The Principles of Clinical Cytogenetics - Extra Materials - Springer

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Fragile X 501 (KH domains) and clusters of arginine and glycine residues (RGG boxes), features typical of RNAbinding proteins (74,77). Second, FMRP contains both a nuclear localization signal and a nuclear export signal (78). FMRP is primarily a cytosolic protein, but its presence in the nucleus has been reported by nuclear staining experiments (66,79). Furthermore, FMRP has been detected in the nuclear pore (80). Taken together, current evidence suggests that FMRP shuttles between the nucleus and the cytoplasm. In addition, experimental evidence suggests that FMRP is involved in translational activities. FMRP forms complexes with messenger ribonuclear particles (mRNP) and is associated with translating ribosomes (78,81,82). Because RNP particles are formed in the nucleus, this observation further supports the hypothesis that FMRP shuttles between the nucleus and the cytoplasm. Recent experiments suggest that FMRP might play a role in regulation of translation for certain messages. Laggerbauer et al. (83) demonstrated that FMRP suppresses translation by preventing the assembly of the 80S subunit of the ribosome on the target RNAs. New evidence suggests that translational control might be mediated through the RNA interference (RNAi) and/or micro-RNA (miRNA) pathways (84,85). The two major activities identified for FMRP, cytoplasm–nucleus shuttling and translational regulation, imply that FMRP is a facilitator for the expression and localization of several messages and proteins. The search for FMRP’s partners has identified at least seven such proteins, one of which includes FMRP itself (71). In contrast, very few specific mRNAs that bind FMRP have been identified. FMRP was shown to bind its own mRNA and also approximately 4% of fetal brain mRNAs (74). Nearly a decade would pass before the identity of the specific mRNAs (other than the FMR1 transcript) binding to FMRP would be identified (86–88). These mRNAs contain a G-quartet structure, a specific nucleic acid structure that facilitates binding to FMRP. Recent work also shows that FMRP can be phosphorylated, a mechanism that possibly affects the binding of specific mRNAs (89). Undoubtedly, research in the next decade will identify additional mRNA targets, whose roles will be crucial for not only the understanding of the fragile X syndrome but other human behavioral and cognitive disorders as well. CLINICAL ASPECTS OF FRAGILE X SYNDROME Full Mutation Phenotypes Physical Phenotype In males, the classic features of fragile X syndrome are X-linked mental retardation, macroorchidism, and minor dysmorphic facial features including a long, oblong face with a large mandible and large and/or prominent ears. At least 80% of affected males have one or more of these features, but expression varies with age. Other frequent features are a high-arched palate, hyperextensible finger joints, velvet-like skin, and flat feet. A small subgroup of males with a “Prader-Willi-like” phenotype has been described by Fryns et al. (90). Heterozygous females express these same features of fragile X syndrome, with manifestations being more common in females with mental disability than in those of normal intelligence. Behavioral Phenotype The behavior of males with fraX, especially in childhood, is more consistent and diagnostic than the physical features. They are typically hyperactive and delayed speech. Other complicating features can include irritability, hypotonia, perseveration in speech and behavior, and autistic-like features such as hand flapping, hand biting, and poor eye contact. Social anxiety and avoidance are prominent features of fragile X syndrome in both sexes. Recently, Hagerman (91) reviewed in detail the physical and behavioral phenotype of fragile X syndrome (see also reference 92). The variability of expression makes clinical diagnosis difficult. Therefore, fragile X syndrome should be considered in the differential diagnosis of all mentally retarded individuals.
502 Dana Crawford and Patricia Howard-Peebles Cognitive Phenotype In males, preliminary evidence suggests there are specific deficits in arithmetic, visual-motor skills, short-term auditory memory, and spatial skills. The IQ decreases with age, although the reason for this longitudinal decline is unclear (93). Adult males with fraX function within the moderate to severe retarded range. IQ is not correlated with the size of the CGG repeat. However, it does appear to be correlated with the mosaic status of the male. Affected males with both somatic full mutation and premutation size repeats or those who are methylation mosaics have higher IQs than the affected males who are nonmosaic or fully methylated. On occasion, such males will test in the normal/low normal range (94). In recent studies of protein expression, FMRP appears to be a good predictor of IQ in these males (95). In females, cognitive studies indicate specific weaknesses in arithmetic as well as short-term auditory memory, and visual-spatial tasks. They also have significant deficits in executive function. Full mutation females have mean IQs in the low average range (IQ = 74–91), and, as in males, the IQ is not correlated with CGG repeat size. Most studies have found a relationship between IQ and X inactivation ratios. Recent studies of protein expression show a strong correlation between FMRP and IQ (95,96). Other Clinical Aspects A recent review explores the neurologic and pathologic findings in fragile X syndrome (92). Medical follow-up, pharmacotherapy, treatment of emotional and behavioral problems, and intervention approaches for fragile X syndrome have also been reviewed (97). Premutation Carrier Phenotypes Transmitting Male Carriers Unlike the full mutation, the existence of a phenotypic consequence of the premutation in males is controversial. Among the few phenotypic studies of male premutation carriers, many are case reports of individuals ascertained in a clinic setting, including descriptions of boys with learning deficits who inherited the premutation (98) and a recently ascertained group of adult male premutation carriers with intention tremor, parkinsonism, and general brain atrophy (99). These case reports are tantalizing; however, given the obvious problem of ascertainment bias, the premutation cannot be associated with the phenotype until a proper controlled study has been performed and replicated. Unfortunately, few proper studies are available for male premutation carriers and the results from these studies are conflicting (100–102). Although cognitive or behavioral deficits have not been definitively subscribed to the premutation in males, a molecular phenotype related to this repeat size range has emerged. Early on, investigators examined levels of FMR1 mRNA and FMRP from the lymphocytes of carriers of premutation alleles and found that the levels were not significantly different compared with controls (58,66). Recent changes in technology, however, have made measurements of FMR1 mRNA more sensitive and accurate. Using this technology, Tassone et al. re-examined the levels of FMR1 mRNA and FMRP in premutation male carriers and found that carriers with 100–200 CGG repeats had a fivefold increase in FMR1 mRNA levels (103), whereas carriers with 55–100 repeats had a twofold increase (104) compared with controls. Moreover, these high-end premutation carriers (100–200 repeats) had reduced levels of FMRP compared with controls (103). Additional experiments suggest that the elevated level of FMR1 mRNA is correlated with CGG repeat size (105) and is not simply a response to decreased levels of FMRP (104). Female Carriers Many conflicting reports exist in the literature concerning cognitive, behavioral, and physical phenotypes among female premutation carriers. These reports have recently been reviewed (106,107). For reports on cognitive ability, studies of varying designs have shown that the prevalence of mental retardation, the range of cognitive ability (108), or the range of IQ scores among adult female premutation carriers did not differ compared with control groups (102). However, at least two studies
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The Principles of Clinical Cytogene
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The Principles of Clinical Cytogene
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v Preface In the summer of 1989, on
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vii Preface to First Edition The st
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ix Contents Preface ...............
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Contributors SARAH HUTCHINGS CLARK,
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History of Clinical Cytogenetics 1
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4 Steven Gersen The hypotonic solut
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6 Steven Gersen marrow aspiration,
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8 Steven Gersen 9. Hsu, T.C. (1952)
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10 Martha Keagle Fig. 1. DNA struct
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12 Martha Keagle Fig. 3. Transcript
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14 Martha Keagle Fig. 5. Translatio
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16 Martha Keagle Fig. 7. The levels
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18 Martha Keagle single-copy DNA is
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20 Martha Keagle Fig. 10. Mitosis.
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22 Martha Keagle Fig. 11. Schematic
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24 Martha Keagle Fig. 13. Spermatog
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Human Chromosome Nomenclature 27 IN
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Human Chromosome Nomenclature 29 Fi
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Human Chromosome Nomenclature 33 Ta
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Human Chromosome Nomenclature 47 In
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Human Chromosome Nomenclature 49 Ma
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Human Chromosome Nomenclature 51 Un
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Human Chromosome Nomenclature 53 Ta
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Human Chromosome Nomenclature 55 46
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Human Chromosome Nomenclature 57 nu
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Basic Laboratory Procedures 59 II E
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Basic Laboratory Procedures 63 INTR
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Basic Laboratory Procedures 65 amni
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Basic Laboratory Procedures 67 Prep
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Basic Laboratory Procedures 69 Fig.
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Basic Laboratory Procedures 77 Lack
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Basic Laboratory Procedures 79 Once
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82 Christopher McAleer Fig. 1. Sche
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84 Christopher McAleer measurements
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86 Christopher McAleer allow light
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88 Christopher McAleer High-dry obj
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90 Christopher McAleer Fig. 3. Sche
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Quality Control and Quality Assuran
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Automation in the Cytogenetics Labo
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Autosomal Aneuploidy 131 III Clinic
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Autosomal Aneuploidy 133 INTRODUCTI
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135 Table 1 Parental and Meiotic/Mi
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Autosomal Aneuploidy 137 Fig. 2. Sc
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Autosomal Aneuploidy 139 forming ab
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Autosomal Aneuploidy 141 Fig. 5. Th
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Autosomal Aneuploidy 143 Fig. 6. Pr
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Autosomal Aneuploidy 145 Fig. 8. An
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Autosomal Aneuploidy 147 trisomies,
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Autosomal Aneuploidy 149 21 and ind
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Autosomal Aneuploidy 151 molecular
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Autosomal Aneuploidy 153 Fig. 10. T
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Autosomal Aneuploidy 155 This marke
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Autosomal Aneuploidy 157 47. Hawley
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Autosomal Aneuploidy 159 110. Lindo
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Autosomal Aneuploidy 161 171. Moghe
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Autosomal Aneuploidy 163 231. Reese
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Structural Chromosome Rearrangement
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177 Prader-Willi Paternal deletion
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179 Table 2 Some Recurring Duplicat
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Sex Chromosomes and Sex Chromosome
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Cytogenetics of Infertility 247 INT
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Cytogenetics of Infertility 249 Amo
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Cytogenetics of Infertility 251 Tab
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Cytogenetics of Infertility 253 gen
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255 Primary ciliary dyskinesia Auto
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Cytogenetics of Infertility 257 cha
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Cytogenetics of Infertility 259 Tab
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Cytogenetics of Infertility 261 Fig
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Cytogenetics of Infertility 263 rat
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Cytogenetics of Infertility 265 39.
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268 Linda Marie Randolph By 1986, m
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270 Linda Marie Randolph Table 1 Ch
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272 Linda Marie Randolph Table 4 Th
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274 Linda Marie Randolph Table 6 Fr
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276 Linda Marie Randolph rate of 14
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278 Table 8 Outcome in Early (11-14
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280 Linda Marie Randolph Table 9 Vo
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282 Linda Marie Randolph In 1995, O
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284 Linda Marie Randolph Fig. 1. Il
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286 Linda Marie Randolph reported c
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288 Linda Marie Randolph The underl
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290 Linda Marie Randolph Fig. 3. Ul
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296 Linda Marie Randolph Fig. 6. De
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298 Linda Marie Randolph Choroid Pl
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300 Linda Marie Randolph Table 13 C
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302 Linda Marie Randolph Table 14 U
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304 Linda Marie Randolph then that
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306 Table 15 Prenatal Results for R
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308 Linda Marie Randolph Table 17 O
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310 Linda Marie Randolph DNA marker
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312 Linda Marie Randolph XX and XY
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314 Linda Marie Randolph 54. Simpso
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316 Linda Marie Randolph 116. Wang,
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318 Linda Marie Randolph 173. Cicer
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320 Linda Marie Randolph 232. Benn,
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Cytogenetics of Spontaneous Abortio
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348 Xiao-Xiang Zhang Fig. 1. An exa
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350 Xiao-Xiang Zhang cases availabl
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352 Xiao-Xiang Zhang Fig. 2. Metaph
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354 Xiao-Xiang Zhang patients, grea
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356 Xiao-Xiang Zhang Fig. 5. G-Band
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358 Xiao-Xiang Zhang Fig. 7. Sister
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360 Xiao-Xiang Zhang REFERENCES 1.
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Cytogenetics of Hematologic Neoplas
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387 Table 5 Association of Recurren
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389 del(8)(q22) t(8;16)(p11.2;p13)
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391 +17 -17 2° assoc. with +21 i(1
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Cytogenetics of Solid Tumors 421 IN
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423 Aytpical (see well-differentiat
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Cytogenetics of Solid Tumors 425 So
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Cytogenetics of Solid Tumors 427 ca
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Cytogenetics of Solid Tumors 429 do
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Cytogenetics of Solid Tumors 431 cl
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Cytogenetics of Solid Tumors 433 Fi
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Cytogenetics of Solid Tumors 439 no
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Cytogenetics of Solid Tumors 445 8.
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Page 469 and 470: 454 Daynna Wolff and Stuart Schwart
Page 506: Fragile X 491 VI Beyond Chromosomes
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Page 531 and 532: 516 Jin-Chen Wang Fig. 1. Diagramma
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Page 551 and 552: 536 Jin-Chen Wang 138. Dryja, T.P.,
Page 553 and 554: 538 Jin-Chen Wang 192. Karanjawala,
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Page 557 and 558: 542 Sarah Hutchings Clark condition
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552 Sarah Hutchings Clark often at
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554 Sarah Hutchings Clark The relat
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556 Sarah Hutchings Clark Although,
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558 Sarah Hutchings Clark 33. Nicol
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560 Index Abnormalities, order of,
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562 Index Anus, imperforate, 310 AP
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564 Index CDK4, 394 CDK6, 396 CDKN2
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566 Index mosaicism, in amniotic fl
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568 Index Cutaneous anaplastic larg
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570 Index proximal 15q, 178, t179 p
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572 Index Folic acid pathway, 75 Fo
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574 Index Hereditary neuropathy wit
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576 Index Intrachromosomal recombin
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578 Index Male-specific region, Y c
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580 Index MTX, 76 Mucosa-associated
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582 Index Octamer, 14 Okazaki fragm
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584 Index Premature separation of s
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586 Index Recombinant chromosomes n
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588 Index Sézary syndrome (SS), t3
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590 Index t(4;14), 475 t(5;10), 375
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592 Index Treacher Collins syndrome
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594 Index Xq deletions, 225 Y trans
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596 Index XX males, 467, f468 and a
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