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Andrea Christoforou - One of the best experts on this subject based on the ideXlab platform.
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DNA methylation in a Scottish family multiply affected by bipolar disorder and major depressive disorder.
Clinical epigenetics, 2016Co-Authors: Rosie M. Walker, Andrea Christoforou, Stewart W Morris, Susan Anderson, Helen S Torrance, Daniel L. Mccartney, Nicholas A. Kennedy, Peter Morten, Alix Macdonald, Jessika E. SussmannAbstract:Background Bipolar disorder (BD) is a severe, familial psychiatric condition. Progress in understanding the aetiology of BD has been hampered by substantial phenotypic and genetic heterogeneity. We sought to mitigate these confounders by studying a multi-generational family multiply affected by BD and major depressive disorder (MDD), who carry an illness-linked haplotype on Chromosome 4p. Within a family, aetiological heterogeneity is likely to be reduced, thus conferring greater power to detect illness-related changes. As accumulating evidence suggests that altered DNA methylation confers risk for BD and MDD, we compared genome-wide methylation between (i) affected carriers of the linked haplotype (ALH) and married-in controls (MIs), (ii) well unaffected haplotype carriers (ULH) and MI, (iii) ALH and ULH and (iv) all haplotype carriers (LH) and MI.
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convergence of linkage association and gwas findings for a candidate region for bipolar disorder and schizophrenia on Chromosome 4p
Molecular Psychiatry, 2011Co-Authors: Andrea Christoforou, Kevin A Mcghee, Stewart W Morris, P A Thomson, Susan Anderson, Alan W Mclean, Helen S Torrance, Le S HellardAbstract:Convergence of linkage, association and GWAS findings for a candidate region for bipolar disorder and schizophrenia on Chromosome 4p
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haplotype analysis and a novel allele sharing method refines a Chromosome 4p locus linked to bipolar affective disorder
Biological Psychiatry, 2007Co-Authors: Stephanie Le Hellard, Stewart W Morris, Susan Anderson, Helen S Torrance, Andrew J Lee, Sarah Underwood, Pippa A Thomson, Richard R Adams, Pau Navarro, Andrea ChristoforouAbstract:Background: Bipolar affective disorder (BPAD) and schizophrenia (SCZ) are common conditions. Their causes are unknown, but they include a substantial genetic component. Previously, we described significant linkage of BPAD to a Chromosome 4p locus within a large pedigree (F22). Others subsequently have found evidence for linkage of BPAD and SCZ to this region. Methods: We constructed high-resolution haplotypes for four linked families, calculated logarithm of the odds (LOD) scores, and developed a novel method to assess the extent of allele sharing within genes between the families. Results: We describe an increase in the F22 LOD score for this region. Definition and comparison of the linked haplotypes allowed us to prioritize two subregions of 3.8 and 4.4 Mb. Analysis of the extent of allele sharing within these subregions identified 200 kb that shows increased allele sharing between families. Conclusions: Linkage of BPAD to Chromosome 4p has been strengthened. Haplotype analysis in the additional linked families refined the 20-Mb linkage region. Development of a novel allele-sharing method allowed us to bridge the gap between conventional linkage and association studies. Description of a 200-kb region of increased allele sharing prioritizes this region, which contains two functional candidate genes for BPAD, SLC2A9, and WDR1, for subsequent studies.
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association analysis of the Chromosome 4p located g protein coupled receptor 78 gpr78 gene in bipolar affective disorder and schizophrenia
Molecular Psychiatry, 2006Co-Authors: S L Underwood, Andrea Christoforou, Le S Hellard, Pippa A Thomson, S W Morris, Naomi R. Wray, Albert Tenesa, John C. Whittaker, Richard Adams, Douglas BlackwoodAbstract:The orphan G protein-coupled receptor 78 (GPR78) gene lies within a region of Chromosome 4p where we have previously shown linkage to bipolar affective disorder (BPAD) in a large Scottish family. GPR78 was screened for single-nucleotide polymorphisms (SNPs) and a linkage disequilibrium map was constructed. Six tagging SNPs were selected and tested for association on a sample of 377 BPAD, 392 schizophrenia (SCZ) and 470 control individuals. Using standard χ2 statistics and a backwards logistic regression approach to adjust for the effect of sex, SNP rs1282, located approximately 3 kb upstream of the coding region, was identified as a potentially important variant in SCZ (χ2 P = 0.044; LRT P = 0.065). When the analysis was restricted to females, the strength of association increased to an uncorrected allele P-value of 0.015 (odds ratios (OR) = 1.688, 95% confidence intervals (CI): 1.104-2.581) and uncorrected genotype P-value of 0.015 (OR = 5.991, 95% CI: 1.545-23.232). Under the recessive model, the genotype P-value improved further to 0.005 (OR = 5.618, 95% CI: 1.460-21.617) and remained significant after correcting for multiple testing (P = 0.017). No single-marker association was detected in the SCZ males, in the BPAD individuals or with any other SNP. Haplotype analysis of the case-control samples revealed several global and individual haplotypes, with P-values <0.05, all but one of which contained SNP rs1282. After correcting for multiple testing, two haplotypes remained significant in both the female BPAD individuals (P = 0.038 and 0.032) and in the full sample of affected female individuals (P = 0.044 and 0.033). Our results provide preliminary evidence for the involvement of GPR78 in susceptibility to BPAD and SCZ in the Scottish population.
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Association analysis of the Chromosome 4p-located G protein-coupled receptor 78 ( GPR78 ) gene in bipolar affective disorder and schizophrenia
Molecular psychiatry, 2006Co-Authors: S L Underwood, Andrea Christoforou, Stewart W Morris, Pippa A Thomson, Naomi R. Wray, Albert Tenesa, John C. Whittaker, Richard Adams, S. Le Hellard, Douglas BlackwoodAbstract:The orphan G protein-coupled receptor 78 (GPR78) gene lies within a region of Chromosome 4p where we have previously shown linkage to bipolar affective disorder (BPAD) in a large Scottish family. GPR78 was screened for single-nucleotide polymorphisms (SNPs) and a linkage disequilibrium map was constructed. Six tagging SNPs were selected and tested for association on a sample of 377 BPAD, 392 schizophrenia (SCZ) and 470 control individuals. Using standard χ2 statistics and a backwards logistic regression approach to adjust for the effect of sex, SNP rs1282, located approximately 3 kb upstream of the coding region, was identified as a potentially important variant in SCZ (χ2 P = 0.044; LRT P = 0.065). When the analysis was restricted to females, the strength of association increased to an uncorrected allele P-value of 0.015 (odds ratios (OR) = 1.688, 95% confidence intervals (CI): 1.104-2.581) and uncorrected genotype P-value of 0.015 (OR = 5.991, 95% CI: 1.545-23.232). Under the recessive model, the genotype P-value improved further to 0.005 (OR = 5.618, 95% CI: 1.460-21.617) and remained significant after correcting for multiple testing (P = 0.017). No single-marker association was detected in the SCZ males, in the BPAD individuals or with any other SNP. Haplotype analysis of the case-control samples revealed several global and individual haplotypes, with P-values
Kathleen W. Rao - One of the best experts on this subject based on the ideXlab platform.
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Preliminary phenotypic map of Chromosome 4p16 based on 4p deletions.
American journal of medical genetics, 1995Co-Authors: Laurel L. Estabrooks, Kathleen W. Rao, Bruce R. Korf, Deborah A. Driscoll, Barbara F. Crandall, John Dean, Elina Ikonen, Arthur S. AylsworthAbstract:We have collected and analyzed clinical information from 11 patients with Chromosome 4p deletions or rearrangements characterized by various molecular techniques. Comparing the extent of these patients' deletions with their respective clinical presentations led to the proposal of a preliminary phenotypic map of Chromosome 4p. This map consists of regions which, when deleted, are associated with specific clinical manifestations. Nonspecific changes such as mental and growth retardation are not localized, and probably result from the deletion of more than one gene or region. The region associated with most of the facial traits considered typical in Wolf-Hirschhorn syndrome (WHS) patients coincides with the currently proposed WHS critical region (WHSCR), but some anomalies commonly seen in WHS appear to map outside of the WHSCR. The observation of clinodactyly in 2 patients with nonoverlapping deletions allows assignment of these defects to at least 2 separate regions in 4p16. These initial observations and attempts at genotype/phenotype correlation lay the groundwork for identifying the genetic basis of these malformations, a common objective of gene mapping efforts and Chromosome deletion studies.
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Molecular characterisation of Chromosome 4p deletions resulting in Wolf-Hirschhorn syndrome.
Journal of medical genetics, 1994Co-Authors: Laurel L. Estabrooks, Allen N. Lamb, Arthur S. Aylsworth, Nancy P. Callanan, Kathleen W. RaoAbstract:We present three patients with Wolf-Hirschhorn syndrome with small cytogenetic deletions of 4p16. One case is a de novo translocation and two cases represent de novo deletions. Using molecular techniques we determined the extent of these deletions and attempted to ascertain parental origin. Case 1 had a deletion of 4p16.3 with a breakpoint proximal to D4S10, case 2 had a larger deletion including D4S62 in 4p16.2, and case 3 had the largest deletion which included D4S240, but not the Raf2 locus in 4p16.1. The parental origin of the deletion in case 3 was paternal; the other two cases were indeterminable. Our results show that these three deletions include the currently proposed Wolf-Hirschhorn syndrome critical region within the most distal 2 Mb of 4p16.3 and offer supportive evidence for continuous terminal deletions.
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Interstitial deletion of distal Chromosome 4p in a patient without classical Wolf-Hirschhorn syndrome
American journal of medical genetics, 1993Co-Authors: Laurel L. Estabrooks, Kathleen W. Rao, Bruce R. KorfAbstract:We report on a patient with a de novo interstitial deletion of Chromosome 4p; 46,XY,del(4) (p15.31p16.3). The cytogenetic diagnosis would predict a patient with the Wolf-Hirschhorn syndrome (WHS) since deletions of 4p16 are associated with WHS [Wilson et al., 1981]. This patient lacks the facial characteristics of WHS, but has some anomalies of WHS that are also commonly seen in other syndromes, i.e., severe growth retardation, developmental delay, and hypospadias. His molecular distal breakpoint occurs in 4p16.3 as defined by fluorescence in situ hybridization and Southern blot analysis, and his deletion does not overlap with the currently proposed WHS critical region. This case gives further support to the distal position of the WHS critical region and demonstrates some of the WHS associated phenotypes that can be attributed to a deletion of the proximal third of 4p16.3. © 1993 Wiley-Liss, Inc.
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A molecular deletion of distal Chromosome 4p in two families with a satellited Chromosome 4 lacking the Wolf-Hirschhorn syndrome phenotype.
American journal of human genetics, 1992Co-Authors: Laurel L. Estabrooks, Allen N. Lamb, Nancy P. Callanan, Henry N. Kirkman, Kathleen W. RaoAbstract:The authors report two families with a satellited Chromosome 4 short arm (4ps). Satellites and stalks normally occur on the short arms of acrocentric Chromosomes; however, the literature cites several reports of satellited nonacrocentric Chromosomes, which presumably result from a translocation with an acrocentric Chromosome. This is the first report of 4ps Chromosomes. The families are remarkable in that both unaffected and affected individuals carry the 4ps Chromosome. The phenotypes observed in affected individuals, although dissimilar, were sufficient to encourage a search for a deletion of Chromosome 4p. By Southern blot analysis and fluorescence in situ hybridization, a deletion of material mapping approximately 150 kb from Chromosome 4pter was discovered. This deletion is notable because it does not result in the Wolf-Hirschhorn syndrome and can result in an apparently normal phenotype. The authors speculate that homology between subterminal repeat sequences on 4p and sequences on the acrocentric short arms may explain the origin of the rearrangement and that position effect may play a role in the expression of the abnormal phenotype. 36 refs., 4 figs., 3 tabs.
Gregor K Wenning - One of the best experts on this subject based on the ideXlab platform.
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the s18y polymorphism in the uchl1 gene is a genetic modifier in huntington s disease
Neurogenetics, 2006Co-Authors: Silke Metzger, Peter Bauer, Jurgen Tomiuk, Franco Laccone, Stefano Didonato, Cinzia Gellera, P Soliveri, Herwig W Lange, Helga Weirichschwaiger, Gregor K WenningAbstract:An expanded polyglutamine stretch in the huntingtin protein has been identified as the pathogenetic cause of Huntington's disease (HD). Although the length of the expanded polyglutamine repeat is inversely correlated with the age-at-onset, additional genetic factors are thought to modify the variance in the disease onset. As linkage analysis suggested a modifier locus on Chromosome 4p, we investigated the functional relevance of S18Y polymorphism of the ubiquitin carboxy-terminal hydrolase L1 in 946 Caucasian HD patients. In this group, the allelic variation on locus S18Y is responsible for 1.1% of the variance in the HD age-at-onset, and the rare Y allele is associated with younger-aged cases.
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The S18Y polymorphism in the UCHL1 gene is a genetic modifier in Huntington’s disease
Neurogenetics, 2006Co-Authors: Silke Metzger, Peter Bauer, Jurgen Tomiuk, Franco Laccone, Stefano Didonato, Cinzia Gellera, P Soliveri, Herwig W Lange, Helga Weirich-schwaiger, Gregor K WenningAbstract:An expanded polyglutamine stretch in the huntingtin protein has been identified as the pathogenetic cause of Huntington's disease (HD). Although the length of the expanded polyglutamine repeat is inversely correlated with the age-at-onset, additional genetic factors are thought to modify the variance in the disease onset. As linkage analysis suggested a modifier locus on Chromosome 4p, we investigated the functional relevance of S18Y polymorphism of the ubiquitin carboxy-terminal hydrolase L1 in 946 Caucasian HD patients. In this group, the allelic variation on locus S18Y is responsible for 1.1% of the variance in the HD age-at-onset, and the rare Y allele is associated with younger-aged cases.
Joris Vermeesch - One of the best experts on this subject based on the ideXlab platform.
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Telomere healing following DNA polymerase arrest-induced breakages is likely the main mechanism generating Chromosome 4p terminal deletions†
Human mutation, 2010Co-Authors: Femke Hannes, Jeroen Van Houdt, Oliver W. Quarrell, Martin Poot, Ron Hochstenbach, Jean-pierre Fryns, Joris VermeeschAbstract:Constitutional developmental disorders are frequently caused by terminal chromosomal deletions. The mechanisms and/or architectural features that might underlie those Chromosome breakages remain largely unexplored. Because telomeres are the vital DNA protein complexes stabilizing linear Chromosomes against Chromosome degradation, fusion, and incomplete replication, those terminal-deleted Chromosomes acquired new telomeres either by telomere healing or by telomere capture. To unravel the mechanisms leading to chromosomal breakage and healing, we sequenced nine Chromosome 4p terminal deletion boundaries. A computational analysis of the breakpoint flanking region, including 12 previously published pure terminal breakage sites, was performed in order to identify architectural features that might be involved in this process. All terminal 4p truncations were likely stabilized by telomerase-mediated telomere healing. In the majority of breakpoints multiple genetic elements have a potential to induce secondary structures and an enrichment in replication stalling site motifs were identified. These findings suggest DNA replication stalling-induced Chromosome breakage during early development is the first mechanistic step leading toward terminal deletion syndromes.
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Telomere Healing Following DNA polymerase Arrest Induced Breakages is likely the Main Mechanism Generating Chromosome 4p Terminal Deletions
Human Mutation, 2010Co-Authors: Femke Hannes, Jeroen Van Houdt, Oliver W. Quarrell, Martin Poot, Ron Hochstenbach, Jean-pierre Fryns, Joris VermeeschAbstract:Constitutional developmental disorders are frequently caused by terminal chromosomal deletions. The mechanisms and/or architectural features that might underlie those Chromosome breakages remain largely unexplored. Since telomeres are the vital DNA protein complexes stabilizing linear Chromosomes against Chromosome degradation, fusion and incomplete replication, those terminal deleted Chromosomes acquired new telomeres either by telomere healing or by telomere capture. To unravel the mechanisms leading to chromosomal breakage and healing, we sequenced nine Chromosome 4p terminal deletion boundaries. A computational analysis of the breakpoint flanking region, including 12 previously published pure terminal breakage sites, was performed in order to identify architectural features that might be involved in this process. All terminal 4p truncations were likely stabilized by telomerase mediated telomere healing. In the majority of breakpoints multiple genetic elements have a potential to induce secondary structures and an enrichment in replication stalling site motifs were identified. These findings suggest DNA replication stalling induced Chromosome breakage during early development is the first mechanistic step leading towards terminal deletion syndromes.
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duplication of the wolf hirschhorn syndrome critical region causes neurodevelopmental delay
European Journal of Medical Genetics, 2010Co-Authors: Femke Hannes, Joris Vermeesch, Malgorzata Drozniewska, Olga HausAbstract:Abstract Wolf-Hirschhorn Syndrome (WHS) is caused by deletions on Chromosome 4p and is clinically well defined. Genotype-phenotype correlations of patients with WHS point to a critical locus to be responsible for the main characteristics of this disorder. Submicroscopic duplications of this region, however, are not known. Here we report a patient with an interstitial 560 kb duplication overlapping this critical locus. The present case shows that not only deletions but also duplications of the Wolf-Hirshhorn critical region cause mental retardation and multiple congenital anomalies. Interestingly, the duplication phenotype overlaps partially with the deletion phenotype. However, his facial phenotype differs from the typical WHS gestalt.
Laurel L. Estabrooks - One of the best experts on this subject based on the ideXlab platform.
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Preliminary phenotypic map of Chromosome 4p16 based on 4p deletions.
American journal of medical genetics, 1995Co-Authors: Laurel L. Estabrooks, Kathleen W. Rao, Bruce R. Korf, Deborah A. Driscoll, Barbara F. Crandall, John Dean, Elina Ikonen, Arthur S. AylsworthAbstract:We have collected and analyzed clinical information from 11 patients with Chromosome 4p deletions or rearrangements characterized by various molecular techniques. Comparing the extent of these patients' deletions with their respective clinical presentations led to the proposal of a preliminary phenotypic map of Chromosome 4p. This map consists of regions which, when deleted, are associated with specific clinical manifestations. Nonspecific changes such as mental and growth retardation are not localized, and probably result from the deletion of more than one gene or region. The region associated with most of the facial traits considered typical in Wolf-Hirschhorn syndrome (WHS) patients coincides with the currently proposed WHS critical region (WHSCR), but some anomalies commonly seen in WHS appear to map outside of the WHSCR. The observation of clinodactyly in 2 patients with nonoverlapping deletions allows assignment of these defects to at least 2 separate regions in 4p16. These initial observations and attempts at genotype/phenotype correlation lay the groundwork for identifying the genetic basis of these malformations, a common objective of gene mapping efforts and Chromosome deletion studies.
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Summary of the 1993 ASHG ancillary meeting recent research on Chromosome 4p syndromes and genes
American journal of medical genetics, 1995Co-Authors: Laurel L. Estabrooks, David H Ledbetter, Michael R Hayden, Richard M. Myers, W. Roy Breg, Herman E. Wyandt, Teresa L. Yang-feng, Kurt HirschhornAbstract:The following is a summary of presentations given during an ancillary meeting to the 1993 American Society of Human Genetics Meeting in New Orleans, LA. This ancillary meeting, entitled "Recent Research on Chromosome 4p Syndromes and Genes," reviewed the history of the Wolf-Hirschhorn syndrome (WHS), the natural history of patients with WHS, and the smallest region of deletion associated with the WHS. The proximal 4p deletion syndrome and the duplication 4p syndrome were also described and advice was offered regarding detection of Chromosome 4p deletions, duplications, and rearrangements. The current status of the physical map of Chromosome 4p with emphasis on the genes that map to the 4p16 region was presented along with a preliminary phenotypic map of 4p16. The goal of this format was to provide a comprehensive review of the clinical presentations, diagnostic capabilities, and genetic mapping advances involving Chromosome 4p.
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Molecular characterisation of Chromosome 4p deletions resulting in Wolf-Hirschhorn syndrome.
Journal of medical genetics, 1994Co-Authors: Laurel L. Estabrooks, Allen N. Lamb, Arthur S. Aylsworth, Nancy P. Callanan, Kathleen W. RaoAbstract:We present three patients with Wolf-Hirschhorn syndrome with small cytogenetic deletions of 4p16. One case is a de novo translocation and two cases represent de novo deletions. Using molecular techniques we determined the extent of these deletions and attempted to ascertain parental origin. Case 1 had a deletion of 4p16.3 with a breakpoint proximal to D4S10, case 2 had a larger deletion including D4S62 in 4p16.2, and case 3 had the largest deletion which included D4S240, but not the Raf2 locus in 4p16.1. The parental origin of the deletion in case 3 was paternal; the other two cases were indeterminable. Our results show that these three deletions include the currently proposed Wolf-Hirschhorn syndrome critical region within the most distal 2 Mb of 4p16.3 and offer supportive evidence for continuous terminal deletions.
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Interstitial deletion of distal Chromosome 4p in a patient without classical Wolf-Hirschhorn syndrome
American journal of medical genetics, 1993Co-Authors: Laurel L. Estabrooks, Kathleen W. Rao, Bruce R. KorfAbstract:We report on a patient with a de novo interstitial deletion of Chromosome 4p; 46,XY,del(4) (p15.31p16.3). The cytogenetic diagnosis would predict a patient with the Wolf-Hirschhorn syndrome (WHS) since deletions of 4p16 are associated with WHS [Wilson et al., 1981]. This patient lacks the facial characteristics of WHS, but has some anomalies of WHS that are also commonly seen in other syndromes, i.e., severe growth retardation, developmental delay, and hypospadias. His molecular distal breakpoint occurs in 4p16.3 as defined by fluorescence in situ hybridization and Southern blot analysis, and his deletion does not overlap with the currently proposed WHS critical region. This case gives further support to the distal position of the WHS critical region and demonstrates some of the WHS associated phenotypes that can be attributed to a deletion of the proximal third of 4p16.3. © 1993 Wiley-Liss, Inc.
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A molecular deletion of distal Chromosome 4p in two families with a satellited Chromosome 4 lacking the Wolf-Hirschhorn syndrome phenotype.
American journal of human genetics, 1992Co-Authors: Laurel L. Estabrooks, Allen N. Lamb, Nancy P. Callanan, Henry N. Kirkman, Kathleen W. RaoAbstract:The authors report two families with a satellited Chromosome 4 short arm (4ps). Satellites and stalks normally occur on the short arms of acrocentric Chromosomes; however, the literature cites several reports of satellited nonacrocentric Chromosomes, which presumably result from a translocation with an acrocentric Chromosome. This is the first report of 4ps Chromosomes. The families are remarkable in that both unaffected and affected individuals carry the 4ps Chromosome. The phenotypes observed in affected individuals, although dissimilar, were sufficient to encourage a search for a deletion of Chromosome 4p. By Southern blot analysis and fluorescence in situ hybridization, a deletion of material mapping approximately 150 kb from Chromosome 4pter was discovered. This deletion is notable because it does not result in the Wolf-Hirschhorn syndrome and can result in an apparently normal phenotype. The authors speculate that homology between subterminal repeat sequences on 4p and sequences on the acrocentric short arms may explain the origin of the rearrangement and that position effect may play a role in the expression of the abnormal phenotype. 36 refs., 4 figs., 3 tabs.