Genomic Imprinting and Uniparental Disomy in Medicine

PREFACE xiii

thank the funding agencies, most notably the Swiss National Science Foundation for supporting our research projects. We would also wish to thank Mrs. Georgette Chapuis, Tu-Mai Besson, and Katia Casada for their secretarial assistance, and Luna Han and Collette Bean of John Wiley & Sons for the expert editorial assistance.

ERIC ENGEL

STYLIANOS E. ANTONARAKIS

Acknowledgments

Eric Engel is most grateful to Oliver P. Engel, Ph.D. electronic engineer, for his consistent help and warm encouragements in preparing the first draft of this manuscript.

Stylianos E. Antonarakis thanks all members of this pedigree for the genes and life sharing.

xiv

Genomic Imprinting and

Uniparental Disomy

in Medicine

Index

Acrocentric chromosomes, centric fusion of, chromosome translocations, 32–34

Acrylamide gel electrophoresis, DNA polymorphisms, 15

Age level. See Maternal age Allele-specific amplification, DNA

polymorphisms, 15 Allele-specific expression: detection by FISH, 21

parent-of-origin, detection methods, 16–18 Allele-specific oligonucleotide hybridization,

DNA polymorphisms, 15 Amniocentesis, trisomy rescue, 26 Aneuploidy, frequency of, 1–2 Angelman syndrome (AS), 7, 18, 163,

187–209

clinical profile of, 187–189 described, 140–143

genetic counseling in, 203–204 imprinting box, 200

imprinting mutations in, 199–200 laboratory tests, 202

maternal deletion of 15q11-q13 in, 191–195

cytogenic studies, 191–192 deletion prone area, 194–195 molecular studies, 192–194

mutations in UBE3A gene, 197–199 paternal UPD 15 in, 189–191

phenotype-genotype correlations in, 200–201

studies of causes, 195–197

Antisense transcript, Beckwith-Wiedemann syndrome (BWS), 220–221

Autosomal recessive diseases, summary table, 51. See also Recessive disorders

Balanced interchanges (reciprocal translocations):

chromosome translocations, 34, 36–38

prenatal diagnosis, 237 Beckwith-Wiedemann syndrome (BWS), 7,

210–226

CDKN1C gene, 214–216 chromosomal abnormalities, 216–217 clinical profile of, 210–211 described, 136–137

genetic counseling in, 222 imprinted genes in, 218–221 IGF2 and H19, 218–219 KVLQT gene, 220–221

methylation deregulation of IGF2/H19, 219–220

laboratory tests, 222 paternal UPD11, 211–214

279

280 INDEX

CDKN1C gene, Beckwith-Wiedemann syndrome (BWS), 214–216

Chemical cleavage of nucleotide mismatches, DNA polymorphisms, 15

Chromosomal heteromorphisms, polymorphisms or, mechanisms, 42

Chromosomal loss, trisomy rescue, 27–29 Chromosomal mosaicism, trisomy rescue and, prenatal diagnosis, 231–236

Chromosomal polymorphisms, heteromorphisms or, mechanisms, 42

Chromosome(s), 49–132. See also Maternal chromosomes; Paternal chromosomes

chromosome 1 (maternal), 49–53 chromosome 2 (maternal), 55–58,

148–150, 231 chromosome 3 (maternal), 58

chromosome 4 (maternal), 58–59 chromosome 5 (maternal), 60 chromosome 6 (maternal), 60–61 chromosome 7 (maternal), 66–72, 135,

228–229 (See also Silver-Russell syndrome)

chromosome 8 (maternal), 73–74 chromosome 9 (maternal), 75–78 chromosome 10 (maternal), 78–79 chromosome 11 (maternal), 79 chromosome 13 (maternal), 81–82 chromosome 14 (maternal), 84–93,

143–145, 229–230 chromosome 15 (maternal), 96–100,

137–139, 176–178

chromosome 16 (maternal), 105–111, 150–154, 231

chromosome 17 (maternal), 112 chromosome 20 (maternal), 114 chromosome 21 (maternal), 114–115 chromosome 22 (maternal), 117–118 chromosome 12 (maternal and paternal),

81

chromosome 18 (maternal and paternal), 113

chromosome 19 (maternal and paternal), 113

chromosome 1 (paternal), 53–54 chromosome 2 (paternal), 54–55, 231 chromosome 4 (paternal), 59 chromosome 5 (paternal), 60 chromosome 6 (paternal), 61–66,

133–134, 227–228 (See also Neonatal transient diabetes mellitus)

chromosome 7 (paternal), 72–73 chromosome 8 (paternal), 74–75

chromosome 9 (paternal), 78 chromosome 10 (paternal), 79 chromosome 11 (paternal), 80–81,

136–137, 211–214 (See also Beckwith-Wiedemann syndrome (BWS))

chromosome 13 (paternal), 83–84 chromosome 14 (paternal), 93–96,

145–147, 229–230 chromosome 15 (paternal), 100–105,

137–139, 141–143, 187, 189–191 (See also Angelman syndrome (AS))

chromosome 16 (paternal), 111–112, 231 chromosome 17 (paternal), 113 chromosome 20 (paternal), 114 chromosome 21 (paternal), 116–117 chromosome 22 (paternal), 118–119 marker chromosomes, 41–42

X chromosome (maternal), 119–121 X chromosome (paternal), 121

XY chromosome, 122

Chromosome 6, supernumerary marker chromosomes, 42

Chromosome 15:

Angelman syndrome, 141–143, 187, 189–191 (See also Angelman syndrome (AS))

pericentric inversions of, 40

Prader-Willi syndrome, 137–139, 175–176 (See also Prader-Willi syndrome (PWS))

Chromosome translocations, 32–38 acrocentric chromosomes, centric fusion

of, 32–34 prenatal diagnosis, 236

reciprocal translocations (balanced interchanges), 34, 36–38

CVS, trisomy rescue, 26

Deletions:

Angelman syndrome (AS), maternal deletion of 15q11-q13 in, 191–195

detection methods:

DNA polymorphisms analysis, 15–16 of (micro)deletions by FISH, 20–21

Prader-Willi syndrome (PWS):

paternal 15q11-q13 deletion, 166–170 phenotypic differences between 15q

deletions and maternal UPD15 in, 176–178

Denaturing gradient gel electrophoresis, DNA polymorphisms, 15

Denaturing high-pressure liquid chromatography, DNA polymorphisms, 15

De novo somatic recombination (mitotic homologous interchanges), 38–39

Detection methods, 13–24. See also Laboratory tests; Prenatal diagnosis

of allele-specific expression by FISH, 21 Angelman syndrome (AS), 202 Beckwith-Wiedemann syndrome (BWS),

222

of deletions by DNA polymorphisms analysis, 15–16

of differential methylation by restriction analysis, 18–19

DNA polymorphisms, 13–15 basis of, 14

techniques, 15 types of, 13–14

of methylation differences by PCR, 19–20 of (micro)deletions by FISH, 20–21

of parent-of-origin allele-specific expression, 16–18

Prader-Willi syndrome (PWS), 178–179 trisomy rescue, 26

Diabetes mellitus, transient neonatal. See Neonatal transient diabetes mellitus

Diagnosis. See Prenatal diagnosis Differential methylation, detection by

restriction analysis, 18–19

Disomy. See also Uniparental disomy (UPD) defined, 1

gamete complementation, 3 DNA polymorphisms:

basis of detection, 14 techniques for detection, 15 types of, 13–14

Dwarfing, 7

Enzymatic cleavage of nucleotide mismatches, DNA polymorphisms, 15

Epiglyphes, imprinting mechanisms, 7 Evolutionary significance:

imprinting mechanisms, 275–276 uniparental disomy (UPD), 272–273

Familial heterologous Robertsonian translocations, 32–33

Familial homologous Robertsonian translocations, 33

Fetal diagnosis. See Prenatal diagnosis Fluorescence in situ hybridization (FISH).

See also Detection methods

INDEX 281

allele-specific expression detected by, 21 Angelman syndrome (AS), 202 (micro)deletions detected by, 20–21 Prader-Willi syndrome (PWS), 179

FNZ127/ZNF127, Prader-Willi syndrome (PWS), 172–173

Frequency, uniparental disomy (UPD), 274

Gamete complementation: mechanisms, 31 uniparental disomy, 2, 3

Gel electrophoresis, DNA polymorphisms, 15, 16

Genetic counseling, 227–241 Angelman syndrome (AS), 203–204 neonatal transient diabetes mellitus,

227–228

Prader-Willi syndrome (PWS), 179–180 Silver-Russell syndrome, 228–229 uniparental disomy (UPD), 7

UPD2, 231 UPD14, 229–230 UPD16, 231

Genomic imprinting. See Imprinting disorders; Imprinting mechanisms; Mouse imprinting mechanisms

Growth retardation, 7

Heterodisomy: defined, 2 isodisomy and, 3–4

Prader-Willi syndrome (PWS), 166 Heterologous de novo centric fusions, 33–34,

35

Heterologous Robertsonian translocations, 32–33

Homologous de novo centric fusions, 34, 35 Homologous Robertsonian translocations, 33 Human studies, imprinting mechanisms,

UPD, 6–8

Imprinted Prader-Willi gene (IPW), PraderWilli syndrome (PWS), 174

Imprinting disorders. See also Imprinting mechanisms; Mechanisms; Syndromes; Uniparental disomy (UPD)

paracentric inversions, 40

pericentric inversions of chromosome 15, 40

reciprocal translocations (balanced interchanges), 34, 36–38

small marker chromosomes, 41–42

282 INDEX

Imprinting disorders (continued) uniparental disomy (UPD) mechanisms

and, 25–48

Imprinting mechanisms. See also Imprinting disorders; Syndromes; Uniparental disomy (UPD)

detection methods, of parent-of-origin allele-specific expression, 16–18

evolutionary significance, 275–276 uniparental disomy (UPD):

human studies, 6–8 mouse studies, 4–6

Indic(15), marker chromosomes, 41 Invdup(15), marker chromosomes, 41 Isodisomy:

defined, 2 heterodisomy and, 3–4

Prader-Willi syndrome (PWS), 166

KVLQT gene, Beckwith-Wiedemann syndrome (BWS), 220–221

Laboratory tests. See also Detection methods; Prenatal diagnosis Angelman syndrome (AS), 202

Beckwith-Wiedemann syndrome (BWS), 222

Prader-Willi syndrome (PWS), 178–179

MAGEL2 gene, Prader-Willi syndrome (PWS), 174

Marker chromosomes: prenatal diagnosis, 236 UPD, 41–42

Maternal age: chromosome 15, 99–100 trisomy rescue, 26

Maternal chromosome 1, case reviews, 49–53

Maternal chromosome 2: case reviews, 55–58 genetic counseling in, 231

potential maternal UPD2 syndrome, 148–150

Maternal chromosome 3, case reviews, 58 Maternal chromosome 4, case reviews,

58–59

Maternal chromosome 5, case reviews, 60 Maternal chromosome 6, case reviews,

60–61

Maternal chromosome 7: case reviews, 66–72

Silver-Russell syndrome, 135–136, 228–229 (See also Silver-Russell syndrome)

Maternal chromosome 8, case reviews, 73–74

Maternal chromosome 9, case reviews, 75–78

Maternal chromosome 10, case reviews, 78–79

Maternal chromosome 11, case reviews, 79

Maternal chromosome 12, case reviews, 81

Maternal chromosome 13, case reviews, 81–82

Maternal chromosome 14: case reviews, 84–93

maternal UPD14 syndrome, 143–145, 229–230

Maternal chromosome 15: case reviews, 96–100

Prader-Willi syndrome, 137–139, 176–178 (See also Prader-Willi syndrome (PWS))

Maternal chromosome 16: case reviews, 105–111 genetic counseling in, 231

maternal UPD16 syndrome (potential), 105–111

Maternal chromosome 17, case reviews, 112 Maternal chromosome 18, case reviews, 113 Maternal chromosome 19, case reviews, 113 Maternal chromosome 20, case reviews, 114 Maternal chromosome 21, case reviews,

114–115

Maternal chromosome 22, case reviews, 117–118

Maternal UPD2 syndrome, 148–150 Maternal UPD14 syndrome:

described, 143–145

genetic counseling in, 229–230 Maternal UPD16 syndrome, 150–154 Maternal X chromosome, case reviews,

119–121 Mechanisms, 2–3, 25–48

chromosomal polymorphisms or heteromorphisms, 42

chromosome translocations, 32–38 acrocentric chromosomes, centric fusion

of, 32–34

reciprocal translocations (balanced interchanges), 34, 36–38

elucidation of, 274

gamete complementation, 31

mitotic homologous interchanges (de novo somatic recombination), 38–39

monosomy rescue, 29–30 paracentric inversions, 40

pericentric inversions of chromosome 15, 40

small marker chromosomes, 41–42 trisomy rescue, 25–29

chromosomal loss, 27–29 detection, 26

frequency, 25 outcomes, 25–27

Methylation deregulation, of IGF2/H19, Beckwith-Wiedemann syndrome (BWS), 219–220

Methylation differences, detection by PCR, 19–20

Methylation status, of chromosome 15 loci in Prader-Willi syndrome (PWS), 175–176

(Micro)deletions, detection by FISH, 20–21 Microsatellites, variable number of, 14 Mitotic homologous interchanges (de novo

somatic recombination), 38–39 Monosomy, trisomy rescue, 3 Monosomy rescue, mechanisms, 29–30 Mouse imprinting mechanisms, 243–270

identification of imprinted genes, 248–254 mechanism, 254–258

minor portion of genome imprinted, 246–248, 249

modeling studies, 259–262 nonequivalence in mice and humans,

243–246 UPD, 4–6

NDN gene, Prader-Willi syndrome (PWS), 174

Necdin, Prader-Willi syndrome (PWS), 174 Neonatal transient diabetes mellitus:

genetic counseling in, 227–228 syndromes (old), 7, 133–134

Nullisomy: defined, 1

gamete complementation, 3

Paracentric inversions: prenatal diagnosis, 236 UPD, 40

Parent-of-origin allele-specific expression, detection methods, 16–18

Parent-of-origin-dependent gene expression, imprinting mechanisms, UPD, 4–6

INDEX 283

Parent-of-origin differential allele expression, detection methods, 18–19

PAR5 and PAR1, Prader-Willi syndrome (PWS), 173–174

Paternal chromosome 1, case reviews, 53–54 Paternal chromosome 2:

case reviews, 54–55 genetic counseling in, 231

Paternal chromosome 4, case reviews, 59 Paternal chromosome 5, case reviews, 60 Paternal chromosome 6:

case reviews, 61–66

neonatal transient diabetes mellitus, 133–134, 227–228 (See also Neonatal transient diabetes mellitus)

Paternal chromosome 7, case reviews, 72–73 Paternal chromosome 8, case reviews, 74–75 Paternal chromosome 9, case reviews, 78 Paternal chromosome 10, case reviews, 79 Paternal chromosome 11:

case reviews, 80–81 Wiedemann-Beckwith syndrome, 136–137,

211–214 (See also BeckwithWiedemann syndrome (BWS))

Paternal chromosome 12, case reviews, 81 Paternal chromosome 13, case reviews,

83–84

Paternal chromosome 14: case reviews, 93–96

genetic counseling in, 229–230

paternal UPD14 syndrome (short stature), 145–147

Paternal chromosome 15:

Angelman syndrome, 141–143, 187, 189–191 (See also Angelman syndrome (AS))

case reviews, 100–105

Prader-Willi syndrome, 137–139 (See also Prader-Willi syndrome (PWS))

Paternal chromosome 16: case reviews, 111–112 genetic counseling in, 231

Paternal chromosome 17, case reviews, 113 Paternal chromosome 18, case reviews,

113

Paternal chromosome 19, case reviews, 113 Paternal chromosome 20, case reviews,

114

Paternal chromosome 21, case reviews, 116–117

Paternal chromosome 22, case reviews, 118–119

Paternal 15q11-q13 deletion, Prader-Willi syndrome (PWS), 166–170

284 INDEX

Paternal UPD14 syndrome (short stature): described, 145–147

genetic counseling in, 229–230

Paternal X chromosome, case reviews, 121 PCR:

methylation differences detected by, 19–20 reverse transcriptase-PCR, of parent-of-

origin allele-specific expression, 17–18

Pericentric inversions, of chromosome 15, 40

Phenotype-genotype correlation: Angelman syndrome (AS), 142–143,

200–201

Prader-Willi syndrome (PWS), 138–140 Polymerase chain reaction amplification,

DNA polymorphisms, 15 Potential syndromes. See Syndromes

(potential)

Prader-Willi critical region 1 (PWCR1) gene, Prader-Willi syndrome (PWS), 175

Prader-Willi syndrome (PWS), 7, 18, 163–186, 187

chromosome abnormalities or balanced translocations in, 170–171

described, 137–140, 163–164

genes and loci within critical region, 172 genetic counseling in, 179–180 imprinted Prader-Willi gene (IPW), 174 imprinting box, 170

imprinting mutations, 168–170 laboratory tests in, 178–179 MAGEL2 gene, 174

maternal UPD15 in, 164–166 methylation status of chromosome 15 loci

in, 175–176 molecular categories, 164 NDN gene, 174

PAR5 and PAR1, 173–174

paternal 15q11-q13 deletion, 166–168 phenotypic differences between 15q

deletions and maternal UPD15 in, 176–178

PWCR1 gene, 175

small nucleoribonucleoprotein polypeptide N (SNRPN), 173

ZNF127/FNZ127, 172–173 Premature sexual development, 7 Prenatal diagnosis, 231–238. See also

Detection methods

balanced reciprocal translocations, 237 chromosomal mosaicism and trisomy

rescue, 231–236 future directions, 274

parental translocations, inversions and chromosomal markers, 236

UPD, 7

UPD previous pregnancy, 237–238 Previous pregnancy, UPD in, prenatal

diagnosis, 237–238

Recessive disorders: summary table, 51

uniparental disomy (UPD), 275 Reciprocal translocations (balanced

interchanges):

chromosome translocations, 34, 36–38 prenatal diagnosis, 237

Rescue. See Trisomy rescue

Restriction analysis, differential methylation detection by, 18–19

Restriction endonuclease analysis, DNA polymorphisms, 15

Retrotransposons, presence or absence of, 14

Reverse transcriptase-PCR, of parent-of- origin allele-specific expression, 17–18

Robertsonian translocations, 32–33 Russell-Silver syndrome. See Silver-Russell

syndrome

Segmental uniparental disomy (UPD), 273–274

Sequence analysis, DNA polymorphisms, 15 Short sequence repeat (SSR), variable

number of, 14

Short stature (paternal UPD14 syndrome), 145–147

Silver-Russell syndrome, 7 described, 135–136

genetic counseling in, 228–229 maternal chromosome 7, 70–72

Single nucleotide polymorphism (SNP), 13–14

Single-stranded conformation analysis, DNA polymorphisms, 15

Small marker chromosomes: prenatal diagnosis, 237 UPD, 41–42

Small nucleoribonucleoprotein polypeptide N (SNRPN), Prader-Willi syndrome (PWS), 173

Supernumerary marker chromosomes, 42 Syndromes (new), 143–147, 275

maternal UPD14 syndrome, 143–145 paternal UPD14 syndrome (short stature),

145–147

Syndromes (old), 133–143

Angelman syndrome (AS), 140–143, 187–209 (See also Angelman syndrome (AS))

neonatal transient diabetes mellitus, 133–134, 227–228

Prader-Willi syndrome (PWS), 137–140, 163–186 (See also Prader-Willi syndrome (PWS))

Silver-Russell syndrome, 135–136 Wiedemann-Beckwith syndrome, 136–137

Syndromes (potential), 147–154 maternal UPD2 syndrome, 148–150 maternal UPD16 syndrome, 150–154

Transient neonatal diabetes mellitus. See also Neonatal transient diabetes mellitus

Trisomies, frequency of, 1 Trisomy rescue, 25–29

chromosomal loss, 27–29 frequency, 25

outcomes, 25–26

prenatal diagnosis, 231–236 term of, 2–3

UBE3A gene, mutations in, Angelman syndrome (AS), 197–199

Uniparental disomy (UPD). See also Imprinting disorders; Imprinting mechanisms; Syndromes

chromosomes in, 49–132 concepts of, 1–2

detection methods, 13–24 (See also Detection methods)

INDEX 285

evolutionary significance of, 272–273, 275–276

frequency of, 274

future research trends, 271–276 genetic control of, 272

human disorders and, 271 imprinting mechanisms: human studies, 6–8 mouse studies, 4–6 indications of, 238–239

lethal forms, 273

mechanisms and consequences of, 2–3, 25–48, 274 (See also Mechanisms)

prenatal diagnosis, 231–238, 274 (See also Prenatal diagnosis)

recessive disorders, 275 segmental forms, 273–274

Uniparental isodisomy, concepts of, 1–2

Variable number of longer repeats, 14 Variable number of short sequence repeat

(SSR), 14

Wiedemann-Beckwith syndrome (WBS). See Beckwith-Wiedemann syndrome (BWS)

X chromosome (maternal), case reviews, 119–121

X chromosome (paternal), case reviews, 121 XY chromosome, case studies, 122

ZNF127/FNZ127, Prader-Willi syndrome (PWS), 172–173