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1.
Uniparental disomy explains the occurrence of the Angelman or Prader-Willi syndrome in patients with an additional small inv dup(15) chromosome. 总被引:5,自引:2,他引:5
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W P Robinson J Wagstaff F Bernasconi C Baccichetti L Artifoni E Franzoni L Suslak L Y Shih H Aviv A A Schinzel 《Journal of medical genetics》1993,30(9):756-760
A patient with Angelman syndrome and a 46,XY/47,XY,+inv dup(15)(pter-->q11: q11-->pter) karyotype and a patient with Prader-Willi syndrome and a 46,XY/47,XY,+inv dup(15)(pter-->q12: q12-->pter) karyotype were investigated with molecular markers along chromosome 15. Paternal uniparental isodisomy was found for all informative markers in the first case which indicates that this, rather than the presence of the extra chromosome, is the cause of the Angelman syndrome phenotype. Similarly, the PWS patient showed maternal uniparental distomy with absence of PWS region material on the inv dup(15) chromosome. If (1) marker chromosomes are an occasional by product of 'rescuing' a trisomic fertilisation, or (2) if duplication of the normal homologue in a zygote which has inherited a marker in place of the normal corresponding chromosome 'rescues' an aneuploid fertilisation, or (3) if the presence or formation of a marker chromosome increases the probability of non-disjunction, then uniparental disomy might be found occasionally in other subjects with de novo marker chromosomes. 相似文献
2.
Kabuki syndrome-like features in monozygotic twin boys with a pseudodicentric chromosome 13. 总被引:1,自引:0,他引:1
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We present monozygotic twin boys with features of Kabuki syndrome. The twins were discordant for cleft palate and coarctation of the aorta. The occurrence of Kabuki syndrome in monozygotic twins has not been previously reported and reinforces the belief that this condition has a genetic basis. Chromosomal analysis on the boys showed a pseudodicentric chromosome 13 with an inactive centromere and satellite stalks at 13q12.11: 46,XY,psu dic(13)(13pter-->13q12.11::13p12-->13q11.00:: 13q12.11-->13qter). Their phenotypically normal mother appears to carry the same pseudodicentric chromosome 13. 相似文献
3.
We report a female baby with multiple congenital anomalies including left upper amelia, congenital short bowel with malrotation and pseudo-obstruction, dextrocardia with situs solitus, patent ductus arteriosus, and a tiny atrophic spleen. Chromosome study showed de novo 46,XX/46,XX,-4, + r(4)(p16-->q22.3)/47,XX,4, + r(4) (p16-->q22.3), + del(4)(pter-->q22.3:). The clinical findings in the patient were probably caused by the interaction of partial trisomy 4pter-->q22.3 or 4p16-->q22.3 and partial monosomy of 4q22.3-->4qter. This karyotype and phenotype have not previously been reported. 相似文献
4.
Interstitial deletion of bands 4q12-->q13.1: case report and review of proximal 4q deletions.
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We report a 6 year old child with a small de novo interstitial deletion of proximal 4q, karyotype 46,XX,del(4)(pter-->q12::q13.1-->qter). She has made good developmental progress and attends normal school with minimal assistance. We review published reports and clinical findings in patients with proximal 4q deletions. 相似文献
5.
Disclosure of five breakpoints in a complex chromosome rearrangement by microdissection and FISH.
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J J Engelen W J Loots J C Albrechts P C Motoh J P Fryns A J Hamers J P Geraedts 《Journal of medical genetics》1996,33(7):562-566
Microdissection and fluorescence in situ hybridisation (FISH) were used to elucidate the nature of a complex chromosome translocation, after GTG banding failed in the complete characterisation of the structural rearrangement between chromosomes 6 and 12. These chromosomes were painted with chromosome specific paints and one of the chromosome regions involved in the translocation was isolated by microdissection. Ten copies of the microdissected region were collected with microneedles from GTG banded metaphases, transferred to a collecting drop, and amplified by means of DOP-PCR. The PCR product was labelled with biotin-14-dATP and used as a FISH probe for hybridisation to normal metaphase chromosomes and metaphase chromosomes of the patients (microFISH). FISH with this chromosome region specific painting probe and with chromosome band specific probes enabled the characterisation of a complex chromosome rearrangement with five breakpoints in two chromosomes. This resulted in the following karyotype: 46,XY,t(6;12)(6pter--> 6q12::12q24.1-->12qter;12qter-->12q13.3:: 6q16.2-->6q26::12q13.3-->12q24.1::6q12--> 6q16.2::6q26-->6qter). 相似文献
6.
Collinson MN Roberts SE Crolla JA Dennis NR 《American journal of medical genetics. Part A》2004,(1):27-32
We reascertained a family in which first cousins were affected by Angelman syndrome and Prader-Willi syndrome. A paracentric inversion of 15q11-q15 had previously been reported in this family but we show, using fluorescence in situ hybridization (FISH), that the rearrangement segregating in this family is not a paracentric inversion but an inverted intrachromosomal insertion, inv ins(15)(q15q13q11.2). We also describe a further recombinant resulting in a maternal duplication of the Prader-Willi/Angelman critical region. This family illustrates the importance of distinguishing paracentric inversions from intrachromosomal insertions. 相似文献
7.
J Jacobsen B H King B L Leventhal S L Christian D H Ledbetter E H Cook Jr 《Journal of medical genetics》1998,35(7):534-538
Paternal or maternal deletions in the 15q11.2-q13 region are known to result in Prader-Willi syndrome (PWS) or Angelman syndrome (AS), respectively. Maternal duplications in 15q11.2-q13 have been found in patients with autism. A population of adults with moderate to profound mental retardation was studied to examine the usefulness of PCR based molecular methods in screening for proximal chromosome 15 abnormalities. Two hundred and eighty-five subjects were initially screened at five microsatellite markers with average heterozygosity values of 0.74 (range 0.54-0.82). Of these subjects, four had a single allele at all five loci, suggestive of a deletion or uniparental isodisomy. The four samples were further screened with additional markers located within 15q11.2-q13 as well as markers telomeric to this region. One subject had uniparental disomy (UPD) and three subjects had a deletion. To determine the parental origin of the 15q11-q13 region containing the single haplotype, samples were analysed with a newly developed methylation specific PCR technique at the SNRPN locus. Each of the four subjects showed presence of the paternal allele and absence of the maternal allele. All cases had a phenotype consistent with Angelman syndrome as expected for the level of mental retardation, but the subject with UPD was distinct from the other subjects with an absence of a history of seizures and presence of bilateral undescended testes and Parkinsonism. Although Angelman syndrome has an estimated population prevalence of 0.008%, at least 1.4% of the moderately to profoundly mentally retarded subjects screened were found to have Angelman syndrome. 相似文献
8.
T Mattina M Pierluigi D Mazzone S Scardilli C Perfumo F Mollica 《Journal of medical genetics》1997,34(11):945-948
We describe a patient with double trisomy 9q34.1-->qter and 21pter-->q22.1 resulting from 3:1 segregation of a maternal balanced translocation. The patient shows a clinical syndrome similar to that observed in patients with duplication of the chromosome 9q distal region, while no signs of trisomy 21 were observed. The use of high resolution banding and FISH were of fundamental importance for the cytogenetic diagnosis and for definition of the breakpoints on both chromosomes 9 and 21. 相似文献
9.
Antonietta Coppola Patrizia Ruosi Lia Santulli Salvatore Striano Federico Zara Pasquale Striano Sanjay M. Sisodiya 《European journal of medical genetics》2013,56(11):614-618
Various rearrangements occurring in the 15q11-q13 region have been reported in association with epilepsy. Deletions are the most frequent and are associated with Angelman or Prader–Willi syndrome. Duplications feature complex phenotypes including developmental delay, autistic-like behaviour and seizures. Among these, trisomy has been described as a milder phenotype compared to tetrasomy, but reports are rare and the phenotype is not yet defined. Here we report two adult cases with a 15q11.2-13.1 duplication showing a complex and similar epileptic phenotype. 相似文献
10.
We report the case of a Moroccan boy with mental retardation, hyperactivity, epilepsy, developmental problems and behavioural disorders. Cytogenetic analysis showed the presence of a supernumerary marker chromosome. Molecular cytogenetics allowed us to determine the marker as an inverted duplication of chromosome 15. It is the first case of a Moroccan patient with tetrasomy 15q in which fluorescence in situ hybridization (FISH) enabled us to specify the diagnosis. Interestingly, this patient has an infantile autism with cytogenetic abnormalities on chromosomal region 15q11-q13 as reported in patients with Autistic Disorder. 相似文献
11.
Gimelli G Pujana MA Patricelli MG Russo S Giardino D Larizza L Cheung J Armengol L Schinzel A Estivill X Zuffardi O 《Human molecular genetics》2003,12(8):849-858
Parental submicroscopic genomic inversions have recently been demonstrated to be present in several genomic disorders. These inversions are genomic polymorphisms that facilitate misalignment and abnormal recombination between flanking segmental duplications. Angelman syndrome (AS; MIM 105830) is associated with specific abnormalities of chromosome 15q11-q13, with about 70% of cases being mother-of-origin 4 Mb deletions. We present here evidence that some mothers of AS patients with deletions of the 15q11-q13 region have a heterozygous inversion involving the region that is deleted in the affected offspring. The inversion was detected in the mothers of four of six AS cases with the breakpoint 2-3 (BP2/3) 15q11-q13 deletion, but not in seven mothers of AS due to paternal uniparental disomy (UPD) 15. We have identified variable inversion breakpoints within BP segmental duplications in the inverted AS mothers, as well as in AS deleted patients. Interestingly, the BP2-BP3 region is inverted in the mouse draft genome sequence with respect to the human draft sequence. The BP2-BP3 chromosome 15q11-q13 inversion was detected in four of 44 subjects (9%) of the general population (P<0.004). The BP2/3 inversion should be an intermediate estate that facilitates the occurrence of 15q11-q13 BP2/3 deletions in the offspring. 相似文献
12.
Counselling dilemmas associated with the molecular characterisation of two Angelman syndrome families.
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H L Gilbert J L Buxton C T Chan T McKay S Cottrell S Ramsden R M Winter M E Pembrey S Malcolm 《Journal of medical genetics》1997,34(8):651-655
We report the molecular characterisation of two families with Angelman syndrome referred for prenatal diagnosis, in which atypical molecular findings resulted in counselling dilemmas. The first is a familial case of Angelman syndrome in which the two affected children have mutations which affect the imprinting mechanism, as shown by the presence of paternal DNA methylation patterns at D15S63 and SNRPN and biparental inheritance of 15q11-q13 markers. DNA prepared from a 21 week fetal blood sample detected a fetus with normal maternal and paternal DNA methylation patterns at D15S63, but inheritance of the same maternal chromosome 15q11-q13 as the two affected sibs. This is probably a result of germline mosaicism in the mother. The second is a case of Angelman syndrome with an atypical deletion of 15q11-q13, which involves both unusual proximal and distal breakpoints. The deletion was characterised in order to assess the risk of Angelman syndrome in a second pregnancy in the mother of this child. 相似文献
13.
Sahoo T Shaw CA Young AS Whitehouse NL Schroer RJ Stevenson RE Beaudet AL 《American journal of medical genetics. Part A》2005,(2):106-113
Genomic rearrangements of chromosome 15q11-q13 cause diverse phenotypes including autism, Prader-Willi syndrome (PWS), and Angelman syndrome (AS). This region is subject to genomic imprinting and characterized by complex combinations of low copy repeat elements. Prader-Willi and Angelman syndrome are caused primarily by 15q11-13 deletions of paternal and maternal origin, respectively. Autism is seen with maternal, but not paternal, interstitial duplications. Isodicentric 15q, most often of maternal origin, is associated with a complex phenotype often including autistic features. Limitations of conventional cytogenetic tests preclude a detailed analysis in most patients with 15q rearrangements. We have developed a microarray for comparative genomic hybridization utilizing 106 genomic clones from chromosome 15q to characterize this region. The array accurately localized all breakpoints associated with gains or losses on 15q. The results confirmed the location of the common breakpoints associated with interstitial deletions and duplications. The majority of idic(15q) chromosomes are comprised of symmetrical arms with four copies of the breakpoint 1 to breakpoint 5 region. Patients with less common breakpoints that are not distinguished by routine cytogenetic methods were more accurately characterized by array analysis. This microarray provides a detailed characterization for chromosomal abnormalities involving 15q11-q14 and is useful for more precise genotype-phenotype correlations for autism, PWS, AS, and idic(15) syndrome. 相似文献
14.
Flori E Biancalana V Girard-Lemaire F Favre R Flori J Doray B Mandel JL 《European journal of human genetics : EJHG》2004,12(3):181-186
Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are associated with a loss of function of imprinted genes in the 15q11-q13 region mostly due to deletions or uniparental disomies (UPD). These anomalies usually occur de novo with a very low recurrence risk. However, in rare cases, familial translocations are observed, giving rise to a high recurrence risk. We report on the difficulties of genetic counseling and prenatal diagnosis in a family segregating for a translocation (14;15)(q11;q13) where two consanguineous parents carry the same familial translocation in this chromosome 15 imprinting region. Both children of the couple inherited a chromosomal anomaly leading to PWS. However, a paternal 15q11-q13 deletion was responsible for PWS in the first child, whereas prenatal diagnosis demonstrated that PWS was associated with a maternal 15q11-q13 UPD in the fetus. This report demonstrates that both conventional and molecular cytogenetic parental analyses have to be performed when a deletion is responsible for PWS or AS in order not to overlook a familial translocation and to insure reliable diagnosis and genetic counseling. 相似文献
15.
A patient with Turner phenotype was found to carry two de novo chromosome aberrations: a 45,X line and a whole arm reciprocal translocation t(3;9). Fluorescence in situ hybridisation on metaphase cells using alpha satellite DNA for chromosome 3 and beta satellite and 'classical' satellite DNA for chromosome 9 showed that the centromeric region of chromosome 3 was retained in the 3q9q translocation derivative, as was the secondary constriction heterochromatin of chromosome 9. No signals were observed in the 3p9p derivative with the three probes. This suggests that the breakpoints were on 3p11 and 9q11. The karyotype was 45,X,t(3;9)(3qter-->3p11::9q11-->9qter; 9qter-->9q11::3p11-->3pter). 相似文献
16.
De novo der(X)t(X;10)(q26;q21) with features of distal trisomy 10q: case report of paternal origin identified by late replication with BrdU and the human androgen receptor assay (HAR). 总被引:1,自引:0,他引:1
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We describe an 11 year old girl with a de novo unbalanced t(X;10) that resulted in a deletion of Xq26-->Xqter and a trisomy of 10q21-->10qter. Her clinical features were of distal trisomy 10q, but she lacked the cardiovascular and renal malformations observed in duplications of 10q24-->10qter and had only moderate mental retardation. X inactivation was assessed on peripheral blood lymphocytes by late replication with BrdU (LR) and the human androgen receptor assay (HAR). By LR the der(X) was inactive without spreading to 10q21-->10qter in all cells. The HAR assay showed skewed methylation of the paternal allele (90%). The correlation of HAR and LR suggests that the der(X) was paternally inherited and is consistent with data from other de novo balanced and unbalanced X;autosome translocations detected in females. This is the first report of parental origin of a de novo trisomy 10q. 相似文献
17.
Thomas NS Durkie M Potts G Sandford R Van Zyl B Youings S Dennis NR Jacobs PA 《European journal of human genetics : EJHG》2006,14(7):831-837
Non-allelic homologous recombination between chromosome-specific LCRs is the most common mechanism leading to recurrent microdeletions and duplications. To look for locus-specific differences, we have used microsatellites to determine the parental and chromosomal origins of a large series of patients with de novo deletions of chromosome 7q11.23 (Williams syndrome), 15q11-q13 (Angelman syndrome, Prader-Willi syndrome) and 22q11 (Di George syndrome) and duplications of 15q11-q13. Overall the majority of rearrangements were interchromosomal, so arising from unequal meiotic exchange, and there were approximately equal numbers of maternal and paternal deletions. Duplications and deletions of 15q11-q13 appear to be reciprocal products that arise by the same mechanisms. The proportion arising from interchromosomal exchanges varied among deletions with 22q11 the highest and 15q11-q13 the lowest. However, parental and chromosomal origins were not always independent. For 15q11-q13, maternal deletions tended to be interchromosomal while paternal deletions tended to be intrachromosomal; for 22q11 there was a possible excess of maternal cases among intrachromosomal deletions. Several factors are likely to be involved in the formation of recurrent rearrangements and the relative importance of these appear to be locus-specific. 相似文献
18.
C. A. Williams R. T. Zori J. W. Stone B. A. Gray E. S. Cantu H. Ostrer 《American journal of medical genetics. Part A》1990,35(3):350-353
Six persons with the classical Angelman syndrome (AS) phenotype and de novo deletions of chromosome 15q11-q13 were studied to determine the parental origin of the chromosome deletion. Four of the 6 patients had informative cytogenetic studies and all demonstrated maternal inheritance of the deletion. These findings, together with other reported cases of the origin of the chromosome 15 deletion in AS, suggest that deletion of the maternally contributed chromosome leads to the AS phenotype. This contrasts with the Prader-Willi syndrome (PWS) in which a similar deletion of the paternally contributed chromosome 15 is observed. In deletion cases, a parental gamete effect such as genomic imprinting may be the best model to explain why apparently identical 15q11-q13 deletions may develop the different phenotypes of AS or PWS. 相似文献
19.
Maternal origin of 15q11-13 deletions in Angelman syndrome suggests a role for genomic imprinting 总被引:12,自引:0,他引:12
C A Williams R T Zori J W Stone B A Gray E S Cantu H Ostrer 《American journal of medical genetics》1990,35(3):350-353
Six persons with the classical Angelman syndrome (AS) phenotype and de novo deletions of chromosome 15q11-q13 were studied to determine the parental origin of the chromosome deletion. Four of the 6 patients had informative cytogenetic studies and all demonstrated maternal inheritance of the deletion. These findings, together with other reported cases of the origin of the chromosome 15 deletion in AS, suggest that deletion of the maternally contributed chromosome leads to the AS phenotype. This contrasts with the Prader-Willi syndrome (PWS) in which a similar deletion of the paternally contributed chromosome 15 is observed. In deletion cases, a parental gamete effect such as genomic imprinting may be the best model to explain why apparently identical 15q11-q13 deletions may develop the different phenotypes of AS or PWS. 相似文献
20.
Molecular characterisation of four cases of intrachromosomal triplication of chromosome 15q11-q14 总被引:1,自引:0,他引:1
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Ungaro P Christian SL Fantes JA Mutirangura A Black S Reynolds J Malcolm S Dobyns WB Ledbetter DH 《Journal of medical genetics》2001,38(1):26-34
CONTEXT—Chromosomal abnormalities that involve the proximal region of chromosome 15q occur relatively frequently in the human population. However, interstitial triplications involving one 15 homologue are very rare with three cases reported to date.
OBJECTIVE—To provide a detailed molecular characterisation of four additional patients with interstitial triplications of chromosome 15q11-q14.
DESIGN—Molecular analyses were performed using DNA markers and probes specific for the 15q11-q14 region.
SETTING—Molecular cytogenetics laboratory at the University of Chicago.
SUBJECTS—Four patients with mild to severe mental retardation and features of Prader-Willi syndrome (PWS) or Angelman syndrome (AS) were referred for molecular cytogenetic analysis following identification of a suspected duplication/triplication of chromosome 15q11-q14 by routine cytogenetic analysis.
MAIN OUTCOME MEASURES—Fluorescence in situ hybridisation (FISH) was performed to determine the type of chromosomal abnormality present, the extent of the abnormal region, and the orientation of the extra chromosomal segments. Molecular polymorphism analysis was performed to determine the parental origin of the abnormality. Methylation and northern blot analyses of the SNRPN gene were performed to determine the effect of extra copies of the SNRPN gene on its methylation pattern and expression.
RESULTS—Fluorescence in situ hybridisation (FISH) using probes within and flanking the Prader-Willi/Angelman syndrome critical region indicated that all patients carried an intrachromosomal triplication of proximal 15q11-q14 in one of the two chromosome 15 homologues (trip(15)). In all patients the orientation of the triplicated segments was normal-inverted-normal, suggesting that a common mechanism of rearrangement may have been involved. Microsatellite analysis showed the parental origin of the trip(15) to be maternal in three cases and paternal in one case. The paternal triplication patient had features similar to PWS, one maternal triplication patient had features similar to AS, and the other two maternal triplication patients had non-specific findings including hypotonia and mental retardation. Methylation analysis at exon 1 of the SNRPN locus showed increased dosage of either the paternal or maternal bands in the paternal or maternal triplication patients, respectively, suggesting that the methylation pattern shows a dose dependent increase that correlates with the parental origin of the triplication. In addition, the expression of SNRPN was analysed by northern blotting and expression levels were consistent with dosage and parental origin of the triplication.
CONCLUSIONS—These four additional cases of trip(15) will provide additional information towards understanding the phenotypic effects of this abnormality and aid in understanding the mechanism of formation of other chromosome 15 rearrangements.
Keywords: chromosome 15 triplication; Prader-Willi syndrome; Angelman syndrome; autism 相似文献
OBJECTIVE—To provide a detailed molecular characterisation of four additional patients with interstitial triplications of chromosome 15q11-q14.
DESIGN—Molecular analyses were performed using DNA markers and probes specific for the 15q11-q14 region.
SETTING—Molecular cytogenetics laboratory at the University of Chicago.
SUBJECTS—Four patients with mild to severe mental retardation and features of Prader-Willi syndrome (PWS) or Angelman syndrome (AS) were referred for molecular cytogenetic analysis following identification of a suspected duplication/triplication of chromosome 15q11-q14 by routine cytogenetic analysis.
MAIN OUTCOME MEASURES—Fluorescence in situ hybridisation (FISH) was performed to determine the type of chromosomal abnormality present, the extent of the abnormal region, and the orientation of the extra chromosomal segments. Molecular polymorphism analysis was performed to determine the parental origin of the abnormality. Methylation and northern blot analyses of the SNRPN gene were performed to determine the effect of extra copies of the SNRPN gene on its methylation pattern and expression.
RESULTS—Fluorescence in situ hybridisation (FISH) using probes within and flanking the Prader-Willi/Angelman syndrome critical region indicated that all patients carried an intrachromosomal triplication of proximal 15q11-q14 in one of the two chromosome 15 homologues (trip(15)). In all patients the orientation of the triplicated segments was normal-inverted-normal, suggesting that a common mechanism of rearrangement may have been involved. Microsatellite analysis showed the parental origin of the trip(15) to be maternal in three cases and paternal in one case. The paternal triplication patient had features similar to PWS, one maternal triplication patient had features similar to AS, and the other two maternal triplication patients had non-specific findings including hypotonia and mental retardation. Methylation analysis at exon 1 of the SNRPN locus showed increased dosage of either the paternal or maternal bands in the paternal or maternal triplication patients, respectively, suggesting that the methylation pattern shows a dose dependent increase that correlates with the parental origin of the triplication. In addition, the expression of SNRPN was analysed by northern blotting and expression levels were consistent with dosage and parental origin of the triplication.
CONCLUSIONS—These four additional cases of trip(15) will provide additional information towards understanding the phenotypic effects of this abnormality and aid in understanding the mechanism of formation of other chromosome 15 rearrangements.
Keywords: chromosome 15 triplication; Prader-Willi syndrome; Angelman syndrome; autism 相似文献