Genomic and Clinical Characteristics of Microduplications in Chromosome 17 Oleg A

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 significant 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. 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 chromosome 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

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 transcriptase, 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 [Barbouti gene duplication may convey clinical findings which are different, et al., 2004; Carvalho and Lupski, 2008]. Seventy percent of patients and sometimes divergent from the deletion phenotype [Potocki with simple uncommon non-recurrent dup(17)(p11.2p11.2) had et al., 2007; Girirajan et al., 2008; Bi et al., 2009]. their proximal breakpoints mapped in the centromere or 17p LCRs represent repeat DNA sequences ranging from 1 to 200 kb pericentromeric region [Potocki et al., 2007]. in size that share significant sequence homology (>90%). They are particularly common in the pericentromeric and subtelomeric MECHANISMS OF CHROMOSOMAL REARRANGEMENT regions of human chromosomes. LCRs represent 8.6% of the AND THEIR IMPACT ON PHENOTYPE finished sequence in chromosome 17 [Zody et al., 2006]. They play a key role in meiotic recombinations resulting in duplications, Review of breakpoints in recurrent duplication/deletion syn- deletions, and inversions of the intervening DNA. Non-Allelic dromes, such as CMT1A/HNPP and PTLS/SMS, demonstrated Homologous Recombination (NAHR) utilizing LCRs as recombi- that most of them mapped to low-copy repeats flanking the nation substrates are responsible for >99% of cases of CMT1A rearrangements. NAHR between directly oriented LCRs serves as [Zhang et al., 2009], approximately 70% of cases of Potocki–Lupski the general mechanism of recurrent and reciprocal duplications/ syndrome (PTLS, #610883) and the majority of respective recipro- deletions, respectively. Homologous recombination between in- cal microdeletions associated with HNPP and Smith–Magenis verted LCRs results in inversion rearrangements. Although bal- syndrome (SMS, #182290) [Lupski and Stankiewicz, 2005]. anced inversions do not cause gain or loss of genetic information, SHCHELOCHKOV ET AL. 1103 they can predispose to deleterious genomic disorders, such as phenotype and underrecognition of microduplications by conven- 17q21.31 microdeletion syndrome [Stefansson et al., 2005; Koolen tional cytogenetic technologies. et al., 2006, 2008; Lupski, 2006; Sharp et al., 2006; Shaw-Smith et al., 2006]. Many chromosomal rearrangements involving regions lacking BENIGN COPY NUMBER VARIANTS AND LCRs are mediated by non-homologous mechanisms, such as Non- CHROMOSOME 17 Homologous End-Joining (NHEJ) [Shaw and Lupski, 2004]. This Database of Genomic Variants (DGV) lists thousands of loci with mechanism arises from DNA double-strand breaks repaired via structural variations in the human genome (http://projects.tcag.ca/ bridging of the broken DNA ends, their modification to enhance variation, Human Genome Assembly Build 36, hg18). Of these loci, compatibility and finally ligation [Balarin et al., 1999]. End modi- 190 structural variations represent copy number variants and 5 are fication via addition or deletion of nucleotides can leave an NHEJ inversions involving chromosome regions 17p11.2, 17q11.2, 17q12, genomic signature or ‘‘information scar’’ [Lee et al., 2007]. 17q21.32–17q21.31, 17q24.2. Derived from apparently ‘‘healthy Introduction of aCGH into clinical practice revealed that a human cases,’’ DGV is a useful tool to assist healthcare providers in significant proportion of non-recurrent rearrangements are com- interpreting the detected CNVs. Although these catalogued struc- plex, which could not be readily explained by either NAHR or tural changes were not associated with overt phenotypic changes, NHEJ. Sequencing of endpoints in the complex rearrangements one should exercise caution in making predictions about the clinical revealed that in many cases the endpoints were found in many consequences of the detected structural alterations. One cannot different positions and shared microhomology of a few basepairs. exclude the possibility of ‘‘benign’’ CNVs contributing to late-onset Lee et al. [2007] proposed a novel mechanism called Fork Stalling symptoms, complex genetic traits, epigenetic interactions associ- and Template Switching (FoSTeS) to explain such complex rear- ated with these CNVs, and these CNVs acting as susceptibility loci rangements [Lee et al., 2007]. A more specific model of how the [Zhang et al., 2006]. replication can be restarted after fork stalling by collapse of a DNA replication fork was recently proposed by Hastings et al. [2009a]. Microhomology-mediated break-induced replication (MMBIR) is CMT1A AND HNPP AS A MODEL FOR RECIPROCAL proposed to process single-ended, double-stranded DNA resulting DUPLICATIONS AND DELETIONS from collapsed fork repair to explain complex chromosomal changes. It is based on observations from E. coli, yeast, and other Studies of the causative mechanisms underlying CMT1A and model organisms in addition to human cells [Hastings et al., 2009a]. HNPP peripheral neuropathies delineated the paradigm for our The multiple mechanisms for human gene copy number change understanding of reciprocal duplication–deletion genomic disor- have been reviewed recently [Hastings et al., 2009b]. ders. CMT type 1a is an autosomal dominant distal symmetric. A de Several mechanisms have been proposed to explain the effect of novo CMT1A duplication accounts for 76–90% of cases occurring rearrangements on function of genes: loss of gene(s) function sporadically [Lupski et al., 1991a; Hoogendijk et al., 1992; Nelis through direct disruption or deletion, position effect due to dis- et al., 1996]. It is the most common inherited sensory-motor ruption of a regulatory element, gene fusion, unmasking a recessive polyneuropathy with life prevalence of 1 in 2,500 and a nearly trait, or transvection effects [Lupski and Stankiewicz, 2005; Bu- 100%, age-dependent penetrance [Lupski et al., 1992]. Clinically, it chanan and Scherer, 2008; Gu et al., 2008]. The dosage effects via is characterized by abnormal nerve conduction velocities, distal increased expression of dosage-sensitive genes attracted significant muscle weakness, muscle atrophy, and sensory loss. Histologically, attention to explain how phenotypic features can be ascribed to there is a length-dependent segmental demyelination with the particular genes affected by duplication [Lupski et al., 1991a, 1992]. formation of pathognomonic ‘‘onion bulbs’’ [Lupski et al., 1991b]. Dissection of the phenotypic contribution of genes included in a The reciprocal genomic disorder of CMT1A is HNPP, an auto- duplicated segment is challenging. In contiguous gene deletion somal dominant condition caused by a loss-of-function mutation, syndromes[Schmickel, 1986] the contribution of each affectedgene either due to PMP22 deletions or loss-of-function point mutations can be analyzed by studying patients carrying point mutations in [Chance et al., 1993; Mouton et al., 1999]. It results in a peripheral the given gene resulting in its haploinsufficiency. The study of neuropathy manifested by recurrent asymmetric palsies often phenotypic consequences that result from a duplication, relies on elicited by focal pressure usually followed by functional recovery careful characterization of rare patients carrying rearrangements, and electrophysiologic findings of prolonged sensory and motor and frequently requires transgenic animal models to explore the nerve conduction. Peripheral nerve biopsy reveals segmental de- disease mechanisms. Such transgenic animal models are available myelination and characteristic swellings of the myelin sheaths for CMT1A [Sereda et al., 1996; Huxley et al., 1998], PTLS and SMS known as ‘‘tomaculae.’’ [Walz et al., 2003], and 17p13.3 microduplication syndrome [Bi Reciprocal CMT1A duplications and HNPP deletions prompted et al., 2009]. a search for features of genomic architecture in chromosome 17, Both microduplications and microdeletions arising from NAHR which could predispose to recurrent duplication–deletion. Pentao might theoretically demonstrate comparable incidence. However, et al. [1992] identified LCRs, referred to as CMT1A-REPs, flanking clinical experience suggests that the number of microduplication a 1.5 Mb CMT1A-duplication/HNPP-deletion segment. Proximal cases is ascertained less often than their corresponding micro- (centromeric) and distal (telomeric) CMT1A-REPs are 99% iden- deletions. The underdiagnosis of microduplications is likely the tical by sequence and measure approximately 24 kb in length. It was result of ascertainment bias due to a relatively milder or absent proposed that de novo CMT1A duplications and HNPP deletions 1104 AMERICAN JOURNAL OF MEDICAL GENETICS PART A were the result of unequal crossing over via NAHR [Pentao et al., The critical PTLS region deduced from a patient harboring the 1992]. This was later shown at the strand exchange level using PCR smallest 17p11.2 duplication spans a 1.3 Mb interval between amplification of the recombinant CMT1A-REPs from HNPP and the distal SMS-REP and the site approximately 200 kb telomeric to control individuals [Reiter et al., 1998]. the middle SMS-REP [Potocki et al., 2007]. It contains 14 genes Several genomic mechanisms had been proposed to explain how including RAI1, the most likely dosage-sensitive gene responsible partial trisomy 17p in CMT1A results in the observed phenotype. for the major part of PTLS phenotype. RAI1 encoding retinoic acid- These included a potential gene-dosage effect due to duplication; induced protein 1 (RAI1) is ubiquitously expressed, with the loss-of-function of a candidate gene due to sequenceinterruption in highest levels found in brain and heart. Although its exact mecha- the region; stable dominant mutation in duplicated gene(s); posi- nism of action is unclear, RAI1 functions deduced from its domain tion effect caused by the chromosomal rearrangement resulting in structure may include transcriptional regulation and chromatin abnormal expression of candidate gene(s) [Lupski et al., 1991a, remodeling. 1992]. Lupski et al. [1992] provided the first line of evidence that The potential role of RAI1 in the mechanism of PTLS was gene dosage is the most likely mechanism for the disease. Their deduced from transgenic animal studies. Transgenic mice carrying conclusion was independently confirmed by Northern blot analysis chromosome 11 duplication syntenic to human 17p11.2 recapitu- demonstrating a 1.7-fold increase in expression of PMP22 mRNA late some of the physical and behavioral findings seen in PTLS: in Schwann cells of the peripheral nerves obtained from CMT1A growth retardation, increased locomotor activity, and impaired patients [Yoshikawa et al., 1994]. Overexpression of PMP22 in learning (contextual fear conditioning) [Walz et al., 2003, 2004, growth-arrested fibroblasts (NIH-3T3) resulted in apoptotic 2006; Molina et al., 2008]. Similar finding were reported by changes [Fabbretti et al., 1995]. Transgenic animals, for example, Girirajan et al. [2008], who created a mouse model with graded CMT rat and C61 mouse models, with 1.5- to 2-fold overexpression overexpression of Rai1. These transgenic mice showed lower of PMP22, clinically and histologically replicate human findings of weights, decreased forelimb grip strength, locomotor hyperactivity, CMT1A: reduction of nerve conduction velocities, weak motor altered gait, abnormal anxiety-related behavior, impaired cage-top function, and demyelinating peripheral polyneuropathy [Huxley hang test, and a dominant social behavior with a dosage-dependent et al., 1998; Niemann et al., 1999]. Return to the normal PMP22 worsening of the phenotype. Generation of compound heterozy- expression levels in tetracycline-regulated PMP22-transgenic mice gous mice carrying homologous 17p11.2 deletion and duplication leads to reversal of demyelination [Perea et al., 2001]. Thus, resulted in the restoration of normal disomic Rai1 gene dosage and CMT1A, the first described autosomal dominant genomic disorder, rescued physical and behavioral phenotype seen either in the provided the general mechanism to understand other microdupli- heterozygous deletion or duplication animals alone [Walz et al., cation syndromes. 2006]. The commonly reported facial dysmorphic features in patients POTOCKI–LUPSKI SYNDROME with dup(17)(p11.2p11.2) are usually subtle and include triangular facies, relatively broad forehead, downslanting palpebral PTLS [OMIM #610883] is a microduplication syndrome, associat- fissures, long nasal tip, smooth philtrum, and micrognathia. ed with dup(17)(p11.2p11.2), which results in hypotonia, failure to Clinical findings include such non-specific symptoms as oropha- thrive, mental retardation, pervasive developmental disorders, and ryngeal dysfunction, poor feeding, prenatal-onset failure to congenital anomalies [Potocki et al., 2007]. All reported cases occur thrive, obstructive and central sleep apnea, congenital heart sporadically without bias in the parental origin of rearrangements. defects, hypotonia, hypermetropia, EEG abnormalities, develop- Most duplications are 3.7 Mb in size, cannot be detected readily by mental delay, language disorders, and pervasive developmental chromosome analysis, but are identifiable by aCGH. Approximate- disorders [Potocki et al., 2007; Doco-Fenzy et al., 2008]. ly 60% of PTLS patients harbor a microduplication of 17p11.2 Eye examination revealed hypermetropia in 60% of patients. Low reciprocal to the common recurrent 3.7 Mb microdeletion in SMS thyroid stimulating hormone was found in 30% of patients. [Chen et al., 1997; Potocki et al., 2000, 2007; Bi et al., 2003]. The Brain MRI revealed mild brain abnormalities: mild attenuation of common rearrangement results from NAHR between the proximal corpus callosum and delay in myelination. EEG abnormalities and distal SMS repeat gene clusters, called ‘‘SMS-REPs.’’ SMS-REPs were detected, but none had clinical seizures or required anti- are LCRs characterized by high sequence identity of 99%, direct convulsant treatment [Potocki et al., 2007]. Developmental orientation and large size (proximal 256 kb, distal 176 kb) (Fig. 1). delay and speech disorders were found in all affected individuals A third LCR, the middle SMS-REP, is inverted and measures and behavioral assessment showed autistic features in most 240 kb in size [Park et al., 2002]. The remaining 30% of patients patients. with PTLS lack common breakpoints. The proximal breakpoint in In summary, PTLS is associated with dup(17)(p11.2p11.2) and these patients frequently maps to the centromere or the pericen- results in mild facial dysmorphic features, hypermetropia, EEG tromeric region of 17p. The mechanism of non-recurrent PTLS abnormalities, lower intelligence quotients, and autistic spectrum duplication is complex. High-density array and long-range PCR disorders. Infrequently these patients may present with features of analysis revealed regions of microhomology at the breakpoints and connective tissue disorder, lower blood cholesterol, and hypothy- complex rearrangements inconsistent with a recombination-based roidism. The initial workup of these patients should include array mechanism, and point toward the predominant role of FoSTeS or CGH, echocardiogram, EKG, lipid and thyroid panel, urinalysis, MMBIR in the PTLS-associated non-recurrent duplication rear- ophthalmological examination, sleep study, cognitive, and behav- rangements [Zhang et al., 2009]. ioral evaluation. SHCHELOCHKOV ET AL. 1105

FIG. 1. Deletion and duplication syndromes of chromosome 17. Duplications and deletions mapped to chromosome 17. Duplication syndromes, which have been mapped to chromosome 17 include CMT1A, Potocki–Lupski syndrome, and dup17p13.3 syndrome. Their reciprocal deletions are HNPP, Smith–Magenis syndrome, and Miller–Dieker syndrome accordingly. Deletions with corresponding single case report duplications involving bands 17p11.2, 17q12, and 17q21.31 have been described, although their phenotype and disease mechanisms are yet to be elucidated.

17P13.3 DUPLICATION SYNDROME copy number from the mother, who suffered from attention deficit disorder and seizures. Four of seven patients carried simple dupli- Chromosome 17p13.3 duplication is the third microduplication cations; the remaining three individuals had complex rearrange- syndrome described in chromosome 17 [Bi et al., 2009; Roos et al., ments. Sequencing across the breakpoints from three study subjects 2009]. It is reciprocal to the microdeletion encompassing suggested that different mechanism could be responsible for the PAFAH1B1 resulting in MDS. The cohort reported by Bi et al. observed rearrangements. It was concluded that NAHR using [2009] included seven dup(17)(p13.3) patients with duplication SINEs (AluSg) as a recombination substrate was responsible in sizes varying from 0.24 to 3.6 Mb. All but one case of duplication one case, whereas NHEJ or a single FoSTeS event could be represented a de novo change. One patient inherited the gain of the underlying molecular mechanisms in two other affected 1106 AMERICAN JOURNAL OF MEDICAL GENETICS PART A individuals. Roos et al. [2009] reported additional three patients CRK microdeletions show growth restriction of prenatal onset with sporadic microduplications in the 17p13.3 region ranging [Sreenath Nagamani et al., 2009]. from 1.8 to 4 Mb, all encompassing the PAFAH1B1 gene. In summary, patients with dup(17)(p13.3) encompassing Although the total number of patients reported to date is PAFAH1B1 presented with a severe neurobehavioral phenotype, relatively small, some genomotype–phenotype associations can be failure to thrive, and a high incidence of internal organ anomalies. drawn. Duplication of PAFAH1B1 (encoding LIS1) was associated YWHAE and CRK duplications in the reported cohort resulted in with more severe outcome including failure to thrive, craniosyn- subtle shared facial dysmorphisms, a trend for overgrowth, and ostosis, and intestinal malrotation. Facial features in patients with mild neurocognitive abnormalities. Larger studies are necessary to PAFAH1B1 duplication lacked dysmorphic characteristics. Brain detail the clinical features of this microduplication syndrome. MRI revealed structural anomalies: thinning, dysgenesis, and agen- esis of corpus callosum, dysgenesis of splenium, dilation of lateral ventricles, small pituitary gland, and mild cerebellar volume loss. EMERGING GENOMIC DISORDERS ON Neurobehavioral abnormalities included hypotonia, muscle wast- CHROMOSOME 17 ing, mental retardation, autism, attention deficit disorder, and obsessive–compulsive disorder. One of the affected individuals Chromosome regions 17q11.2, 17q12, and 17q21.31 represent three had triplication encompassing PAFAH1B1 (four copies of the more rearrangement-prone ‘‘genomic instability’’ intervals specif- gene), which appeared to correlate with a more severe neurological ically associated with known microdeletion syndromes. Like with outcome lending additional support to a gene-dosage disease most microdeletions mediated by NAHR, one can expect reciprocal model. microduplications. To date, isolated case reports describing pa- Patients carrying dup(17)(p13.3) encompassing YWHAE and tients carrying reciprocal duplications in each locus have been CRK shared subtle craniofacial characteristics including mild syn- described [Kirchhoff et al., 2007; Mefford et al., 2007; Grisart ophrys, broad tip of the nose with overhanging columella, thin et al., 2008; Mencarelli et al., 2008]. The full clinical spectrum of upper lip and pointed chin. In contrast to patients with PAFAH1B1 each microduplication involving regions 17q11.2, 17q12, and duplication, who had microcephaly and severe growth restriction, 17q21.31 is unknown. Although the reported findings in affected individuals with duplicated YWHAE showed a tendency towards individuals with microduplications could be due to mutations or macrosomia and mild neurocognitive phenotype. Four patients structural variants elsewhere, these cases could represent emerging with large dup(17)(p13.3) encompassing all three genes, YWHAE, microduplication syndromes mapped to the long arm of chromo- CRK, and PAFAH1B1, showed a tendency to have mental retarda- some 17. tion, decreased muscle tone, abnormalities of corpus callosum, lack Grisart et al. [2008] described two middle-aged brothers who of severe congenital abnormalities, and normal-to-above average carried a 17q11.2 microduplication detected by array CGH, mea- growth parameters [Bi et al., 2009; Roos et al., 2009]. suring 1.5 Mb in size, encompassing NF1 along with 12 other genes. The structural brain abnormalities seen in patients with dupli- The duplication was flanked by LCRs called NF1REP-P1 and NF1- cated PAFAH1B1 appear to be due to the critical role of LIS1 in the REP-M, which can serve as recombination substrates in recurrent regulation of cell polarity through its interaction with dynein and NF1 microdeletions [Forbes et al., 2004]. The rearrangement was microtubules [Reiner, 2000] and hence its effect on the microtu- stable over at least two generations and was inherited by the siblings bular transport, cell division, and neuronal migration. Studies of from their father. Their clinical presentation was characterized by Pafah1b1 transgenic mice demonstrated that Lis1 overexpression subtle facial dysmorphisms, mental retardation, frontal baldness disrupts neuroepithelial expansion resulting in smaller brains, loss with onset in late teen years, dental enamel hypoplasia, and macro- of cell polarity, abnormal neuronal migration, and increased neu- orchidism. Along with NF1, two other dosage-sensitive genes in the ron apoptosis. Murine neurons overexpressing Lis1 had higher interval, JJAZ1 and OMG, have been implicated in mental retarda- motility compared to control cells, but their migration was disor- tion [Grisart et al., 2008]. ganized [Bi et al., 2009]. The role of protein 14-3-3e encoded by Three publications are available describing phenotypic findings YWHAE in patient with dup(17)(p13.3) is unclear, but can tenta- in individuals with microduplications encompassing 17q12 tively be explained via epistatic interaction with LIS1 [Toyo-oka [Mefford et al., 2007; Mencarelli et al., 2008; Nagamani et al., et al., 2003]. At present, there is no transgenic YWHAE animal 2009]. The mechanism of recurrent rearrangement in this genomic model to study the consequences of isolated 14-3-3e overexpres- ‘‘hotspot’’ has been difficult to elucidate due to extensive copy sion, nor an overexpression animal model for 14-3-3e plus LIS1. number polymorphisms in SD flanking the rearrangement, and a The cause of tendency to macrosomia is currently unknown, but 0.1 Mb assembly gap (hg17 coordinates chr17:31,700,000– copy number variants encompassing CRK (v-crk sarcoma virus 31,800,000). Among multiple genes affected by the rearrangement CT10 oncogene homolog) have been implicated. CRK is involved in gene candidates included HNF1B encoding a transcription factor the regulation of mitogenesis [Nakashima et al., 1999], cellular and LHX1 encoding a putative transcriptional regulator. Such genes growth and differentiation [Feller, 2001], and mediation of down- may explain the observed developmental anomalies and organ stream effects of growth hormone and insulin-like growth factor-1 malformations. Loss-of-function mutations in HNF1B have been [Goh et al., 2000]. Therefore overexpression of C-crk, encoded by reported in MODY5 [Horikawa et al., 1997] and mullerian aplasia CRK, may provide the molecular link between CRK gene duplica- [Lindner et al., 1999], while a targeted deletion of LHX1 was found tion and observed tendency to somatic overgrowth. This conclu- to result in renal and nervous system developmental anomalies in sion is further strengthened by the observation that patients with mouse mutant embryos [Shawlot and Behringer, 1995]. In humans SHCHELOCHKOV ET AL. 1107 recurrent microdeletions of 17q12 [Mefford et al., 2007] are out gingival hyperplasia. One individual with similar symptoms associated with a wide spectrum of clinical findings ranging from carried an apparent de novo microduplication of the same genomic congenital malformations associated with intrauterine fetal demise region. The authors suggested that copy-number mutations on to more subtle findings in older individuals with renal abnormali- chromosome 17q24 may exert a long-range position effect on the ties and maturity-onset diabetes of the young type 5 (MODY5). The local chromatin architecture of SOX9 known to affect the hair clinical consequences of 17q12 microduplication are not clear and follicle stem cells [Sun et al., 2009]. range from focal cortical dysplasia causing epilepsy and severe Farah et al. [2009] reported a 14-year-old female patient carrying congenital anomalies to apparently healthy individuals suggesting an apparently de novo 1.1 Mb duplication on chromosomal band that copy number variant in this genomic region could show 17q21.33. Clinical symptoms included gross and fine motor devel- incomplete penetrance [Mefford et al., 2007; Mencarelli et al., opment delays, small cup-shaped pinnae, conductive hearing loss, 2008; Nagamani et al., 2009]. astigmatism, high narrow palate, severe overbite, and scoliosis. Due Kirchhoff et al. [2007] described a 10-year-old girl of Moroccan to a significant overlap of this patient’s phenotype with a connective descent without history of consanguinity, who was found to have a tissue disorder, it was hypothesized that the observed abnormalities de novo microduplication involving chromosome band 17q21.31. could be due to an overexpression of COL1A1 and PPP1R9B The duplication was reciprocal to the recently reported 17q21.31 encompassed by the microduplication [Farah et al., 2009]. microdeletion syndrome [Koolen et al., 2006, 2008; Sharp et al., A total of nine cases with non-recurrent deletions on chromo- 2006; Shaw-Smith et al., 2006]. Chromosome region 17q21.31 has some band 17q22-q23.2 have been reported [Puusepp et al., 2009]. very complex genomic architecture and contains multiple SD. They Frequent features associated with deletions in this region included are arranged in different orientations [Cruts et al., 2005; Zody et al., hyperopia, strabismus, tracheoesophageal fistula, esophageal atre- 2008] and due to their high sequence homology of >90% can serve sia, symphalagism, joint contractures, vertebral anomalies, and as the recombination substrate for the common 900 kb inversion cryptorchidism. To our knowledge no patients carrying duplica- polymorphism [Stefansson et al., 2005] or microdeletions encom- tions affecting this region have been reported yet. The presence of passing several genes including MAPT [Shaw-Smith et al., 2006]. several presumably dosage-sensitive genes (NOG, RARA, and MAPT encodes microtubule-associated protein tau (MAPT), is TBX4) raises the possibility of describing microduplication patients highly expressed in brain, and has been suggested to play a role in with clinically relevant phenotypes in the future [Ohta et al., 2007; neurodegenerative diseases [Koolen et al., 2008]. Gain-of-function Menke et al., 2008; Chng et al., 2009]. mutations in MAPT have been linked to frontotemporal dementia with parkinsonism [D’Souza et al., 1999]. Whether other genes and COUNSELING genomic elements in this region may contribute to the phenotype merits further investigation. The microduplication found in the CMT1A, PTLS, and the dup(17)(p13.3) syndrome appear to have reported patient measured 0.5 Mb in size completely encompass- highly penetrant phenotypes: peripheral neuropathy, facial dys- ing MAPT. She presented in mid-infancy with postnatal onset of morphic features, neurocognitive, or behavioral abnormalities. failure to thrive. Facial features were remarkable for a short nose CMT1A is inherited as an autosomal dominant trait or it can arise with prominent nasal tip and columella, smooth philtrum, micro- sporadically in association with de novo duplications. PTLS and stomia and micrognathia. Her physical findings included micro- dup(17)(p13.3) microduplication are mostly sporadic, although cephaly, high-arched palate without orofacial clefting, broad examples exist, when the rearrangements could be inherited, thus thumbs, distal broadening of fingers, broad feet, hirsutism, atopic warranting targeted FISH or partial chromosome analysis on dermatitis, hypotonia, and loose joints. She demonstrated severe parents and siblings in all cases. For sporadic cases the recurrence developmental delay: walked at age 5 years and spoke a few words at risk with the subsequent pregnancies is likely low [Doco-Fenzy age 10 years. Brain imaging at age 11 months showed no structural et al., 2008], but such possibility cannot be altogether excluded abnormalities. Echocardiogram demonstrated no structural heart [Carelle-Calmels et al., 2009]. Further investigations of each of the abnormalities. Abdominal ultrasound revealed small cysts in the rearrangement loci are necessary to better understand the potential liver and spleen. Since some of patients’ features resembled those of clinical consequences of copy number variants. Cornelia de Lange syndrome, NIBPL sequencing was performed, but revealed no mutations. Sequencing of SMC3, SMC1A, CREBBP, SUMMARY and EP300 genes was considered, but not performed. Additional regions of non-recurrent rearrangements linked to Chromosome 17 has unique structural features making it vulnera- clinically relevant phenotypes, both deletions and duplications, ble to rearrangements that translate into a number of phenotypes: include 17q24.2-q24.3, 17q21.33, and 17q11-q23.2 [Farah et al., relative abundance of SD and interspersed nucleotide elements, 2009; Puusepp et al., 2009; Sun et al., 2009]. Although the number of high gene content, and the presence of dosage-sensitive genes. reported patients does not permit a detailed delineation of clinical These genomic rearrangements are mediated by diverse mecha- features and genomotype–phenotype correlations, they are worth nisms including NAHR, NHEJ, and MMBIR/FoSTeS. NAHR ap- mentioning as the number of cases reported in the future will likely pears to be the predominant mechanism in recurrent reciprocal continue to grow. rearrangements that result in CMT1A-HNPP and PTLS-SMS, Sun et al. [2009] reported three families whose non-recurrent whereas all three mechanisms play a role in non-recurrent rear- microdeletions of chromosome bands 17q24.2-q24.3 segregated rangements such as dup(17)(p13.3)-MDS. Compared to micro- with congenital generalized hypertrichosis terminalis with or with- deletions, microduplications appear to result in milder phenotypes 1108 AMERICAN JOURNAL OF MEDICAL GENETICS PART A frequently characterized by subtle facial dysmorphic features, non- Cruts M, Rademakers R, Gijselinck I, van der Zee J, Dermaut B, de Pooter T, specific internal organ anomalies, and neurocognitive abnormali- de Rijk P, Del-Favero J, van Broeckhoven C. 2005. Genomic architecture ties often leading to pervasive development delay. Microduplica- of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low-copy repeats in the tau region. Hum Mol tions are less frequently detected compared to prevalence predicted Genet 14:1753–1762. from the mechanism of rearrangement. Such discrepancy can be due to their milder or absent phenotype and underreporting. The Deininger P. 2006. Alu elements. In: Lupski JR, Stankiewicz P, editors. Genomic Disorders: the Genomic Basis of Disease. Totowa, New Jersey: vast majority of reported microduplication was detected by array Humana Press, pp 21–34. CGH, an indispensable diagnostic tool available in the genetic clinic Deininger PL, Batzer MA. 1999. Alu repeats and human disease. Mol Genet today. With the exception for CMT1A, most microduplications Metab 67:183–193. mapping to chromosome 17 occur sporadically. Nevertheless, several examples of inherited duplications exist, warranting paren- Doco-Fenzy M, Holder-Espinasse M, Bieth E, Magdelaine C, Vincent MC, Khoury M, Andrieux J, Zhang F, Lupski JR, Klink R, Schneider A, Goze- tal and sibling testing for detected rearrangements. Martineau O, Cuisset JM, Vallee L, Manouvrier-Hanu S, Gaillard D, de Martinville B. 2008. The clinical spectrum associated with a chromosome 17 short arm proximal duplication (dup 17p11.2) in three patients. Am J ACKNOWLEDGMENTS Med Genet Part A 146A:917–924. We thank Dr. Sandesh C.S. Nagamani for his thoughtful review of D’Souza I, Poorkaj P, Hong M, Nochlin D, Lee VM, Bird TD, Schellenberg this article. GD. 1999. Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proc Natl Acad Sci USA REFERENCES 96:5598–5603. Eickbush TH, Jamburuthugoda VK. 2008. The diversity of retrotranspo- Balarin MA, da Silva Lopes VL, Varella-Garcia M. 1999. A dup(17)- sons and the properties of their reverse transcriptases. Virus Res (p11.2p11.2) detected by fluorescence in situ hybridization in a boy 134:221–234. with Alport syndrome. Am J Med Genet 82:183–186. Fabbretti E, Edomi P, Brancolini C, Schneider C. 1995. Apoptotic pheno- Barbouti A, Stankiewicz P, Nusbaum C, Cuomo C, Cook A, Hoglund€ M, type induced by overexpression of wild-type gas3/PM P22: Its relation to Johansson B, Hagemeijer A, Park SS, Mitelman F, Lupski JR, Fioretos T. the demyelinating peripheral neuropathy CMT1A. Genes Dev 2004. The breakpoint region of the most common isochromosome, 9:1846–1856. i(17q), in human neoplasia is characterized by a complex genomic Farah RZ, Sylvie L, Kim G, Patrice E, Marco AM, Jan MF. 2009. A novel architecture with large, palindromic, low-copy repeats. Am J Hum Genet de novo 1.1 Mb duplication of 17q21.33 associated with cognitive 74:1–10. impairment and other anomalies. Am J Med Genet Part A 149A: Bi W, Park SS, Shaw CJ, Withers MA, Patel PI, Lupski JR. 2003. Reciprocal 1257–1262. crossovers and a positional preference for strand exchange in recombination events resulting in deletion or duplication of chromosome Feller SM. 2001. Crk family adaptors-signalling complex formation and biological roles. Oncogene 20:6348–6371. 17p11.2. Am J Hum Genet 73:1302–1315. Bi W, Sapir T, Shchelochkov OA, Zhang F, Withers M, Hunter JV, Levy T, Forbes SH, Dorschner MO, Le R, Stephens K. 2004. Genomic context of Shinder V, Peiffer DA, Gunderson KL, Nezarati MM, Shotts VA, Amato paralogous recombination hotspots mediating recurrent NF1 region SS, Savage SK, Harris DJ, Day-Salvatore D-L, Horner M, Lu X-Y, Sahoo microdeletion. Genes Chromosomes Cancer 41:12–25. T, Yanagawa Y, Beaudet AL, Cheung SW, Martinez S, Lupski JR, Reiner Girirajan S, Patel N, Slager RE, Tokarz ME, Bucan M, Wiley JL, Elsea SH. O. 2009. Increased LIS1 expression affects human and mouse brain 2008. How much is too much? Phenotypic consequences of Rai1 over- development. Nat Genet 41:168–177. expression in mice. Eur J Hum Genet 16:941–954. Buchanan JA, Scherer SW. 2008. Contemplating effects of genomic struc- Goh ELK, Zhu T, Yakar S, LeRoith D, Lobie PE. 2000. CrkII participation in tural variation. Genet Med 10:639–647. the cellular effects of growth hormone and insulin-like growth factor-1. Carelle-Calmels N, Saugier-Veber P, Girard-Lemaire F, Rudolf G, Doray B, Phosphatidylinositol-3 kinase dependent and independent effects. J Biol Guerin E, Kuhn P, Arrive M, Gilch C, Schmitt E, Fehrenbach S, Chem 275:17683–17692. Schnebelen A, Frebourg T, Flori E. 2009. Genetic compensation in a Goodier JL, Kazazian HHJ. 2008. Retrotransposons revisited: The restraint human genomic disorder. N Engl J Med 360:1211–1216. and rehabilitation of parasites. Cell 135:23–35. Carvalho CMB, Lupski JR. 2008. Copy number variation at the breakpoint Grisart B, Rack K, Vidrequin S, Hilbert P, Deltenre P, Verellen-Dumoulin region of isochromosome 17q. Genome Res 18:1724–1732. C, Destree A. 2008. NF1 microduplication first clinical report: Associa- Chance PF, Alderson MK, Leppig KA, Lensch MW, Matsunami N, Smith B, tion with mild mental retardation, early onset of baldness and dental Swanson PD, Odelberg SJ, Disteche CM, Bird TD. 1993. DNA deletion enamel hypoplasia? Eur J Hum Genet 16:305. associated with hereditary neuropathy with liability to pressure palsies. GuW, ZhangF,Lupski J.2008. Mechanismsfor human genomic rearrange- Cell 72:143–151. ments. PathoGenetics 1:4. Chen KS, Manian P, Koeuth T, Potocki L, Zhao Q, Chinault AC, Lee CC, Hastings PJ, Ira G, Lupski JR. 2009a. A microhomology-mediated break- Lupski JR. 1997. Homologous recombination of a flanking repeat gene induced replication model for the origin of human copy number varia- cluster is a mechanism for a common contiguous gene deletion syn- tion. PLoS Genet 5:e1000327. drome. Nat Genet 17:154–163. Hastings PJ, Lupski JR, Rosenberg SM, Ira G. 2009b. Mechanisms of change Chng WJ, Remstein ED, Fonseca R, Bergsagel PL, Vrana JA, Kurtin PJ, in gene copy number. Nat Rev Genet 10:551. Dogan A. 2009. Gene expression profiling of pulmonary mucosa-associated lymphoid tissue lymphoma identifies new biologic insights with Hoogendijk JE, Hensels GW, Gabreels-Festen AAWM, Gabreels FJM, potential diagnostic and therapeutic applications. Blood 113:635–645. Janssen EAM, De Jonghe P, Martin J-J, Van Broeckhoven C, Valentijn SHCHELOCHKOV ET AL. 1109

LJ, Baas F, de Visser M, Bolhuis PA. 1992. De-novo mutation in Lupski JR, Wise CA, Kuwano A, Pentao L, Parke JT, Glaze DG, Ledbetter hereditary motor and sensory neuropathy type I. Lancet 339:1081– DH, Greenberg F, Patel PI. 1992. Gene dosage is a mechanism for 1082. Charcot-Marie-Tooth disease type 1A. Nat Genet 1:29–33. Horikawa Y, Iwasaki N, Hara M, Furuta H, Hinokio Y, Cockburn BN, Mefford HC, Clauin S, Sharp AJ, Moller RS, Ullmann R, Kapur R, Pinkel D, Lindner T, Yamagata K, Ogata M, Tomonaga O, Kuroki H, Kasahara T, Cooper GM, Ventura M, Ropers HH, Tommerup N, Eichler EE, Iwamoto Y, Bell GI. 1997. Mutation in hepatocyte nuclear factor-1[beta] Bellanne-Chantelot C. 2007. Recurrent reciprocal genomic rearrange- gene (TCF2) associated with MODY. Nat Genet 17:384. ments of 17q12 are associated with renal disease, diabetes, and epilepsy. Am J Hum Genet 81:1057. Hulme AE, Kulpa DA, Garcia-Perez JL, Moran JV. 2006. The impact of LINE-1 retrotransposition on the human genome. In: Lupski JR, Stan- Mencarelli MA, Katzaki E, Papa FT, Sampieri K, Caselli R, Uliana V, kiewicz P, editors. Genomic Disorders: the Genomic Basis of Disease, 1e. Pollazzon M, Canitano R, Mostardini R, Grosso S, Longo I, Ariani F, Totowa, New Jersey: Humana Press, pp 33–55. Meloni I, Hayek J, Balestri P, Mari F, Renieri A. 2008. Private inherited microdeletion/microduplications: Implications in clinical practice. Eur J Huxley C, Passage E, Robertson AM, Youl B,Huston S,Manson A,Saberan- Med Genet 51:409. Djoniedi D, Figarella-Branger D, Pellissier JF, Thomas PK, Fontes M. 1998. Correlation between varying levels of PMP22 expression and the Menke DB, Guenther C, Kingsley DM. 2008. Dual hindlimb control degree of demyelination and reduction in nerve conduction velocity in elements in the Tbx4 gene and region-specific control of bone size in transgenic mice. Hum Mol Genet 7:449–458. vertebrate limbs. Development 135:2543–2553. Kirchhoff M, Bisgaard A-M, Duno M, Hansen FJ, Schwartz M. 2007. A Molina J, Carmona-Mora P, Chrast J, Krall PM, Canales CP, Lupski JR, 17q21.31 microduplication, reciprocal to the newly described 17q21.31 Reymond A, Walz K. 2008. Abnormal social behaviors and altered gene microdeletion, in a girl with severe psychomotor developmental delay expression rates in a mouse model for Potocki-Lupski syndrome. Hum and dysmorphic craniofacial features. Eur J Med Genet 50:256. Mol Genet 17:2486–2495. Koolen DA, Vissers LELM, Pfundt R, de Leeuw N, Knight SJL, Regan R, Mouton P, Tardieu S, Gouider R, Birouk N, Maisonobe T, Dubourg O, Kooy RF, Reyniers E, Romano C, Fichera M, Schinzel A, Baumer A, Brice A, LeGuern E, Bouche P. 1999. Spectrum of clinical and electro- Anderlid B-M, Schoumans J, Knoers NV, van Kessel AG, Sistermans EA, physiologic features in HNPP patients with the 17p11.2 deletion. Neu- Veltman JA, Brunner HG, de Vries BBA. 2006. A new chromosome rology 52:1440–1446. 17q21.31 microdeletion syndrome associated with a common inversion Nagamani SCS, Erez A, Shen J, Li C, Roeder E, Cox S, Karaviti L, Pearson M, polymorphism. Nat Genet 38:999. Kang SH, Sahoo T, Lalani SR, Stankiewicz P, Sutton VR, Cheung SW. Koolen DA, Sharp AJ, Hurst JA, Firth HV, Knight SJL, Goldenberg A, 2009. Clinical spectrum associated with recurrent genomic rearrange- Saugier-Veber P, Pfundt R, Vissers LELM, Destree A, Grisart B, Rooms L, ments in chromosome 17q12. Eur J Hum Genet. [Epub ahead of print]. Van der Aa N, Field M, Hackett A, Bell K, Nowaczyk MJM, Mancini GMS, Nakashima N, Rose DW, Xiao S, Egawa K, Martin SS, Haruta T, Saltiel AR, Poddighe PJ, Schwartz CE, Rossi E, De Gregori M, Antonacci-Fulton LL, Olefsky JM. 1999. The functional role of CrkII in actin cytoskeleton McLellan MD II, Garrett JM, Wiechert MA, Miner TL, Crosby S, Ciccone organization and mitogenesis. J Biol Chem 274:3001–3008. R, Willatt L, Rauch A, Zenker M, Aradhya S, Manning MA, Strom TM, Wagenstaller J, Krepischi-Santos AC, Vianna-Morgante AM, Rosenberg Nelis E, Van Broeckhoven C, De Jonghe P, Lofgren€ A, Vandenberghe A, C, Price SM, Stewart H, Shaw-Smith C, Brunner HG, Wilkie AOM, Latour P, Le Guern E, Brice A, Mostacciuolo ML, Schiavon F, Palau F, Veltman JA, Zuffardi O, Eichler EE, de Vries BBA. 2008. Clinical and Bort S, Upadhyaya M, Rocchi M, Archidiacono N, Mandich P, Bellone E, molecular delineation of the 17q21.31 microdeletion syndrome. J Med Silander K, Savontaus M, Navon R, Goldberg-Stern H, Estivill X, Volpini Genet 45:710–720. V, Friedl W, Gal A, et al. 1996. Estimation of the mutation frequencies in Charcot-Marie-Tooth disease type 1 and hereditary neuropathy with Lee JA, Carvalho CMB, Lupski JR. 2007. A DNA replication mechanism for liability to pressure palsies: A European collaborative study. Eur J Hum generating nonrecurrent rearrangements associated with genomic dis- Genet 4:25–33. orders. Cell 131:1235. Niemann S, Sereda MW, Rossner M, Stewart H, Suter U, Meinck HM, Lindner TH, Njolstad PR, Horikawa Y, Bostad L, Bell GI, Sovik O. 1999. A Griffiths IR, Nave KA. 1999. The ‘‘CMT rat’’: Peripheral neuropathy and novel syndrome of diabetes mellitus, renal dysfunction and genital dysmyelination caused by transgenic overexpression of PMP22. Ann NY malformation associated with a partial deletion of the pseudo-POU Acad Sci 883:254–261. domain of hepatocyte nuclear factor-1beta. Hum Mol Genet 8:2001–2008. Ohta S, Suzuki K, Tachibana K, Tanaka H, Yamada G. 2007. Cessation of gastrulation is mediated by suppression of epithelial-mesenchymal tran- Lupski JR. 1998. Genomic disorders: Structural features of the genome can sition at the ventral ectodermal ridge. Development 134:4315–4324. lead to DNA rearrangements and human disease traits. Trends Genet 14:417. Park SS, Stankiewicz P, Bi W, Shaw C, Lehoczky J, Dewar K, Birren B, Lupski JR. 2002. Structure and evolution of the Smith-Magenis syn- Lupski JR. 2006. Genome structural variation and sporadic disease traits. drome repeat gene clusters, SMS-REPs. Genome Res 12:729–738. Nat Genet 38:974. Pentao L, Wise CA, Chinault AC, Patel PI, Lupski JR. 1992. Charcot-Marie- Lupski JR. 2009. Genomic disorders ten years on. Genome Med 1:42. Tooth type 1A duplication appears to arise from recombination at repeat LupskiJR, Stankiewicz P. 2005.Genomic disorders: Molecular mechanisms sequences flanking the 1.5 Mb monomer unit. Nat Genet 2:292–300. for rearrangements and conveyed phenotypes. PLoS Genet 1:e49. Perea J, Robertson A, Tolmachova T, Muddle J, King RH, Ponsford S, Lupski JR, de Oca-Luna RM, Slaugenhaupt S, Pentao L, Guzzetta V, Trask Thomas PK, Huxley C. 2001. Induced myelination and demyelination in BJ, Saucedo-Cardenas O, Barker DF, Killian JM, Garcia CA, Chakravarti a conditional mouse model of Charcot-Marie-Tooth disease type 1A. A, Patel PI. 1991a. DNA duplication associated with Charcot-Marie- Hum Mol Genet 10:1007–1018. Tooth disease type 1A. Cell 66:219–232. Potocki L, Chen K-S, Park S-S, Osterholm DE, Withers MA, Kimonis V, Lupski JR, Garcia CA, Parry GJ, Patel PI. 1991b. Charcot-Marie-Tooth Summers AM, Meschino WS, Anyane-Yeboa K, Kashork CD, Shaffer LG, polyneuropathy syndrome: Clinical, electrophysiological, and genetic Lupski JR. 2000. Molecular mechanism for duplication 17p11.2— the aspects. In: Appel S, editor. Current Neurology, Vol 11. Chicago: Mosby- homologous recombination reciprocal of the Smith-Magenis micro- Yearbook. pp 1–25. deletion. Nat Genet 24:84. 1110 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

Potocki L, Bi W, Treadwell-Deering D, Carvalho CM, Eifert A, Friedman Stefansson H, Helgason A, Thorleifsson G, Steinthorsdottir V, Masson G, EM, Glaze D, Krull K, Lee JA, Lewis RA, Mendoza-Londono R, Robbins- Barnard J, Baker A, Jonasdottir A, Ingason A, Gudnadottir VG, Desnica Furman P, Shaw C, Shi X, Weissenberger G, Withers M, Yatsenko SA, N, Hicks A, Gylfason A, Gudbjartsson DF, Jonsdottir GM, Sainz J, Zackai EH, Stankiewicz P, Lupski JR. 2007. Characterization of Potocki- Agnarsson K, Birgisdottir B, Ghosh S, Olafsdottir A, Cazier JB, Krist- Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage- jansson K, Frigge ML, Thorgeirsson TE, Gulcher JR, Kong A, Stefansson sensitive critical interval that canconvey anautism phenotype. Am JHum K. 2005. A common inversion under selection in Europeans. Nat Genet Genet 80:633–649. 37:129–137. Puusepp H, Zilina O, Teek R, M€annik K, Parkel S, Kruustuk€ K, Kuuse K, Sun M, Li N, Dong W, Chen Z, Liu Q, Xu Y, He G, Shi Y, Li X, Hao J, Luo Y, Kurg A, O?unap K. 2009. 5.9 Mb microdeletion in chromosome band Shang D, Lv D, Ma F, Zhang D, Hua R, Lu C, Wen Y, Cao L, Irvine AD, 17q22-q23.2 associated with tracheo-esophageal fistula and conductive McLean WHI, Dong Q, Wang M-R, Yu J, He L, Lo WHY, Zhang X. 2009. hearing loss. Eur J Med Genet 52:71. Copy-number mutations on chromosome 17q24.2-q24.3 in congenital generalized hypertrichosis terminalis with or without gingival hyperpla- Reiner O. 2000. LIS1. Let’s interact sometimes (part 1). Neuron 28: sia. Am J Hum Genet 84:807. 633–636. Toyo-oka K, Shionoya A, Gambello MJ, Cardoso C, Leventer R, Ward HL, Reiter LT, Hastings PJ, Nelis E, De Jonghe P, Van Broeckhoven C, Lupski Ayala R, Tsai LH, Dobyns W, Ledbetter D, Hirotsune S, Wynshaw-Boris JR. 1998. Human meiotic recombination products revealed by sequenc- A. 2003. 14-3-3epsilon is important for neuronal migration by binding to ing a hotspot for homologous strand exchange in multiple HNPP NUDEL: A molecular explanation for Miller-Dieker syndrome. Nat deletion patients. Am J Hum Genet 62:1023. Genet 34:274–285. Roos L, Jonch AE, Kjaergaard S, Taudorf K, Simonsen H, Hamborg- Walz K, Caratini-Rivera S, Bi W, Fonseca P, Mansouri DL, Lynch J, Vogel Petersen B, Brondum-Nielsen K, Kirchhoff M. 2009. A new micro- H, Noebels JL, Bradley A, Lupski JR. 2003. Modeling del(17)(p11.2p11.2) duplication syndrome encompassing the region of the Miller-Dieker and dup(17)(p11.2p11.2) contiguous gene syndromes by chromosome – (17p13 deletion) syndrome. J Med Genet 46:703 710. engineering in mice: Phenotypic consequences of gene dosage imbalance. Schmickel RD. 1986. Contiguous gene syndromes: A component of Mol Cell Biol 23:3646–3655. recognizable syndromes. J Pediatr 109:231–2241. Walz K, Spencer C, Kaasik K, Lee CC, Lupski JR, Paylor R. 2004. Behavioral Sereda M, Griffiths I, Puhlhofer€ A, Stewart H, Rossner MJ, Zimmermann F, characterization of mouse models for Smith-Magenis syndrome and Magyar JP, Schneider A, Hund E, Meinck H-M, Suter U, Nave K-A. 1996. dup(17)(p11.2p11.2). Hum Mol Genet 13:367–378. A transgenic rat model of Charcot-Marie-Tooth disease. Neuron Walz K, Paylor R, Yan J, Bi W, Lupski JR. 2006. Rai1 duplication causes 16:1049. physical and behavioral phenotypes in a mouse model of dup(17)- Sharp AJ, Hansen S, Selzer RR, Cheng Z, Regan R, Hurst JA, Stewart H, (p11.2p11.2). J Clin Invest 116:3035–3041. Price SM, Blair E, Hennekam RC, Fitzpatrick CA, Segraves R, Richmond Yoshikawa H, Nishimura T, Nakatsuji Y, Fujimura H, Himoro M, Hay- TA, Guiver C, Albertson DG, Pinkel D, Eis PS, Schwartz S, Knight SJL, asaka K, Sakoda S, Yanagihara T. 1994. Elevated expression of messenger Eichler EE. 2006. Discovery of previously unidentified genomic disorders RNA for peripheral myelin protein 22 in biopsied peripheral nerves of from the duplication architecture of the human genome. Nat Genet patients with Charcot-Marie-Tooth disease type 1A. Ann Neurol 35: 38:1038. 445–455. Shaw CJ, Lupski JR. 2004. Implications of human genome architecture for Zhang J, Feuk L, Duggan GE, Khaja R, Scherer SW. 2006. Development of rearrangement-based disorders: The genomic basis of disease. Hum Mol bioinformatics resources for display and analysis of copy number and Genet 13:R57–R64. other structural variants in the human genome. Cytogenet Genome Res Shaw CJ, Lupski JR. 2005. Non-recurrent 17p11.2 deletions are generated 115:205–214. by homologous and non-homologous mechanisms. Hum Genet Zhang F, Khajavi M, Connolly AM, Towne CF, Batish SD, Lupski JR. 2009. 116:1–7. The DNA replication FoSTeS/MMBIR mechanism can generate geno- Shawlot W, Behringer RR. 1995. Requirement for Lim1 in head-organizer mic, genic and exonic complex rearrangements in humans. Nat Genet function. Nature 374:425. 41:849. Shaw-Smith C, Pittman AM, Willatt L, Martin H, Rickman L, Gribble S, Zody MC, Garber M, Adams DJ, Sharpe T, Harrow J, Lupski JR, Nicholson Curley R, Cumming S, Dunn C, Kalaitzopoulos D, Porter K, Prigmore E, C, Searle SM, Wilming L, Young SK, Abouelleil A, Allen NR, Bi W, Bloom Krepischi-Santos ACV, Varela MC, Koiffmann CP, Lees AJ, Rosenberg C, T, Borowsky ML, Bugalter BE, Butler J, Chang JL, Chen CK, Cook A, Firth HV, de Silva R, Carter NP. 2006. Microdeletion encompassing Corum B, Cuomo CA, de Jong PJ, DeCaprio D, Dewar K, FitzGerald M, MAPT at chromosome 17q21.3 is associated with developmental delay Gilbert J, Gibson R, Gnerre S, Goldstein S, Grafham DV, Grocock R, and learning disability. Nat Genet 38:1032. Hafez N, Hagopian DS, Hart E, Norman CH, Humphray S, Jaffe DB, Jones M, Kamal M, Khodiyar VK, LaButti K, Laird G, Lehoczky J, Liu X, She X, Horvath JE, Jiang Z, Liu G, Furey TS, Christ L, Clark R, Graves T, Lokyitsang T, Loveland J, Lui A, Macdonald P, Major JE, Matthews L, Gulden CL, Alkan C, Bailey JA, Sahinalp C, Rocchi M, Haussler D, Wilson Mauceli E, McCarroll SA, Mihalev AH, Mudge J, Nguyen C, Nicol R, RK, Miller W, Schwartz S, Eichler EE. 2004. The structure and evolution O’Leary SB, Osoegawa K, Schwartz DC, Shaw-Smith C, Stankiewicz P, of centromeric transition regions within the human genome. Nature Steward C, Swarbreck D, Venkataraman V, Whittaker CA, Yang X, 430:857–864. Zimmer AR, Bradley A, Hubbard T, Birren BW, Rogers J, Lander ES, Nusbaum C. 2006. DNA sequence of human chromosome 17 and Sreenath Nagamani SC, Zhang F, Shchelochkov OA, Bi W, Ou Z, Scaglia F, analysis of rearrangement in the human lineage. Nature 440:1045–1049. Probst FJ, Shinawi M, Eng C, Hunter JV, Sparagana S, Lagoe S, Fong Ct, Pearson M, Doco-Fenzy M, Landais E, Mozelle M, Chinault AC, Patel A, Zody MC, Jiang Z, Fung HC, Antonacci F, Hillier LW, Cardone MF, Graves Bacino CA, Sahoo T, Kang SH, Cheung SW, Lupski JR, Stankiewicz P. TA, Kidd JM, Cheng Z, Abouelleil A, Chen L, Wallis J, Glasscock J, Wilson 2009. Microdeletions including YWHAE in the Miller-Dieker syndrome RK, Reily AD, Duckworth J, Ventura M, Hardy J, Warren WC, Eichler EE. region on chromosome 17p13.3 result in facial dysmorphisms, growth 2008. Evolutionary toggling of the MAPT 17q21.31 inversion region. Nat restriction, and cognitive impairment. J Med Genet 46:825–833. Genet 40:1076–1083.