position of the disease locus in the genome, potential dosage-sensitive genes, type and size of

VII ^{A PPENDICES}

A Well-Characterized Rearrangement-Based Diseases and Genome Structual Features at the Locus

403

From: Genomic Disorders: The Genomic Basis of Disease Edited by: J. R. Lupski and P. Stankiewicz © Humana Press, Totowa, NJ

Pawet Stankiewicz, ^MD , ^{P h D} and James R. Lupski, ^MD , ^{P h D}

The following table provides details of well-characterized genomic disorders. It lists the

position of the disease locus in the genome, potential dosage-sensitive genes, type and size of

the rearrangement, and genome architectural features at the locus involved.

RearrangementRecombination substrates InheritanceSizeRepeatIdentityRecombination DisordersOMIMpatternChromosomeGene(s)Type(kb)size (kb)(%)hotspotOrientationType Bartter syndrome type III601678AD1p36.13CLCNKA/Bdel11DG/y Gaucher disease230800AR1q22GBAdel1614DG/y Familial juvenile nephronophthisis256100AR2q13NPHP1del29045>97DG 3q29 microdeletion syndrome6094253q29PAK2,del1500>30>97.5D DLG1? Fascioscapulohumeral muscular158900AD4q35.2FRG1?del25–2223.3D dystrophy/polymorphic copy number Spinal muscular atrophy253300AR5q13.2SMN1inv, dup900500I Sotos syndrome117550AD5q35NSD1del2000400992.5 kbDGC Congenital adrenal hyperplasia201910AR6p21.32CYP21del3096–98DG/y III/21 hydroxylase deficiency Williams-Beuren syndrome194050AD7q11.23ELN,del, inv1600>320983.4 kbCGC LIMK1 inv dup(8p);8p23inv/dup/del40095–97IOR-GC der(8)(pterp23.1::p23.2pter); del(8)(p23.1p23.2) Glucocorticoid-remediable103900AD8q24.3CYP11B1/2dup451095DG aldosteronism δβ-thalassemia (Hb variants Lepore141900AR11p15.4δ- and β-del7DG and Miyada)globin Prader-Willi syndrome176270AD15q11.2q13SNRPN,del3500400CGC NDN, necdin, SnoRNAs? Angelman syndrome105830AD15q11.2q13UBE3Adel3500400CGC dup(15)(q11.2q13) syndrome15q11.2q13?dup3500400CGC triplication 15q11.2q1315q11.2q13?trip3500400CGC inv dup(15)(q11q13)15q11.2q13?inv dup3500400CGC α-thalassemia14180016p13.3α-globindel3.74DS Polycystic kidney disease 1601313AD16p13.3PKD15095

Charcot-Marie-Tooth118220AD17p12PMP22dup14002498.7741 bpDS type 1A disease Hereditary neuropathy with162500AD17p12PMP22del14002498.7557 bpDS liability to pressure palsies Smith-Magenis syndrome182290AD17p11.2RAI1del400020098524 bp/1.1 kbDGC dup(17)(p11.2p11.2) syndromeAD17p11.2RAI1?dup400020098DGC Neurofibromatosis type 1162200AD17q11.2NF1del1400852 KbDG Breast cancer114480AD17q21.3BRCA1del371492624 bpDG Pituitary dwarfism262400AR17q23.3GH1del6.72.2499DS Frontotemporal demetia600274AD17q21.3MAPT?inv570120–50090–99CS DiGeorge syndrome/velocardio-188400/AD22q11.2TBX1del3000/1500225–40097–98CGC facial syndrome192430 dup(22)(q11.2q11.2) syndrome22q11.2?dup3,000225–40097–98CGC triplication 22q11.2q11.222q11.2?trip3000225–40097–98CGC Cat-eye syndrome, inv dup(22)(q11.2)22q11.2?inverted dup225–400225–40097–98CGC CYP2D6 pharmacogenetic trait124030AR22q13.2CYP2D6del/dup9.32.8S Ichthyosis308100XLXp22.31STSdel19001195DS idic(X)(p11.2)isodicentric? Hunter syndrome309900XLXq28IDSinv del203>88G/ψ (mucopolysaccharidosis type II) Rett syndrome/duplication of MECP2312750XLXq28MECP2del/dup Red–green color blindness,303800XLXq28RCPdel03998DG polymorphic copy numberandGCP Emery-Dreifuss muscular dystrophy/310300XLXq28Emerindel/dup/inv4811.399.2 polymorphic inversion of 38 kband FLN1 Incontinentia pigmenti308300XLXq28NEMOdel100.870D Hemophilia A306700XLXq28Factor VIIIinv300–5009.599.9I Male infertility, AZFa microdeletion415000YLYq11.21USP9Y,DBY ?del80010941.3 kbR Male infertility, AZFc microdeletion415000YLYq11.23RBMY, DAZ ?del3,50022999.97933 bpP1/P3 D, autosomal dominant; AR, autosomal recessive; XL, X chromosome-linked; YL, Y chromosome-linked; del, deletion; dup, duplication; trip, triplication; inv, inversion; I, inverted; D, direct; G, gene; y, pseudogene; S, segment of genome, C, complex; P, palindromes; R, retrovirus; OMIM, Online Mendelian Inheritance in Man database (http:// www3.ncbi.nlm.nih.gov/Omim/). (Adapted and expanded from ref.1.)

REFERENCES

1. Stankiewicz P, Lupski JR. Genome architecture, rearrangements, and genomic disorders. Trends Genet 2002;18:74–82.

B Diagnostic Potential for Chromosome Microarray Analysis

Pawel Stankiewicz, ^MD , ^{P h D} , Sau Wai Cheung, ^{P h D} , and Arthur L. Beaudet, ^MD

To overcome the approx 3–10 Mb resolution limitation of conventional, chromosome- based cytogenetic banding and comparative genomic hybridization (CGH) diagnostic meth- ods, arrays of large insert bacterial artificial chromosome (BAC) and P1-derived artificial chromosome (PAC) clones for selected rearrangement-prone genomic regions were immobi- lized on glass slides. This approach enables detection of copy number changes throughout the genome at virtually whatever resolution desired. CGH arrays have been designed initially for the analysis of constitutional abnormalities involving specific targeted chromosome regions and subtelomeric regions of all chromosomes. Arrays have also been constructed for complete coverage of the human genome with overlapping BAC clones. The latter approach, however, has been tempered by high cost associated with array production, challenges in clinical inter- pretation of newly discovered rare variants, and current limitations of the knowledge and clinical relevance of large segmental copy number variants. To circumvent these challenges, a limited number (360–850) of BAC clones have been selected specifically for clinically relevant regions of the genome known to be responsible for genomic disorders and the loca- tions for each of these clones has been verified by fluorescence in situ hybridization. This novel high-resolution custom chromosome microarray analysis (CMA) allows screening of 41 subtelomeric regions, and more than 40 microdeletion/microduplication syndromes and other well-established gene dosage-sensitive genomic disorders in a single test (1,2). The detection rate for abnormalities has been estimated as 8.4% in the current version 5. Furthermore, the approach enables the detection of several genomic changes not visualized by conventional clinical chromosome G-banding techniques. Targeted arrays have also been clinically applied in prenatal diagnosis (3).

This appendix delineates the clinical phenotypes wherein CMA may be useful. Each of these conditions can be owing to a DNA rearrangement of the human genome. In some diseases, a rearrangement represents the major mutational mechanism, whereas in others genomic changes account for a smaller proportion of the cases. It is anticipated that this list may expand substan- tially as high-resolution analysis of the human genome is systematically applied to individuals with diverse phenotypes in both clinical research and medical practice.

The information in the following table is intended to help clinicians in the use of interpre- tation of array CGH in genetic diagnosis. The material covered is very complex and this table is necessarily a simplification to some extent. Users should consult the primary literature and other sources for more detailed information. An updated electronic version of the table with links can be found at http://www.bcm.edu/geneticlabs/tests/cyto/cmaregionsv5/html.

407

From: Genomic Disorders: The Genomic Basis of Disease Edited by: J. R. Lupski and P. Stankiewicz © Humana Press, Totowa, NJ

Selected refs.GeneTests/ OMINIPhenotypeGenesCytogeneticsDetection (%)PMIDGeneReviews General properties VariousVariousVariousDeletions and duplications ofHigh11951177 subtelomeric regions14628292 15904506 15834244 15723295 16024975 VariousVariousVariousDeletions and duplications ofHigh13680362 pericentromeric regions15508017 VariousVariousVariousAneuploidy for any chromosomeHigh Disorders with high detection rates (>50%) 6078721p36 deletion syndromeMultiple1p36 deletion>95–99%10507720– 12915473 256100NPHP1Familial juvenileNPHP1, nephrocystin2q13 homozygous deletion60–70% homozygous9361039+ nephronophthisis9326933 6094253q29 microdeletion syndromePAK2,DLG1?3q29 deletion>95%15918153– 194190WHS Wolf-Hirschhorn syndromeMultiple4p16.3 deletion>95–99%11480768+ 15734578 123450Cri-du-chat syndromeMultiple5p15.2-p13.3 deletion>95–99%11238681+ 15635506 194050WBS Williams-Beuren syndromeELN elastin, LIMK1 LIM kinase 17q11.23 deletion>95–99%11701637+ 12796854 inv dup(8p); der(8)(pterp23.1::UnknownDeletion, inverted duplication 8p23>95%8533823– p23.2pter); del(8)(p23.1p23.2)11231899 150230LGS Langer-Giedion syndromeTRPS1 zinc finger transcription8q23.3-q24.11 deletion>95%7711731+ TRPS1 and EXT1 exostosin 18530105 9q34.3 deletion syndrromeMultiple9q34.4 deletion>95%15805169– 15805155

601362DGS2 DiGeorge syndrome 2Unknown10p14 deletion>95%9781025+ 15253763 601224PSS Potocki-Shaffer syndromeALX4 Aristaless-like-4 and/or11p11.2 deletion>95%8644736+ EXT2exostosin 215852040 147791JBS Jacobsen (11q25 deletion)11q24-q25~65%14597985– syndrome15266616 176270PWS Prader-Willi syndromeSNRPN,NDN necdin, snoRNAs15q11.2-q13 deletion~70%8651269+ 11694676 105830ASAngelman syndromeUBE3A ubiquitin ligase 3A15qa11.2-q13 deletion~70%7625452+ 8651269 dup(15)(q11.2q13) syndrome15q11.2-q13~99%9106540– 15318025 15q21 deletion syndrome15q21 deletion~99%12684692– 247200MDLS Miller-DiekerLIS1 and/or YWHAE17p13.3 deletion>90% for full syndrome11115846+ lissencephally syndrome12621583 118220CMT1A Charcot-Marie-ToothPMP22peripheral myelin17p12 duplication>98%11835373+ type 1A diseaseprotein 2216106622 162500HNPP Heredity neuropathy withPMP22 perioheral myelin17p12 deletion~85%8422677+ liability to pressure palsiesprotein 2210586225 182290SMS Smith-Magenis syndromeRAI1 reinoic acid-induced gene 117p11.2 deletion~99%15148657+ 14614393 dup(17)(p11.2p11.2) syndrome17p11.2 duplication~99%10615134– 115470CES cat-eye syndromeinv dup(22)(q11.2)>90%15756300– 11381032 188400/DGS1 DiGeorge, VCFSTBX1 T-box 1 22q11.2 deletion>95%1349199+ 192430velocardiofacial syndrome9350810 608363dup(22)(q11.2q11.2) syndromePossiblyTBX1 T-box 122q11.2 duplication~99%14526392– 15800846 127300LWD Leri-WeillSHOX/SHOXY shory statureXp22.23/Yp11.3260–80% in LWD,11739418+ dyschondrosteosishomeoboxless in short stature16103983 308100STS steroid sulfatase deficiencyARSC2 aryl sulfatase CXp22.31 deletion>95%2644167+ 3480263 (continued)

Selected refs.GeneTests/ OMINI no.PhenotypeGenesCytogeneticsDetection (%)PMIDGene Reviews STS dup Xp22.31 Unclear ifXp22.31 duplication>95%15060094– benign or disease related16175506 300200AHC Congenital adrenalNROB1 nuclear receptorXp21.2 deletionHigh in contiguous,11032329+ hypoplasiafamily 0 B1low isolated gene15684452 300018DSS Dosage-sensitive sexNROB1 nuclear receptorXp21.2 duplication>95%7951319– reversalfamily 0 B115216557 312080PMDPelizaeus-MerzbacherPLP1 proteolipid protein 1Xp22 duplication or deletion60–70%/<2%12297985+ disease15627202 Disorders with intermediate or uncertain detection rates 2q22.3 deletion2q22.3 deletion15591274 220200DWS Dandy-Walker syndromZIC1,Zic4 zinc finger protein of3q24 deletionUncertain15338008– the cerebellum 1, 4 180500RIEG1 Rieger syndrome, type 1PITX24q25 deletionUncertain8944018+ 12647202 101400SCS Saethre-Chotzen syndromeTWIST homolog of Drosophila7p21.1 deletion10–30%1746608+ TWIST8988166 190350TRPS1 trichorhinophalangealTRSP1 zinc finger transcription8q23.3 deletion<30%9150732+ syndrome 1TRPS111112658 1462555HDR Hypoparathyroidism,GATA3GATA-binding protein 310p14 duplicationUncertain10633131– sensorineural deafness, and10935639 renal disease 608071SHFM3split-hand/foot10p14 duplication12913067+ malformation 3 106210AN2aniridia IIPAX6 paired box gene 611p13 deletion20–35% overall;9482572+ higher in WAGR11479730 607102Wims tumorWT1Wilms tumor 1 gene11p13 deletion20–35% overall;9090524+ higher in WAGR15150775 194072WAGR syndromePAX6 and WT111p13 deletion20–35% overall;9132491+ higher in WAGR12386836

Luekodystrophy11q14.2-q14.3Uncertain14722582– 180200RB1 reinoblastomaRB1 retinoblastoma 113q14.2 deletionLow except contiguous10450867+ gene cases15642837 180849RSTS Rubinstein-Taybi syndromeCREBBPCREB-binding protein16p13.3 deletion~10%12070251+ 14974086 309801MLS Micophthalmia with linearXp22.2 deletionUncertain16059943– skin defects 191092TSC2 tuberous sclerosis 2TSC2tuberin16p13.3 deletion17%8269512+ 10205261 300474GKGlycerol kinase deficiencyGK glycerol kinaseXp22 deletionHigh in contiguous,11032329+ low isolated gene11479736 480000Sex reversal X/Y translocationsSRYsex-determining region YYp11.31 deletionModerate in XX males11480910– and XY females11479736 415000AZFa Azoospermia factoraYq11 deletionUncertain15474244– 15890785 415000AZFb Azoospermia factoraYq11 deletionUncertain15474244– 15890785 415000AZFc Azoopermia factoraYq11.23 deletion5–10%15474244+ 15890785 Disorders with low or very low detection rates 164280Feingold syndromeMYCN2p24.3 deletionVery low8989454– 157170HPE2holoprosencephaly 2SIX3 sine oculis homolog 32p21 deletionLow8824878+ 10369266 122470CDLS Cornelia de LangeNIPBL nipped-B-like5p13.2 deletionVery very low15146185+ syndrome16075459 117550Sotos syndromeNSD1 nuclear receptor binding5q35 deletionLow except in Japanese15942875+ Su-var15805156 119600CCD cleidocranial dysplasiaRUNX2 runt-related transcription6p21.1 deletionVery low8533817+ factor 29182765 1757000GCPS Greig cephalopoly-GLI1 GLI-Kruppel family 37p14.1 deletion5–10%14608643+ syndactyly syndrome1650914 (continued)

Selected refs.GeneTests/ OMINI no.PhenotypeGenesCytogeneticsDetection (%)PMIDGene Reviews 142945HPE3 holoprosencephaly 3SHHsonic hedgehog7q36.3 deletionLow ~5%8896571+ 9254845 214800CHARGE syndromeCHD7 Chromo-domain helicase8q12.2 deletionVery low15300250+ DNA-binding 715666308 See basalHPE7 holoprosencephaly 7Missense mutations0%11941477– cell nevus 109400BCNS basal cell nevus syndromePTCH patched Drosophila homolog9q22.32 deletion<5%8681379+ 8755929 161200NPS Nail-patella syndromeLMS1B LIM-homeo box factor 1β9q33.3 deletionVery low9590287+ 10094193 130650BWS Beckwith-WiedmannIGF2 insulin-like growth factor II,11p15.5 deletion/duplication1–2%9350814+ syndromeCDKN1C cyclin-dependent9781904 kinase inhibitor 1C 163950NS1Noonan syndromePTPN1112q24.13 deletionVery low9412792+ 10636744 603073HPE5 holoprosencephaly 5ZIC2 zinc finger protein13q32.3 deletion<5%7573047+ cerebellum 28418661 209850AutismUncertain15q11.2-q13 maternal duplication1–3%11803514+ 15197683 142340HCD hernia, congenital15q26.1-q26.2 deletionLow15057983+ diaphragmatic15750894 191100TSC1 tuberous sclerosis 1TSC1 hamartin9q34.22%9328481+ 600273PKDTS polycystic kidneyPKD1 polycystin 1, TSC2 tuberin16p13.3 deletion1–2% high for two gene deletion9306341+ disease 1/tuberous sclerosis 214695542 162200NF1 neurofibromatosis type 1NF1 neurofibromin 117q11.2 deletion2–5%15236313+ 15944227 114290CMPD Campomelic dysplasiaSOX9 SRY-box 917q24.3 deletionLow9724758– 15060123 142946HPE4 holoprosencephaly 4TGIF transforming growth18p11.31 deletion<5%10835638+ factor-β induced factor12522553 118450AGS Alagille syndromeJAG1 jagged 120p12.2 deletion5–7%11180599–

11745040 190685Down syndrome critical regionMultiple21q22 duplicationRare compared to2143053+ trisomy 2111280955 236100HPE1 holosencephaly 1TMEM1? transmembrane21q22.3 deletion<5%7633421+ protein 1 101000NF2 neurofibromatosis IINF2 neurofibromin 222q12.2 deletion<10%15645494+ 15681480 300495AUTSX2 autism, X-linkedPossiblyNLGN4Xp22.32 deletionVery low, uncertain10071191+ susceptibility to, 2 308700KAL1Kallmann syndrome 1KAL1 Kallmann syndrome 1Xp22.31 deletionLow exccept2602357+ contiguous gene9727739 300300Bruton agammaglobulinemiaBTK Bruton agammaglobulinemiaXq22.1 deletionVery low except11338284+ tyrosine kinasecontiguous gene 306955X-linked heterotaxyZIC3zinc finger proteinXq26.3 deletionVery low9311745– cerebellum 3 300123MRGH mental retardation X-SOX3 SRY-box 3Xq27.1 deletion or duplicationVery low of all MR15800844– linked with growth hormone deficiency 312750RTT Rett syndromeMECP2methyul-CpG-bindingXq28 deletion/duplication5%?15841480+ protein-216080119 aThe azoospermia regions are not evaluated in prenatal samples.

REFERENCES

1. Bejjani BA, Saleki R, Ballif BD, et al. Use of targeted array-based CGH for the clinical diagnosis of chromo- somal imbalance: is less more? Am J Med Genet 2005;134:259–267.

2. Cheung SW, Shaw CA, Yu W, et al. Development and validation of a CGH microarray for clinical cytogenetic diagnosis. Genet Med 2005;7:422–432.

3. Rickman L, Fiegler H, Shaw-Smith C, et al. Prenatal detection of unbalanced chromosomal rearrangements by array-CGH. J Med Genet 2005; in press.

415

Index

A

ABL1, 334 ACCN1, 214

aCGH, see Array-comparative genomic hybridization ADCY3, 108

AHR, see Allelic homologous recombination

ALD, 76, 77

Allelic homologous recombination (AHR), hotspots of recombination, detection, 344

evolutionary origins, 349–352 features, 344, 346–348 homologous recombination

machinery, 348, 349 importance, 342, 343 overview, 341, 342

prospects for study, 352, 353 ALOX15B, 145

Alu,

amplification rates, 21 chromosomal distribution, 24 copy number, 21

evolution, 24

evolutionary change induction, 29, 30

gene regulation and stability effects, 30

insertion,

mechanisms, 22

mutagenesis and diseases, 24–26 postinsertion damage,

microsatellite instability, 29 recombination, 26–29 splice variants, 29 prospects for study, 30, 31 recombination events in chromo-

some 2q11.2 gene duplication, 200

Angelman syndrome, 199, 295 Aniridia, PAX6 position effects, 359 Anosmia, see Olfaction

ANT1, 363, 364

Array-comparative genomic hybrid- ization (aCGH),

applications, 390 array painting, 392, 393 copy number change analysis,

391, 392

high-resolution analysis of genomic rearrangements, 394, 395 oligonucleotide array analysis,

395, 396 principles, 389–391 prospects, 398 ARSE, 255, 256

AZF loci, see Azoospermia Azoospermia,

etiology, 274

Y chromosome rearrangements, AZF loci identification, 273–

277, 279, 283 AZFa deletion, 279

AZFa duplication and human endogenous retrovirus homogenization, 280, 281 AZFb deletions and duplica-

tions, 282, 283 AZFc deletions,

common deletion, 279, 280 partial deletions, 281, 282 interstitial deletions and male

infertility, 94 phenotype, 274

prospects for study, 283–286

Yq complexity, 275, 276

B

B4GALT7, 242, 243 BCL2, 95, 329 BCR, 199, 334

Beckwith-Wiedemann syndrome, insulators, 361

NSD1 mutations, 240

Blepharophimosis, FOXL2 position effects, 359, 360

BLMH, 214 BPY2, 283 BRCA1, 27

Breakage–fusion–bridge cycle, monosomy 1p36, 305

Campomelic dysplasia, SOX9 position effects, 360 Cancer, see Neoplasia Cat-eye syndrome, 194, 195 CDY, 48

CDY1, 283 CDYL, 48 CECR7, 82

CENP proteins, functions, 121, 123 Centromere,

chromatin association and function, 121, 122

chromosome function assessment, chromosome engineering,

human artificial chromo- somes, 124, 125 minichromosomes, 124 dicentric chromosomes, 122 neocentromeres, 122, 123 normal human centromeres,

123, 124 definition, 115, 116 genomic analysis, 120, 121 organization,

eukaryotes, 116–118 heterochromatin, 116, 118,

122, 125 humans, 118

prospects for study, 125

repositioning and genome plasticity in evolution,

ancestral centromeres and neocentromeres, 156–159 chromosomal distribution,

154–156

chromosome 3 evolution, 159–162

frequency, 153 inactivated centromere

remains, 156 neocentromeres, 153, 154 nonprimate mammals, 163 present-day episodes, 162, 163 α-satellite evolution, 118–120 Cerebral gigantism, see Sotos syndrome CGH, see Comparative genomic

hybridization

Charcot-Marie-Tooth (CMT) disease, CMT1A duplication,

CMT1A-REP, 170–172 de novo duplication, 170 history of study, 5–9, 11–15,

169, 170 mechanism, 172

structure of genomic region, 175 forms, 170

linkage studies, 5 PMP22 gene dosage, 174 restriction fragment length poly-

morphism mapping, 5–7, 10, 11

Chromatin, position effects, see Position effects

Chromosome 1p36, see Monosomy 1p36

Chromosome 22q11.2 rearrangements, Alu-mediated recombination in

gene duplication, 200 cat-eye syndrome, 194, 195 deletion syndrome, 194 der(22) syndrome, 195 low-copy repeats,

architectural features, 201 evolution, 199

gene conversion between

repeats, 201, 202

inversion polymorphisms, 199

modular structure, 199, 200

malignant disorders, 195, 196

overview, 193, 194

segmental duplications, 196 translocations,

novel translocations, 197–199 t(11;22) mechanism, 197 Chromosome 8p23 cryptic inversion,

carriers and unbalanced offspring risk, 294, 295

detection, 291–294

Chromosome 17p11.2 rearrangements, deletion in Smith-Magenis syn-

drome, 179, 180

duplication, 180, 181, 186, 187 i(17q) breakpoint regions, 186 LCR17p repeats, 184–186 low-copy repeats and deletion

breakpoints, 181, 183, 187, 189

overview, 179, 180

primate chromosome evolution, 187 reciprocal crossovers, 183 recombination,

events in deletion or duplica- tion, 183, 184

mechanisms, 186 Chromosome 17q11.2

microdeletions, see Neurofi- bromatosis 1

Chromosome 7q11.23 aberrations, see Williams-Beuren syndrome Chromosome microarray analysis

(CMA),

application potential in human disease, 407–413 overview, 407

Chromosome, see Centromere; Pri- mate chromosome evolution;

specific chromosomes CMA, see Chromosome microarray

analysis

CMT disease, see Charcot-Marie- Tooth disease

CNGA2, 108

Color blindness, pigment gene defects, 250

Comparative genomic hybridization (CGH), see also Array-com- parative genomic hybridization, monosomy 1p36, 304

segmental duplications and evolution, 80

Congenital anomaly disorder, 194–196 COX10, 171

CPD, 214

Cre-loxP system, chromosomal rearrangement induction in mice, 375–378

Cruciform,

chromosomal rearrangement induction,

cancer, 94, 95

interstitial deletions and male infertility, 94

overview, 93

RAG-dependent recombina- tion and lymphoid malignancy, 95

site-specific non-Robertsonian chromosome transloca- tions, 93, 94

triplet repeat diseases, 95, 96 discovery, 90

human diseases, 91, 92 prospects for study, 96 structure, 91

CTR, 76 CYBB, 256 CYP2D6, 82 CYP2G1, 108

D4Z4, 363, 364 DAX1, 256

DAZ genes, 281, 282 Der(22) syndrome, 195

DiGeorge syndrome, mouse model, 381–383

Diseases, table of genomic rear-

rangements, 404, 405

DMD, see Duchenne muscular dystrophy

DMPK, 361

DNA conformations, see Cruciform;

Hairpin DNA; Tetraplex DNA; Triplex DNA; Z-DNA DNA microarray, see Array-com-

parative genomic hybridiza- tion; Chromosome microarray analysis

Double-strand break (DSB), 93, 95 Double-strand break repair (DSBR),

93, 302, 306–309

Duchenne muscular dystrophy (DMD), DMD gene, 253, 254

X chromosome rearrangements, 253, 254

Duplications, see Segmental duplications

E

ECP, 82 EDN, 82

Elastin gene, see ELN ELN, 222, 232

EMD, see Emery-Dreifuss muscular dystrophy

Embryonic stem (ES) cells, 374–378, 380, 384

Emery-Dreifuss muscular dystrophy (EMD), gene inversions, 253 ETV6, 328

EWSR1, 328

F12, 241

F8, inversions, 251, 252 Facioscapulohumeral muscular

dystrophy (FSMD), genetics, 363, 364

FANCA, 28

FISH, see Fluorescence in situ hybridization

FKBP6, 223

Fluorescence in situ hybridization (FISH),

centromere repositioning, 154, 155 comparative karyotype analysis, 134 monosomy 1p36, 304

PLP1 aberrations, 266

small marker chromosomes, 316 FOXD4, 143

FOXL2, 359, 360 FRG1, 363, 364 FRG2, 363, 364 Friedrich ataxia,

Alu mutagenic changes of fraxin gene, 29

non-B DNA conformation of gene, 96

FSHMD, see Facioscapulohumeral muscular dystrophy

G

gag, 63

Gene conversion, 201, 202, 285, 286, 341, 342, 346–350 Genomic insulators, 360, 361 GGT, 199

GGTLA, 199

β-Globin locus, insulator in chicken, 361

GPR143, 255 GPRK6, 243

GTF2I, 223, 226–228 GUC2D, 145

H

H19, 361 Hairpin DNA,

chromosomal rearrangement induction,

cancer, 94, 95

interstitial deletions and male infertility, 94

overview, 93

RAG-dependent recombina- tion and lymphoid malignancy, 95

site-specific non-Robertsonian chromosome transloca- tions, 93, 94

triplet repeat diseases, 95, 96 discovery, 90

human diseases, 91, 92

prospects for study, 96

structure, 91

HCCS, 255, 256

Hemophilia A, F8 gene inversions, 251, 252

Hemizygous deletion, 194 Hemizygous males, 247, 256 Hereditary neuropathy with liability

to pressure palsies (HNPP), deletion,

breakpoints, 172, 173

mapping, 179–186, 359, 360 structure of genomic region, 175 PMP22 gene dosage, 174

recombination hotspot in CMT1A-REP, 173, 174 HERVs, see Human endogenous

retroviruses HIP1, 231 HMGCR, 144

HNPP, see Hereditary neuropathy with liability to pressure palsies Human endogenous retroviruses

(HERVs),

AZFa duplication and human endogenous retrovirus homogenization, 280, 281 classification, 64, 65

genomic distribution, 65 history of study, 64 human diseases, 65, 66 replication, 63, 64

Hunter syndrome, IDS gene inversions, 252, 253

I

Ichthyosis, STS gene deletions, 248–250 Idiopathic short stature, SHOX gene

deletions, 254 IDS, inversions, 252, 253 Igf2, 361

IGSF3, 200 IL1RAPL, 256

Incontinentia pigmenti, NEMO gene deletions, 250, 251

inv dup small marker chromosomes, inv dup(15), 317–320

inv dup(22), 320–322

origins, 316, 317

prospects for study, 322, 323 symmetry, 316

triplication, 316, 319, 323 Inversion chromosomes,

chromosome 8p23 cryptic inversion, carriers and unbalanced off-

spring risk, 294, 295 detection, 291–294

cryptic inversions associated with segmental duplications, 290, 291

cryptic paracentric inversions, 295–297

epidemiological studies of classical inversions, 289, 290 prospects for study, 297

recombinant chromosomes from carriers, 290

Isochromosome 17q, formation in neoplasia, 330–334

J

JJAZ1, 216, 217

KAL1, 106, 255 KCNQ10T, 240 KER, 183, 184 KIAA0187, 82 KIAA0563, 217

L1, see LINE-1

Langer mesomelic dysplasia, SHOX gene deletions, 254

LDLR, 28

Leri-Weill dyschondrosteosis, SHOX gene deletions, 254 LIMK1, 227, 228, 231

LINE-1 (L1),

functional analysis, ORF1p, 40 ORF2p, 40, 41

3'-untranslated region, 41

5'-untranslated region, 39, 40

genome diversification, 47, 48 mutagenesis and human disease,

44–46

prospects for study, 49, 50 retrotransposition,

assays, 37, 39 cycle, 41, 42

individual variation, 49 target-site primed reverse

transcription, 41–44 retrotransposon features, 36, 37 structure, 37, 38

LINEs, see LINE-1; Long inter- spersed elements

Long interspersed elements (LINEs), see also LINE-1,

ancient LINEs, 59, 61 classification, 59 Lymphoma,

follicular, 92, 95

MAGEL2, 318 Makorin1-p1, 63

Mammalian-wide interspersed repeat (MIR), 57, 59–61, 67 Matrix-scaffold attachment regions,

position effects, 363 MKRN3, 318

MLL, 328, 330

Mobile elements, 21, 22, 26 Monosomy 1p36

clinical features, 301 frequency, 301, 303

low-copy repeats and segmental duplications, 309

molecular mechanisms, 301, 302 prospects for study, 309, 310 repetitive DNA sequence elements,

307–309 telomere,

aberrations and mental retar- dation, 302, 303 structure and function, 302 terminal deletion generation and

stabilization mechanisms, breakage–fusion–bridge

cycles, 305

overview, 303, 304

stabilization models, 306, 307 telomere capture, 305, 306 telomere healing, 305 MSH2, 27

MSH4, 349 MSH6, 27

Myotonic dystrophy, insulators, 361

NAHR, see Nonallelic homologous recombination

NCF1, 144, 223, 226, 227 NDN, 318

NEMO gene, deletions in incontinentia pigmenti, 250, 251

Neocentromeres, 122, 123, 153–162 Neoplasia,

balanced chromosomal transloca- tions, 328–330, 335 chromosome 22q11.2 rearrange-

ments in malignancy, 195, 196 low-copy repeats and genomic

rearrangements,

isochromosome 17q formation, 330–334

overview, 327, 334, 335 oncogenes, 327, 328

tumor suppressor genes, 327, 328 Neoplasia, mouse models of cancers,

383, 384

Neurofibromatosis 1 (NF1), clinical features, 208 NF1 gene,

duplications, 77, 79 flanking low-copy repeats,

207, 209, 212 meiotic recombination

hotspot, 207, 217 mitotic recombination hotspot,

207, 217 microdeletions,

NF-REP mediation, 209, 212 non-low copy repeat media-

tion, 214, 215 somatic microdeletions,

215–217

mutation profile, 208, 209 parologous recombination

sites, 212, 214 prospects for study, 217 NF1, see Neurofibromatosis 1 NGFR, 145

NHEJ, see Nonhomologous end-joining Nonallelic homologous recombina-

tion (NAHR),

hotspots of recombination, detection, 343, 344

evolutionary origins, 349–352 features, 344, 346–348 homologous recombination

machinery, 348, 349 importance, 342, 343 overview, 341, 342

prospects for study, 352, 353 transgenic mice, 373, 374 X chromosome recombination

between low-copy repeats, color blindness and pigment

gene defects, 250 ichthyosis and STS gene dele-

tions, 248–250 incontinential pigmenti and

NEMO gene deletions, 250, 251

inversions,

Emery-Dreifuss muscular dystrophy and EMD gene, 253

hemophilia A and F8 gene, 251, 252

Hunter syndrome and IDS gene, 252, 253 Nonhomologous end-joining

(NHEJ), 253, 254, 267, 269 NROB1, 256

NSD1, see Sotos syndrome NUP98, 239

NXPH3, 145

Olfaction, diseases,

congenital general anosmia, 105, 106

potential genetic mechanisms, 108, 109

specific anosmia, 106, 107

olfactory receptors, 102–105 overview, 101, 102

phenotype variability, 105 prospects for genetic studies,

109, 110 OMP, 108

Palindrome, 277, 279, 280, 282–286 PAX6, 359

PCR, see Polymerase chain reaction Pelizaeus-Merzbacher disease (PMD),

clinical features, 264 PLP1,

comparison with PMP22 diseases, 264–266 detection of duplications and

deletions, 266 gene dosage, 264

low-copy repeats and human genomic architecture, 269 leukodystrophy, 263

mechanisms of duplications and deletions, 266, 267 structure, 264

Pericentromeric segmental duplication, 153, 154

PKD1, 93

PLP1, see Pelizaeus-Merzbacher disease; Spastic paraplegia type 2

PM2L, 223, 224

PMD, see Pelizaeus-Merzbacher disease

PMP22,

comparison with PLP1 diseases, 264–266

gene dosage in neuropathy, 174, 263 structure and function, 264 pol, 63

Polymerase chain reaction (PCR), array-comparative genomic

hybridization, 390, 391

historical perspective, 3 real-time polymerase chain

reaction, 365 POM, 82

POM121, 223 POR, 231 Position effects,

chromatin structure and function, active chromatin hub, 362 analysis,

ChIP-on-chip analysis, 364, 365

microscopy techniques, 365 real-time polymerase chain

reaction, 365 RNA-TRAP, 364

facioscapulohumeral muscular dystrophy, 363, 364 interphase nuclei functional

organization, 363 matrix-scaffold attachment

regions, 363

cis-regulatory element, 358–362 comparative genomics analysis, 362 contact vs noncontact models,

aniridia and PAX6, 359 blepharophimosis and FOXL2,

359, 360

campomelic dysplasia and SOX9, 360

long-range position effects in humans, 358, 359 preaxial polydactyly and SHH,

358, 359

discovery in Drosophila, 358 genomic insulators,

Beckwith-Wiedemann syndrome, 361 chicken β-globin locus, 361 function, 360, 361

myotonic dystrophy, 361 transvection, 358

Prader-Willi syndrome, 199, 296 Preaxial polydactyly, SHH position

effects, 358, 359

Primate chromosome evolution, centromere repositioning and

genome plasticity in evolution, ancestral centromeres and

neocentromeres, 156–159 chromosomal distribution,

154–156

chromosome 3 evolution, 159–162

frequency, 153 inactivated centromere

remains, 156 neocentromeres, 153, 154 present-day episodes, 162, 163 chromosome 17p11.2 duplica-

tions, 187

evolutionary breakpoint analysis, chromosome 2 fusion, 143 chromosome 3 inversion in

hominoids, 143, 144 chromosome 7 inversion in

great apes, 144 chromosome 12 inversion in

chimpanzee and gorilla, 144, 145

chromosome 14/15 synteny fission in great ape ancestor, 145

chromosome 15 inversion in chimpanzee, 145 chromosome 17 inversion in

chimpanzee, 145 chromosome 18 inversion in

human, 145, 146 reciprocal translocation t(4;19)

in gorilla, 144 human chromosomes,

chromosome 2, 140

chromosome 3, 141

chromosome 4, 141

chromosome 5, 141

chromosome 6, 141

chromosome 7, 141

chromosome 9, 142

chromosome 10, 142, 143

Y chromosome, 143

karyotype reconstruction,

ancestral primate karyotype, 135, 136

hominoids, 138, 139 landmark rearrangements,

139, 140

New World monkeys, 137, 138 Old World monkeys, 138 prosimians, 136, 137 overview, 133–135

patterns of genomic changes, 146, 147

prospects for study, 147, 148 rates and direction of evolution-

ary changes, 146 PRKX, 84

PRKY, 84 pro, 63

PROP1, 241, 242 Pseudogenes,

amplification of processed pseudogenes, 61, 62 classification, 61

human diseases, 63 origins, 61, 62

retrotransposition, 62, 63

RAG, recombination and lymphoid malignancy, 95

RAI1, 180 RASA1, 144 RecA, 349

Reciprocal chromosome painting, primate chromosome evolu- tion, 134, 135

Repetitive elements, classification, 58 Retrotransposon, definition, 58, 59 ROCK1, 145

S

Satellite DNA, 116, 118, 120, 123, 125 SCAND2, 63

Segmental duplications, distribution,

nonrandom distribution, 79, 80 pericentromeric regions, 76–78 subtelomeric regions, 78, 79

evolution, 80, 82

genomic variation, 82–84 interchromosomal duplications, 76 intrachromosomal duplications,

74, 75 overview, 73, 74 prospects for study, 84 SHH, 358, 359

Short interspersed elements (SINEs), ancient SINEs, 61 SHOX gene, deletions in disease, 254 SINEs, see Short interspersed elements Single nucleotide polymorphisms

(SNPs), olfactory disease, 108, 109

SIX5, 361 SLFN, 214

Small marker chromosomes (SMCs), see also inv dup small marker chromosomes, detection, 317

incidence at birth, 316, 317 SMCs, see Small marker chromosomes Smell, see Olfaction

Smith-Magenis syndrome (SMS), animal models, 186, 187 chromosome 17p11.2

deletion, 179, 180 low-copy repeats at

breakpoints, 181, 183, 187, 189

uncommon deletions, 185, 186 clinical features, 180

mouse model, 383

SMS, see Smith-Magenis syndrome SNPs, see Single nucleotide

polymorphisms SNURF, 318

SoS, see Sotos syndrome Sotos syndrome (SoS),

clinical features, 237, 238

contiguous genes, 241–243

diagnosis, 238

microdeletion analysis, 241 NSD1 gene,

genotype/phenotype correlation, 239, 240

mutations, 239

overgrowth syndromes and mutations, 240

structure and function, 238, 239 5q35 breakpoint, 238 prospects for study, 243 SOX9, 360

Spastic paraplegia type 2 (SPG2), PLP1 gene,

comparison with PMP22 dis- eases, 264–266 detection of duplications and

deletions, 266 gene dosage, 264

low-copy repeats and human genomic architecture, 269 mechanisms of duplications and

deletions, 266, 267 structure, 264

Spermatogenic failure, 274–276, 281–284

SPG2, see Spastic paraplegia type 2 Spo11, 348

STAG3, 223

STS, deletions in ichthyosis, 248–250

Target-site primed reverse transcrip- tion (TPRT), LINE-1, 41–44 Telomere,

aberrations and mental retardation, 302, 303

structure and function, 302 terminal deletion generation and

stabilization mechanisms in monosomy 1p36

breakage–fusion–bridge cycles, 305 overview, 303, 304

stabilization models, 306, 307 telomere capture, 305, 306 telomere healing, 305

Tetraplex DNA,

chromosomal rearrangement induction,

cancer, 94, 95

interstitial deletions and male infertility, 94

overview, 93

RAG-dependent recombina- tion and lymphoid malignancy, 95

site-specific non-Robertsonian chromosome transloca- tions, 93, 94

triplet repeat diseases, 95, 96 discovery, 90

human diseases, 91, 92 prospects for study, 96 structure, 91

Threshold sensitivity, 108 TPRT, see Target-site primed

reverse transcription Transgenic mouse,

construction, 374, 375

Cre-loxP system for chromosomal rearrangement induction, 375–378

embryonic stem cell irradiation for chromosomal rearrange- ment induction, 377 HPRT selection system, 375–377 human disease models,

cancers, 383, 384

DiGeorge syndrome, 381–383 Smith-Magenis syndrome, 383 insertion vectors, 378

low-copy repeat engineering, 373 MICER clones, 378

nonallelic homologous recombi- nation, 373, 374

recombineering, 379, 380 Transposons,

abundance in human genome, 66 definition, 58, 59

pathogenic potential, 66, 67 TRIM50, 223

Triplex DNA,

chromosomal rearrangement induction,

cancer, 94, 95

interstitial deletions and male infertility, 94

overview, 93

RAG-dependent recombina- tion and lymphoid malignancy, 95

site-specific non-Robertsonian chromosome transloca- tions, 93, 94

triplet repeat diseases, 95, 96 discovery, 90

human diseases, 91, 92 prospects for study, 96 structure, 91

U

U3b genes, 332 UBE3A, 319 UGT2A1, 108 USP4, 145 USP6, 82 USP9Y, 273 USP18, 199

WBS, see Williams-Beuren syndrome

WBSCR20, 223

Weaver syndrome, NSD1 mutations, 240

Williams-Beuren syndrome (WBS), clinical features, 221, 222 deletions,

common deletions, 226, 227 flanking low-copy repeats, 221 large deletions, 228

recombination events, 225 small deletions, 227, 228 structure, 222–224

syntenic region in nonhuman species, 224

developmental delay, 228, 231 duplications, 231

inversions, WBSinv-1

carrier transmission risks, 229, 231

detection, 228, 229 recombination events, 229 WBSinv-2, 231

prospects for study, 231, 232

X

X chromosome rearrangements, contiguous gene syndromes,

overview, 254, 255 Xp21, 256

Xp22.3, 255, 256

nonallelic homologous recombi- nation between low-copy repeats,

color blindness and pigment gene defects, 250 ichthyosis and STS gene

deletions, 248–250 incontinential pigmenti and

NEMO gene deletions, 250, 251

inversions,

Emery-Dreifuss muscular dystrophy and EMD gene, 253

hemophilia A and F8 gene, 251, 252

Hunter syndrome and IDS gene, 252, 253 nonhomologous end-joining

(NHEJ) deletions and duplications, 253, 254 overview, 247, 248

prospects for study, 257, 258 SHOX gene deletions, 254

Y chromosome rearrangements, azoospermia,

AZF loci identification, 273–

277, 279, 283 AZFa deletion, 279

AZFa duplication and human endogenous retrovirus homogenization, 280, 281 AZFb deletions and duplications,

282, 283 AZFc deletions,

common deletion, 279, 280 partial deletions, 281, 282 interstitial deletions and male

infertility, 94

phenotype, 274

prospects for study, 283–286 Yq complexity, 275, 276 chimpanzee comparative studies,

285

gene conversion, 285, 286 haploidy advantages in study,

284, 285

sequencing, 276, 277, 279, 284

Z-DNA,

chromosomal rearrangement induction,

cancer, 94, 95

interstitial deletions and male infertility, 94

overview, 93

RAG-dependent recombination and lymphoid

malignancy, 95

site-specific non-Robertsonian chromosome transloca- tions, 93, 94

triplet repeat diseases, 95, 96 discovery, 90

human diseases, 91, 92 prospects for study, 96 structure, 93

ZP3, 82

About the Editors

Jim Lupski received his initial scientific training at the Cold Spring Harbor Laboratory as an Undergraduate Research Participant (URP) and at New York University, completing the MD/PhD program in 1985 in bacterial genet- ics. In 1986, he moved to Houston, TX for clinical training in pediatrics (1986–1989) and medical genetics (1989–

1992), later establishing his own laboratory at Baylor Col- lege of Medicine where he remains as the Cullen Professor of Molecular and Human Genetics since 1995. His labora- tory determines molecular mechanisms for disease using molecular biological, genomic, and human genetic approaches to investigate clinical phenotypes. Through stud- ies of Charcot-Marie-Tooth peripheral neuropathy, a com-

mon autosomal dominant trait owing to a submicroscopic 1.4-Mb duplication, and Smith-Magenis syndrome, a microdeletion syndrome, his laboratory has delineated the concept of “genomic disorders” and established the critical role of gene dosage in conveying human disease phenotypes. An increasing number of human diseases are recognized as the result of recurrent DNA rearrangements involving unstable genomic regions and have thus been classified as genomic disorders. Dr. Lupski’s laboratory has also developed mouse models for genomic disorders. He recently completed a sabbatical at the Wellcome Trust Sanger Institute (2004–2005) in Cambridge, England where he studied mouse genetics and genomics.

Pawel Stankiewicz graduated Medical University of Warsaw in 1991. He received his scientific training in clini- cal cytogenetics in the Department of Medical Genetics, National Research Institute of Mother and Child in War- saw, Poland (1994–2000), in the Institute of Human Genet- ics, University of Göttingen, Göttingen, and in the Institute of Human Genetics and Medical Biology, University Halle- Wittenberg, in Halle/Saale, Germany (1996–1997, German Academic Exchange Service, DAAD). He obtained his PhD in molecular cytogenetics in 1999. In 2000, he moved to Houston, TX where he worked as a postdoctoral fellow in Dr. Lupski’s laboratory in the Department of Molecular &

Human Genetics at Baylor College of Medicine. His

research focused on elucidation of molecular mechanisms of genomic rearrangements

in proximal chromosome 17p. While characterizing the breakpoints of chromosome

aberrations in patients with Smith-Magenis syndrome using fluorescence in situ hybrid-

ization, pulsed-field gel electrophoresis, and computational analyses, he identified the

role of complex genomic architecture involving low-copy repeats in formation of con-

stitutional, evolutionarily, and somatic rearrangements. Since 2003, he has been work-

ing as an Assistant Professor in the Department of Molecular & Human Genetics, Baylor

College of Medicine, Houston, TX.