’’ as opposed to the ‘‘trans- RNA-binding, endonuclease, and reverse transcriptase activities genetics’’ focus of Mendelism) [Bi et al., 2009]. The need for the new [Hulme et al., 2006]. Autonomous promoter, endonuclease, and term arose from the observation that phenotypes can result from reverse transcriptase activities facilitate random integration of various genomic changes, which may not encompass known transposons instigating LINE-mediated recombination and mobi- genes or may contain multiple genes, only one or some of lization of non-autonomous retrotransposons such as Alu [Hulme which could contribute to the same phenotype. The focus on et al., 2006]. genomotype–phenotype correlations will help elucidate the SINEs are short non-coding retrotransposons, 300–500 bp in ‘‘genomic code’’ of the entire genome, as opposed to the focus on length, thought to have had originated from the RN7SL1 non- the coding sequences, which account for less than 2% of the genome coding RNA [Eickbush and Jamburuthugoda, 2008]. Compared to to which the genetic code and the term ‘‘genotype’’ apply. the average 13% of the human genome content, SINEs form about 22% of the finished chromosome 17 sequence [Zody et al., 2006]. In GENOMIC STRUCTURE OF CHROMOSOME 17 contrast to LINEs, SINEs lack a sequence encoding reverse tran- scriptase, and therefore rely on cellular or autonomous LINE- The finished sequence of human chromosome 17 presented by derived endonuclease and reverse transcriptase activity for genomic Zody et al. [2006] provided us further insight into how its structure integration [Deininger, 2006]. B1 and Alu are the most common predisposes to genomic rearrangements. Structural features of types of SINEs [Goodier and Kazazian, 2008], which due to high chromosome 17 which may predispose to clinically relevant geno- sequence identity can facilitate ectopic homologous recombination mic rearrangements include high gene density, dosage sensitive or NAHR [Deininger and Batzer, 1999]. Interspersed repetitive genes, excess of segmental duplications (SD), and relative abun- elements are sometimes utilized as recombination substrate in dance of short interspersed nucleotide elements (SINE). chromosome band 17p11.2 leading to deletions associated with Chromosome 17 has the second highest gene content amongst all SMS [Shaw and Lupski, 2005], or chromosome band 17p13.3 chromosomes [Zody et al., 2006]. It harbors several dosage-sensi- resulting in either Miller–Dieker syndrome (MDS) or dup(17)- tive genes, including PMP22, PAFAH1B1, YWHAE, RAI1, and NF1, (p13.3) [Bi et al., 2009]. which have been implicated in a number of genomic disorders Another structural feature of chromosome 17 predisposing to [Lupski, 1998, 2009]. Flanked by SD, alternatively termed low-copy non-recurrent rearrangements includes the pericentromeric and repeats (LCRs), these genes are frequently affected by recurrent centromeric regions of 17p and 17q, one of the most variable duplications or deletions resulting in recognizable phenotypes genomic structures in the human genome. They are enriched in [Lupski and Stankiewicz, 2005]. Decreased expression resulting LCRs. Proximal 17p is one of the sixteen pericentromeric regions from a gene deletion causes a phenotype usually similar to that with the most extensive zones of duplications [She et al., 2004]. observed with loss-of-function point mutations, for example, These LCRs are likely responsible for instigating multiple copy nonsense and frame-shift alleles for a ‘‘dosage-sensitive’’ gene. number variants in this genomic region and recurrent i(17q) Increased expression of a dosage-sensitive gene resulting from a rearrangement seen in the human neoplastic cells