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Mette Gilling,
Allan Lind-Thomsen,
Yuan Mang,
Mads Bak,
Morten Møller,
Reinhard Ullmann,
Ulf Kristoffersson,
Vera M Kalscheuer,
Karen Friis Henriksen, Merete Bugge,
Zeynep Tümer,
Niels Tommerup
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ABSTRACT: In a monozygotic twin couple with mental retardation (MR), we identified a maternally inherited inversion and a paternally inherited translocation: 46,XY,inv(10)(p11.2q21.2)mat,t(9;18)(p22;q21.1)pat. The maternally inherited inv(10) was a benign variant without any apparent phenotypical implications. The translocation breakpoint at 9p was within a cluster of interferon α genes and the 18q21 breakpoint truncated ZBTB7C (zinc finger and BTB containing 7C gene). In addition, analyses with array-CGH revealed a 931 kb maternally inherited deletion on chromosome 8q22 as well as an 875 kb maternally inherited duplication on 5p14. The deletion encompasses the RIM2 (Rab3A-interacting molecule 2), FZD6 (Frizzled homolog 6) and BAALC (Brain and Acute Leukemia Gene, Cytoplasmic) genes and the duplication includes the 5' end of the CDH9 (cadherin 9) gene. Exome sequencing did not reveal any additional mutations that could explain the MR phenotype. The protein products of the above mentioned genes are involved in different aspects of brain development and/or maintenance of the neurons which suggest that accumulation of genetic defects segregating from both parents might be the basis of MR in the twins. This hypothesis was further supported by protein interaction analysis.
European journal of medical genetics 03/2011; 54(4):e383-8. · 1.57 Impact Factor
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American Journal of Medical Genetics Part A 02/2011; 155A(3):652-5. · 2.39 Impact Factor
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Merete Bugge
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ABSTRACT: Seven pairs of twins, two monozygotic (MZ), two dizygotic (DZ), and three like-sex pairs of unknown zygosity are described. The twin pairs were all discordant for omphalocele except for one pair of conjoined twins. The 8 infants with omphalocele represent 3.1% of the 253 infants with omphalocele, ascertained in an almost complete nationwide data set of live- and stillborn infants with abdominal wall defects in two decades in Denmark (1970-1989). The occurrence of twins with omphalocele was not significantly different from the occurrence of twins in the Danish population in the same period. To our knowledge this is the first report of the occurrence of twins with omphalocele in a systematic nationwide epidemiological study.
American Journal of Medical Genetics Part A 08/2010; 152A(8):2048-52. · 2.39 Impact Factor
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ABSTRACT: In a patient with severe myoclonic epilepsy of infancy (SMEI), we identified a de novo balanced translocation, t(2;5)(q24.3,q34). The breakpoint on chromosome 2q24.3 truncated the SCN1A gene and the 5q34 breakpoint was within a highly conserved genomic region. Point mutations or microdeletions of SCN1A have previously been identified in SMEI patients, but this is the first report of a balanced translocation disrupting the SCN1A gene in an epilepsy patient. We therefore recommend that SMEI patients without SCN1A microdeletions or point mutations should be investigated for chromosomal rearrangements.
Epilepsia 07/2008; 49(6):1091-4. · 3.96 Impact Factor
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Merete Bugge,
Andrew Collins,
Jens Michael Hertz,
Hans Eiberg,
Claes Lundsteen,
Carsten A Brandt,
Mads Bak,
Claus Hansen,
Celia D Delozier,
James Lespinasse,
Lisbeth Tranebjaerg,
Johanne M D Hahnemann,
Kirsten Rasmussen,
Gert Bruun-Petersen,
Laurence Duprez,
Niels Tommerup,
Michael B Petersen
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ABSTRACT: We performed a molecular study with 21 microsatellites on a sample of 82 trisomy 13 conceptuses, the largest number of cases studied to date. The parental origin was determined in every case and in 89% the extra chromosome 13 was of maternal origin with an almost equal number of maternal MI and MII errors. The latter finding is unique among human autosomal trisomies, where maternal MI (trisomies 15, 16, 21, 22) or MII (trisomy 18) errors dominate. Of the nine paternally derived cases five were of MII origin but none arose from MI errors. There was some evidence for elevated maternal age in cases with maternal meiotic origin for liveborn infants. Maternal and paternal ages were elevated in cases with paternal meiotic origin. This is in contrast to results from a similar study of non-disjunction of trisomy 21 where paternal but not maternal age was elevated. We find clear evidence for reduced recombination in both maternal MI and MII errors and the former is associated with a significant number of tetrads (33%) that are nullichiasmate, which do not appear to be a feature of normal chromosome 13 meiosis. This study supports the evidence for subtle chromosome-specific influences on the mechanisms that determine non-disjunction of human chromosomes, consistent with the diversity of findings for other trisomies.
Human Molecular Genetics 09/2007; 16(16):2004-10. · 7.64 Impact Factor
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Vera M Kalscheuer,
David FitzPatrick,
Niels Tommerup, Merete Bugge,
Erik Niebuhr,
Luitgard M Neumann,
Andreas Tzschach,
Sarah A Shoichet,
Corinna Menzel,
Fikret Erdogan,
Ger Arkesteijn,
Hans-Hilger Ropers,
Reinhard Ullmann
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ABSTRACT: We report on three unrelated mentally disabled patients, each carrying a de novo balanced translocation that truncates the autism susceptibility candidate 2 (AUTS2) gene at 7q11.2. One of our patients shows relatively mild mental retardation; the other two display more profound disorders. One patient is also physically disabled, exhibiting urogenital and limb malformations in addition to severe mental retardation. The function of AUTS2 is presently unknown, but it has been shown to be disrupted in monozygotic twins with autism and mental retardation, both carrying a translocation t(7;20)(q11.2;p11.2) (de la Barra et al. in Rev Chil Pediatr 57:549-554, 1986; Sultana et al. in Genomics 80:129-134, 2002). Given the overlap of this autism/mental retardation (MR) phenotype and the MR-associated disorders in our patients, together with the fact that mapping of the additional autosomal breakpoints involved did not disclose obvious candidate disease genes, we ascertain with this study that AUTS2 mutations are clearly linked to autosomal dominant mental retardation.
Human Genetics 06/2007; 121(3-4):501-9. · 5.07 Impact Factor
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Iben Bache,
Mads Hjorth, Merete Bugge,
Søren Holstebroe,
Jørgen Hilden,
Lone Schmidt,
Karen Brondum-Nielsen,
Gert Bruun-Petersen,
Peter K A Jensen,
Claes Lundsteen,
Erik Niebuhr,
Kirsten Rasmussen,
Niels Tommerup
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ABSTRACT: Balanced reciprocal translocations associated with genetic disorders have facilitated the identification of a variety of genes for early-onset monogenic disorders, but only rarely the genes associated with common and complex disorders. To assess the potential of chromosomal breakpoints associated with common/ complex disorders, we investigated the full spectrum of diseases in 731 carriers of balanced reciprocal translocations without known early-onset disorders in a nation-wide questionnaire-based re-examination. In 42 families, one of the breakpoints at the cytogenetic level concurred with known linkage data and/or the translocation co-segregated with the reported phenotype, for example, we found a significant linkage (lod score=2.1) of dyslexia and a co-segregating translocation with a breakpoint in a previously confirmed locus for dyslexia. Furthermore, we identified 441 instances of at least two unrelated carriers with concordant breakpoints and traits. If applied to other populations, re-examination of translocation carriers may identify additional genotype-phenotype associations, some of which may be novel and others that may coincide with and provide additional support of data presented here.
European Journal of HumanGenetics 05/2006; 14(4):410-7. · 4.40 Impact Factor
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ABSTRACT: The Pierre Robin Sequence (PRS) is subgroup of the cleft palate population. As with the etiology of cleft lip or palate, the etiology of PRS is generally unknown. Some factors are suggestive of a genetic basis for PRS. The purpose of this study was to compare genetic information on PRS available in the literature and in a cytogenetic database to facilitate focused genetic studies of PRS.
After searching Medline for "pierre robin and genetics," the Mendelian Cytogenetics Network database for "robin" and "pierre robin," and two reviews from the Human Cytogenetics Database for "cleft palate" and "micrognathia," a comparison of the data and a search in Online Mendelian Inheritance in Man (OMIM) Gene Map was performed to identify relevant candidate genes.
The findings revealed consistency to a certain degree to loci 2q24.1-33.3, 4q32-qter, 11q21-23.1, and 17q21-24.3. A search in the OMIM Gene Map provided many candidate genes for PRS in these regions. The GAD67 on 2q31, the PVRL1 on 11q23-q24, and the SOX9 gene on 17q24.3-q25.1 are suggested to be of particular importance.
Candidate loci and a few potential candidate genes for PRS are proposed from the present study. This may enable researchers to focus their effort in the studies of PRS.
The Cleft Palate-Craniofacial Journal 04/2006; 43(2):155-9. · 0.82 Impact Factor
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ABSTRACT: We report on a liveborn infant with trisomy 10 mosaicism combined with maternal uniparental heterodisomy for chromosome 10. The mosaicism 47,XY,+10/46,XY was found in five different tissues, including one blood sample, while cultured lymphocytes from two other blood samples showed a normal karyotype, 46,XY. DNA analysis with six PCR-based microsatellite markers demonstrated the trisomic cell line to be a result of maternal meiotic nondisjunction, and revealed maternal uniparental heterodisomy in the diploid cell line, suggesting that the formation of the diploid cell line was due to trisomy rescue. The boy had severe growth retardation, major dysmorphism, and malformations, and died at 37 days. We reviewed the previous nine reports of infants and fetuses with trisomy 10 mosaicism reported in the literature. We suggest that a common clinical syndrome can be defined comprising skull, jaw and ear abnormalities, cleft lip/palate, malformations of eyes, heart and kidneys, deformity of hands and feet, and most often death neonatally or in early infancy. The cytogenetic findings in the present patient demonstrate the importance of karyotyping more than one tissue, and not only lymphocytes, when a chromosomal aberration is strongly suspected.
American Journal of Medical Genetics Part A 11/2005; 138A(2):150-4. · 2.39 Impact Factor
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ABSTRACT: We have used 20 PCR-based DNA polymorphisms to determine whether trisomy 13 due to de novo rea(13q;13q) in six cases is caused by translocation (13q;13q) or isochromosome (13q;13q); to determine the parental origin of the rearrangements and the mechanisms of formation. The six probands were three liveborn children with clinical features characteristic of Patau's syndrome and three fetuses diagnosed prenatally by amniocentesis or CVS. Five cases were isochromosomes with two identical q arms, one of maternal and four of paternal origin. Only one case was a Robertsonian translocation of maternal origin.
American Journal of Medical Genetics Part A 02/2005; 132A(3):310-3. · 2.39 Impact Factor
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Iben Bache,
Elvire Van Assche,
Sultan Cingoz, Merete Bugge,
Zeynep Tümer,
Mads Hjorth,
Claes Lundsteen,
James Lespinasse,
Kirsten Winther,
Anita Niebuhr, [......],
Margarita Stefanova,
Lisbeth Tranebjerg,
Catherine Turleau,
Carl Birger van der Hagen,
Michel Vekemans,
Nadja Kokalj Vokac,
Klaus Wagner,
Jan Wahlstroem,
Leopoldo Zelante,
Niels Tommerup
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ABSTRACT: In a search for potential infertility loci, which might be revealed by clustering of chromosomal breakpoints, we compiled 464 infertile males with a balanced rearrangement from Mendelian Cytogenetics Network database (MCNdb) and compared their karyotypes with those of a Danish nation-wide cohort. We excluded Robertsonian translocations, rearrangements involving sex chromosomes and common variants. We identified 10 autosomal bands, five of which were on chromosome 1, with a large excess of breakpoints in the infertility group. Some of these could potentially harbour a male-specific infertility locus. However, a general excess of breakpoints almost everywhere on chromosome 1 was observed among the infertile males: 26.5 versus 14.5% in the cohort. This excess was observed both for translocation and inversion carriers, especially pericentric inversions, both for published and unpublished cases, and was significantly associated with azoospermia. The largest number of breakpoints was reported in 1q21; FISH mapping of four of these breakpoints revealed that they did not involve the same region at the molecular level. We suggest that chromosome 1 harbours a critical domain whose integrity is essential for male fertility.
European Journal of HumanGenetics 01/2005; 12(12):993-1000. · 4.40 Impact Factor
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ABSTRACT: The description of isochromosomes 18 has so far mainly been by cytogenetic studies and based on identical banding pattern of the two arms. However, only molecular techniques are capable to distinguish an isochromosome from a translocation, whole arm or reciprocal, between two chromosomes 18. We have used 23 PCR-based DNA polymorphisms to determine the parental origin and mechanisms of formation in four patients with isochromosomes 18q and to demonstrate that they were consistent with true isochromosomes. Three of the probands were liveborn children with clinical features characteristic of Edwards syndrome, one proband was a fetus diagnosed at prenatal diagnosis. In one case the isochromosome was monocentric with two identical q arms of maternal origin, formed by misdivision of the centromere and loss of p arm material. Another monocentric case had 47 chromosomes with isochromosomes i(18p) and i(18q) formed by maternal postzygotic centromeric misdivision and segregation of both isochromosomes, or by meiosis II centromeric misdivision and nondisjunction (without recombination in meiosis I). In two cases, the isochromosomes were dicentric with genetically identical arms composed of a part of the short and the whole long arm of chromosome 18 of paternal origin. The formation of the fused chromosomes can be explained by postzygotic exchange of sister chromatids on the short arm of chromosome 18, followed by breakage and U-shape reunion of sister chromatids.
American Journal of Medical Genetics Part A 07/2004; 127A(3):230-3. · 2.39 Impact Factor
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ABSTRACT: In 1927, Oluf Thomsen, in a classic paper, described a seven-generation family with autosomal dominant axial synpolydactyly (SPD)--the Vordingborgtyp of axis duplication and dysostosis. Expansion of a polyalanine tract in the HOXD13 gene is known to cause synpolydactyly. We have rediscovered part of the family described by Thomsen, and detected a 9 triplet polyalanine expansion within HOXD13segregating with the disorder. The phenotypic spectrum in mutation carriers ranged from severe to inapparent bone malformations. In the latter case, only dermatoglyphics revealed the genetic status.
American Journal of Medical Genetics 07/2002; 110(2):116-21.
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ABSTRACT: The recessive autosomal disorder known as ICF syndrome (for immunodeficiency, centromere instability and facial anomalies; Mendelian Inheritance in Man number 242860) is characterized by variable reductions in serum immunoglobulin levels which cause most ICF patients to succumb to infectious diseases before adulthood. Mild facial anomalies include hypertelorism, low-set ears, epicanthal folds and macroglossia. The cytogenetic abnormalities in lymphocytes are exuberant: juxtacentromeric heterochromatin is greatly elongated and thread-like in metaphase chromosomes, which is associated with the formation of complex multiradiate chromosomes. The same juxtacentromeric regions are subject to persistent interphase self-associations and are extruded into nuclear blebs or micronuclei. Abnormalities are largely confined to tracts of classical satellites 2 and 3 at juxtacentromeric regions of chromosomes 1, 9 and 16. Classical satellite DNA is normally heavily methylated at cytosine residues, but in ICF syndrome it is almost completely unmethylated in all tissues. ICF syndrome is the only genetic disorder known to involve constitutive abnormalities of genomic methylation patterns. Here we show that five unrelated ICF patients have mutations in both alleles of the gene that encodes DNA methyltransferase 3B (refs 5, 6). Cytosine methylation is essential for the organization and stabilization of a specific type of heterochromatin, and this methylation appears to be carried out by an enzyme specialized for the purpose.
Nature 12/1999; · 36.28 Impact Factor
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Nature 11/1999; 402(6758):187-191. · 36.28 Impact Factor
