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Dieter Kotzot - One of the best experts on this subject based on the ideXlab platform.
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mosaicism and Uniparental Disomy in prenatal diagnosis
Trends in Molecular Medicine, 2015Co-Authors: Thomas Eggermann, Lukas Soellner, Karin Buiting, Dieter KotzotAbstract:Chromosomal mosaicism is the presence of numerous cell lines with different chromosomal complements in the same individual. Uniparental Disomy (UPD) is the inheritance of two homologous chromosomes from the same parent. These genetic anomalies arise from errors in meiosis and/or mitosis and can occur independently or in combination. Due to the formation mechanisms of UPD, low-level or undetected mosaicisms are assumed for a significant number of UPD cases. The pre- and postnatal clinical consequences of mosaicism for chromosomal aberrations and/or UPD depend on the gene content of the involved chromosome. In prenatal evaluation of chromosomal mosaicism and UPD, genetic counseling should be offered before any laboratory testing.
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complex and segmental Uniparental Disomy updated
Journal of Medical Genetics, 2008Co-Authors: Dieter KotzotAbstract:Objective: To review all cases with segmental and/or complex Uniparental Disomy (UPD) and to discuss the impact of these cases on Medical Genetics. Design: Searching for published reports in Pubmed and in the abstract books of the annual meetings of the American Society of Human Genetics and the European Society of Human Genetics up to March 2008. Results: In total, 26 cases with segmental UPD and a normal karyotype, 38 cases with UPD of a whole chromosome and a simple reciprocal or non-homologous Robertsonisn translocation, four cases each with two isochromosomes and UPD of the short arm isochromosme and opposite UPD of the long arm isochromosome, three cases with UPD and an isochromosome of the short arm and the long arm of a metacentric or a submetacentric chromosome, one case with maternal UPD and an isochromosome 8 associated with a homozygous deletion (8)(p23.3pter), 42 cases with UPD and an isochromosome of the long arm of an acrocentric chromosome, 33 cases with UPD and a supernumerary marker or ring chromosome, 17 cases with UPD of a whole or parts of a chromosome and a complex karyotype, 13 cases with most likely mosaicism for genome-wide paternal UPD, and 3 cases with most likely mosaicism for genome-wide maternal UPD were found. Conclusion: This update shows that particularly the number of reported cases with segmental UPD or UPD associated with a marker chromosome clearly increased within the last years, and that the investigation of both parents in cases with homozygosity of an autosomal recessively inherited mutation in some cases might help improving genetic counselling coming to a reduced recurrence risk in the case of UPD. Moreover, cases with segmental or complex UPD show that meiosis and early postzygotic mitoses seem to be more complex events than previously thought. For the formation of all kinds of segmental or complex UPD or genome-wide UPD mosaicism always a fortunate cooccurrence of meiotic or mitotic recombination, abnormal segregation, and subsequent correction are necessary. No case of recurrence has been reported until now. Therefore, in subsequent pregnancies invasive prenatal diagnosis is not necessarily indicated.
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Uniparental Disomy upd other than 15 phenotypes and bibliography updated
American Journal of Medical Genetics Part A, 2005Co-Authors: Dieter Kotzot, Gerd UtermannAbstract:Uniparental Disomy (UPD) describes the inheritance of a pair of chromosomes from only one parent. The concept was introduced in Medical Genetics by Engel (1980); Am J Med Genet 6:137-143. Aside UPD 15, which is the most frequent one, up to now (February 2005) 197 cases with whole chromosome maternal UPD other than 15 (124 X heteroDisomy, 59 X isoDisomy, and 14 cases without information of the mode of UPD) and 68 cases with whole chromosome paternal UPD other than 15 (13 X heterDisomy, 53 X isoDisomy, and 2 cases without information of the mode of UPD) have been reported. In this review we discuss briefly the problems associated with UPD and provide a comprehensive clinical summary with a bibliography for each UPD other than 15 as a guide for genetic counseling.
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complex and segmental Uniparental Disomy upd review and lessons from rare chromosomal complements
Journal of Medical Genetics, 2001Co-Authors: Dieter KotzotAbstract:OBJECTIVE—To review all cases with segmental and/or complex Uniparental Disomy (UPD), to study aetiology and mechanisms of formation, and to draw conclusions. DESIGN—Searching published reports in Medline. RESULTS—The survey found at least nine cases with segmental UPD and a normal karyotype, 22 cases with UPD of a whole chromosome and a simple or a non-homologous Robertsonian translocation, eight cases with UPD and two isochromosomes, one of the short arm and one of the long arm of a non-acrocentric chromosome, 39 cases with UPD and an isochromosome of the long arm of two homologous acrocentric chromosomes, one case of UPD and an isochromosome 8 associated with a homozygous del(8)(p23.3pter), and 21 cases with UPD of a whole or parts of a chromosome associated with a complex karyotype. Segmental UPD is formed by somatic recombination (isoDisomy) or by trisomy rescue. In the latter mechanism, a meiosis I error is associated with meiotic recombination and an additional somatic exchange between two non-Uniparental chromatids. Subsequently, the chromatid that originated from the disomic gamete is lost (iso- and heteroDisomy). In cases of UPD associated with one isochromosome of the short arm and one isochromosome of the long arm of a non-acrocentric chromosome and in cases of UPD associated with a true isochromosome of an acrocentric chromosome, mitotic complementation is assumed. This term describes the formation by misdivision at the centromere during an early mitosis of a monosomic zygote. In cases of UPD associated with an additional marker chromosome, either mitotic formation of the marker chromosome in a trisomic zygote or fertilisation of a gamete with a marker chromosome formed in meiosis by a disomic gamete or by a normal gamete and subsequent duplication are possible. CONCLUSIONS—Research in the field of segmental and/or complex UPD may help to explain undiagnosed non-Mendelian disorders, to recognise hotspots for meiotic and mitotic recombinations, and to show that chromosomal segregation is more complex than previously thought. It may also be helpful to map autosomal recessively inherited genes, genes/regions of genomic imprinting, and dysmorphic phenotypes. Last but not least it would improve genetic counselling. Keywords: genomic imprinting; isochromosome; Robertsonian translocation; Uniparental Disomy (UPD)
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Uniparental Disomy 7 in silver russell syndrome and primordial growth retardation
Human Molecular Genetics, 1995Co-Authors: Silke Schmitt, Helena G Ilyina, Dieter Kotzot, Iosif W Lurie, Wendy P. Robinson, Fosco Bernasconi, K MéhesAbstract:: Maternal Uniparental Disomy for the entire chromosome 7 has so far been reported in three patients with intrauterine and postnatal growth retardation. Two were detected because they were homozygous for a cystic fibrosis mutation for which only the mother was heterozygous, and one because he was homozygous for a rare COL1A2 mutation. We investigated 35 patients with either the Silver-Russell syndrome or primordial growth retardation and their parents with PCR markers to search for Uniparental Disomy 7. Four of 35 patients were found to have maternal Disomy, including three with isoDisomy and one with heteroDisomy. The data confirm the hypothetical localization of a maternally imprinted gene (or more than one such gene) on chromosome 7. It is suggested to search for UPD 7 in families with an offspring with sporadic Silver-Russell syndrome or primordial growth retardation.
Wendy P. Robinson - One of the best experts on this subject based on the ideXlab platform.
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evidence for imprinting on chromosome 16 the effect of Uniparental Disomy on the outcome of mosaic trisomy 16 pregnancies
American Journal of Medical Genetics, 2002Co-Authors: Paul J Yong, I J Barrett, Dagmar K Kalousek, S A Marion, Wendy P. RobinsonAbstract:Although a number of infants with maternal Uniparental Disomy of chromosome 16 (upd(16)mat) have been reported, the evidence for imprinting on chromosome 16 is not yet conclusive. To test the hypothesis that upd(16)mat has a distinct phenotype, which would support the existence of imprinted gene(s) on chromosome 16, statistical analysis was performed on a large series (n = 83) of mosaic trisomy 16 cases with molecular determination of Uniparental Disomy status. The incidence of upd(16)mat was 40%, which is consistent with the expected one third from random chromosome loss during trisomy rescue (P = 0.262). In pairwise comparisons, upd(16)mat was found to be associated with fetal growth restriction (P = 0.029) and with increased risk of major malformation (RR = 1.43; P = 0.053). Regression modeling showed that the effect of upd(16)mat on fetal/neonatal weight and malformation is independent of the degree of trisomy detected in the fetus. Regression modeling to control for the degree of trisomy detected in the placenta was not possible due to limited sample size. We conclude that upd(16)mat is associated with more severe growth restriction, and possibly, with higher risk of malformation. Our hypothesis is that imprinted gene(s) exist on chromosome 16 and that abnormal expression of these gene(s) in upd(16)mat cells during development results in decreased cell proliferation. Although we do not advocate prenatal testing for upd(16), studies on the long-term outcome of upd(16)mat neonates is necessary for counseling purposes.
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two cases of confined placental mosaicism for chromosome 4 including one with maternal Uniparental Disomy
Prenatal Diagnosis, 2001Co-Authors: Brian D Kuchinka, Dagmar K Kalousek, Sylvie Langlois, I J Barrett, G Moya, J M Sanchez, Siuli Yong, Wendy P. RobinsonAbstract:Two cases of trisomy 4 mosaicism are reported including one with molecularly confirmed Uniparental Disomy (UPD) of chromosome 4. Cytogenetic analysis of a chorionic villus sample (CVS) in Case 1 showed complete trisomy 4 in trophoblast and diploidy in chorionic stroma. Amniotic fluid analysis demonstrated a 46,XX complement. After intrauterine fetal death at 30 weeks, molecular analysis confirmed the presence of trisomy 4 of maternal meiotic origin, while fetal tissues showed maternal UPD for chromosome 4. Cultured CVS in Case 2 revealed trisomy 4 in 2/30 cells analyzed. This pregnancy resulted in a healthy livebirth with biparental inheritance of chromosome 4. Molecularly confirmed UPD4 has not been previously reported, and therefore, although the adverse outcome in Case 1 is likely due to the trisomy 4 in the placenta, an imprinting effect associated with UPD4 cannot be excluded.
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mechanisms leading to Uniparental Disomy and their clinical consequences
BioEssays, 2000Co-Authors: Wendy P. RobinsonAbstract:Uniparental Disomy (UPD) refers to the situation in which both copies of a chromosome pair have originated from one parent. In humans, it can result in clinical conditions by producing either homozygosity for recessive mutations or aberrant patterns of imprinting. Furthermore, UPD is frequently found in conjunction with mosaicism for a chromosomally abnormal cell line, which can also contribute to phenotypic abnormalities. Investigations into the mechanisms by which UPD may arise have helped to expand our general awareness of the impact of chromosomal abnormalities and chromosomal mosaicism in normal human development. Specifically, it appears that errors in the transmission of a chromosome from parent to gamete and during early somatic cell divisions are remarkably common but that embryo and cell selection during early embryogenesis help to ensure the presence of a numerically balanced chromosome complement in the developing fetus. UPD is also likely to occur within a portion of cells in all individuals simply as a consequence of somatic recombination occurring during mitotic cell divisions. This can be an important step in cancer development as well as a contributing factor to other late onset diseases. This review summarizes mechanisms by which UPD may arise and their associated clinical consequences. BioEssays 22:452—459, 2000. © 2000 John Wiley & Sons, Inc.
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Uniparental Disomy 7 in silver russell syndrome and primordial growth retardation
Human Molecular Genetics, 1995Co-Authors: Silke Schmitt, Helena G Ilyina, Dieter Kotzot, Iosif W Lurie, Wendy P. Robinson, Fosco Bernasconi, K MéhesAbstract:: Maternal Uniparental Disomy for the entire chromosome 7 has so far been reported in three patients with intrauterine and postnatal growth retardation. Two were detected because they were homozygous for a cystic fibrosis mutation for which only the mother was heterozygous, and one because he was homozygous for a rare COL1A2 mutation. We investigated 35 patients with either the Silver-Russell syndrome or primordial growth retardation and their parents with PCR markers to search for Uniparental Disomy 7. Four of 35 patients were found to have maternal Disomy, including three with isoDisomy and one with heteroDisomy. The data confirm the hypothetical localization of a maternally imprinted gene (or more than one such gene) on chromosome 7. It is suggested to search for UPD 7 in families with an offspring with sporadic Silver-Russell syndrome or primordial growth retardation.
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Angelman syndrome due to paternal Uniparental Disomy of chromosome 15: a milder phenotype?
American journal of medical genetics, 1994Co-Authors: A. Bottani, Wendy P. Robinson, C. D. Delozier-blanchet, Eric Engel, Michael A. Morris, B. Schmitt, L. Thun‐hohenstein, Albert SchinzelAbstract:The Angelman syndrome (AS) is a neurological disorder characterized by severe mental retardation, absent speech, seizures, gait disturbances, and a typical age-dependent facial phenotype. Most cases are due to an interstitial deletion on the maternally inherited chromosome 15, in the critical region q11-q13. Rare cases also result from paternal Uniparental Disomy of chromosome 15. In a group of 14 patients with sporadic AS diagnosed in Switzerland, we found 2 unrelated females with paternal isoDisomy for the entire chromosome 15. Their phenotypes were milder than usually seen in this syndrome: one girl did not show the typical AS facial changes; both patients had late-onset mild seizures; as they grew older, they had largely undisturbed gross motor functions, in particular no severe ataxia. Both girls were born to older fathers (45 and 43 years old, respectively). The apparent association of a relatively milder phenotype in AS with paternal Uniparental Disomy will have to be confirmed by detailed clinical descriptions of further patients.
Bryan D Young - One of the best experts on this subject based on the ideXlab platform.
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novel regions of acquired Uniparental Disomy discovered in acute myeloid leukemia
Genes Chromosomes and Cancer, 2008Co-Authors: Manu Gupta, Manoj Raghavan, Jeanbaptiste Cazier, Tracy Chaplin, Rosemary E Gale, Claude Chelala, Christopher Allen, Gael Molloy, David C Linch, Bryan D YoungAbstract:The acquisition of Uniparental Disomy (aUPD) in acute myeloid leukemia (AML) results in homozygosity for known gene mutations. Uncovering novel regions of aUPD has the potential to identify previously unknown mutational targets. We therefore aimed to develop a map of the regions of aUPD in AML. Here, we have analyzed a large set of diagnostic AML samples (n = 454) from young adults (age: 15-55 years) using genotype arrays. Acquired UPD was found in 17% of the samples with a nonrandom distribution particularly affecting chromosome arms 13q, 11p, and 11q. Novel recurrent regions of aUPD were uncovered at 2p, 17p, 2q, 17q, 1p, and Xq. Overall, aUPDs were observed across all cytogenetic risk groups, although samples with aUPD13q (5.4% of samples) belonged exclusively to the intermediate-risk group as defined by cytogenetics. All cases with a high FLT3-ITD level, measured previously, had aUPD13q covering the FLT3 gene. Significantly, none of the samples with FLT3-ITD(-)/FLT3-TKD(+) mutation exhibited aUPD13q. Of the 119 aUPDs observed, the majority (87%) were due to mitotic recombination while only 13% were due to nondisjunction. This study demonstrates aUPD is a frequent and significant finding in AML and pinpoints regions that may contain novel mutational targets.
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association between acquired Uniparental Disomy and homozygous gene mutation in acute myeloid leukemias
Cancer Research, 2005Co-Authors: Jude Fitzgibbon, Lanlan Smith, Manoj Raghavan, Matthew L Smith, Silvana Debernardi, Spyros Skoulakis, Debra M Lillington, Andrew T Lister, Bryan D YoungAbstract:Genome-wide single nucleotide polymorphism analysis has revealed large-scale cryptic regions of acquired homozygosity in the form of segmental Uniparental Disomy in approximately 20% of acute myeloid leukemias. We have investigated whether such regions, which are the consequence of mitotic recombination, contain homozygous mutations in genes known to be mutational targets in leukemia. In 7 of 13 cases with Uniparental Disomy, we identified concurrent homozygous mutations at four distinct loci (WT1, FLT3, CEBPA, and RUNX1). This implies that mutation precedes mitotic recombination which acts as a "second hit" responsible for removal of the remaining wild-type allele, as has recently been shown for the JAK2 gene in myeloproliferative disorders.
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genomewide single nucleotide polymorphism microarray mapping in basal cell carcinomas unveils Uniparental Disomy as a key somatic event
Cancer Research, 2005Co-Authors: Muyteck Teh, Manoj Raghavan, Spyros Skoulakis, Diana C Blaydon, Tracy Chaplin, Nicola J Foot, C A Harwood, Charlotte M Proby, Michael P Philpott, Bryan D YoungAbstract:Basal cell carcinoma is the most common human cancer with increasing incidence reported worldwide. Despite the aberrant signaling role of the Hedgehog pathway, little is known about the genetic mechanisms underlying basal cell carcinomas. Towards a better understanding of global genetic events, we have employed the Affymetrix Mapping 10K single nucleotide polymorphism (SNP) microarray technique for "fingerprinting" genomewide allelic imbalance in 14 basal cell carcinoma-blood pair samples. This rapid high-resolution SNP genotyping technique has revealed a somatic recombination event-Uniparental Disomy, leading to a loss of heterozygosity (LOH), as a key alternative genetic mechanism to allelic imbalances in basal cell carcinomas. A highly conserved LOH region at 9q21-q31 was found in 13 of 14 (93%) basal cell carcinomas. Further statistical and fluorescence in situ hybridization analyses confirmed that the 9q LOH was a result of Uniparental Disomy in 5 of 13 (38%) basal cell carcinomas. De novo mutations in the Patched 1 gene (PTCH) were found in 9 of 13 (69%) basal cell carcinomas with 9q LOH. A second important locus, containing LOH at 6q23-q27 was found in 5 of 14 (36%) basal cell carcinomas, suggesting that the presence of an additional putative tumor suppressor gene may be contributing to basal cell carcinoma development. This study shows that the rate of 9q LOH in basal cell carcinomas has been previously underestimated. Furthermore, we provide the first evidence that Uniparental Disomy due to somatic recombination constitutes one of the mechanisms of LOH in basal cell carcinoma tumorigenesis.
Lisa G Shaffer - One of the best experts on this subject based on the ideXlab platform.
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risk estimates for Uniparental Disomy following prenatal detection of a nonhomologous robertsonian translocation
Prenatal Diagnosis, 2006Co-Authors: Lisa G ShafferAbstract:Carriers of nonhomologous Robertsonian translocations (ROB) are at risk for having offspring with Uniparental Disomy (UPD). Although risk estimates have been calculated in several independent studies, the estimates have not been optimal because most studies are not of sufficient size and UPD events are rare. However, these collective data have provided the opportunity to derive an overall risk estimate for UPD in the fetus after the prenatal identification of a ROB.
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epigenetic detection of human chromosome 14 Uniparental Disomy
Human Mutation, 2003Co-Authors: Susan K Murphy, Philip D. Cotter, Lisa G Shaffer, Andrew A Wylie, Karen J Coveler, P R Papenhausen, V R Sutton, Randy L JirtleAbstract:The recent demonstration of genomic imprinting of DLK1 and MEG3 on human chromosome 14q32 indicates that these genes might contribute to the discordant phenotypes associated with Uniparental Disomy (UPD) of chromosome 14. Regulation of imprinted expression of DLK1 and MEG3 involves a differentially methylated region (DMR) that encompasses the MEG3 promoter. We exploited the normal differential methylation of the DLK1/MEG3 region to develop a rapid diagnostic PCR assay based upon an individual's epigenetic profile. We used methylation-specific multiplex PCR in a retrospective analysis to amplify divergent lengths of the methylated and unmethylated MEG3 DMR in a single reaction and accurately identified normal, maternal UPD14, and paternal UPD14 in bisulfite converted DNA samples. This approach, which is based solely on differential epigenetic profiles, may be generally applicable for rapidly and economically screening for other imprinting defects associated with Uniparental Disomy, determining loss of heterozygosity of imprinted tumor suppressor genes, and identifying gene-specific hypermethylation events associated with neoplastic progression.
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american college of medical genetics statement on diagnostic testing for Uniparental Disomy
Genetics in Medicine, 2001Co-Authors: Lisa G Shaffer, David H Ledbetter, Noelle Agan, James D Goldberg, John W Longshore, Suzanne B CassidyAbstract:American College of Medical Genetics Statement on Diagnostic Testing for Uniparental Disomy
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Identification of Uniparental Disomy following prenatal detection of Robertsonian translocations and isochromosomes.
American Journal of Human Genetics, 2000Co-Authors: Sue Ann Berend, Christopher Mccaskill, Juli Horwitz, Lisa G ShafferAbstract:Rearrangements of the acrocentric chromosomes (Robertsonian translocations and isochromosomes) are associated with an increased risk of aneuploidy. Given this, and the large number of reported cases of Uniparental Disomy (UPD) associated with an acrocentric rearrangement, carriers are presumed to be at risk for UPD. However, an accurate risk estimate for UPD associated with these rearrangements is lacking. A total of 174 prenatally identified acrocentric rearrangements, including both Robertsonian translocations and isochromosomes, were studied prospectively to identify UPD for the chromosomes involved in the rearrangements. The overall goal of the study was to provide an estimate of the risk of UPD associated with nonhomologous Robertsonian translocations and homologous acrocentric rearrangements. Of the 168 nonhomologous Robertsonian translocations studied, one showed UPD for chromosome 13, providing a risk estimate of 0.6%. Four of the six homologous acrocentric rearrangements showed UPD, providing a risk estimate of 66%. These cases have also allowed delineation of the mechanisms involved in producing UPD unique to Robertsonian translocations. Given the relatively high risk for UPD in prenatally identified Robertsonian translocations and isochromosomes, UPD testing should be considered, especially for cases involving the acrocentric chromosomes 14 and 15, in which UPD is associated with adverse clinical outcomes.
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identification of a case of maternal Uniparental Disomy of chromosome 10 associated with confined placental mosaicism
Prenatal Diagnosis, 1995Co-Authors: Carrie Jones, Rhonda Spiro, Carol Booth, Debra Rita, Lydia Jazmines, Brian Mcculloch, Christopher Mccaskill, Lisa G ShafferAbstract:We report a case of maternal Uniparental Disomy of chromosome 10 discovered after chorionic villus sampling (CVS). Direct preparations revealed mosaic trisomy 10, while cultured CVS cells, as well as amniotic fluid cells, showed only a normal 46,XY complement. DNA analysis using microsatellite markers showed both chromosomes 10 to have been inherited from the mother. The pregnancy was complicated by polyhydramnios. A phenotypically normal male infant of appropriate size was delivered by Caesarean section at 41 weeks' gestation. Since only the direct preparations showed trisomy 10, this case illustrates the importance of CVS direct preparations in the detection of pregnancies at risk of Uniparental Disomy (UPD). Although the increased frequency of confined placental mosaicism (CPM) diagnosed when direct preparations are performed has been viewed negatively, identification of both CPM and UPD may have biological and clinical significance for a pregnancy. Even though only a single case of maternal Disomy 10 is reported here, the apparently normal phenotype provides evidence that there are no major imprinted loci on chromosome 10 that affect in utero growth and development. However, other potential effects such as mental retardation will require long-term follow-up of this as well as additional cases.
Denise A S Batista - One of the best experts on this subject based on the ideXlab platform.
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myoclonus dystonia and silver russell syndrome resulting from maternal Uniparental Disomy of chromosome 7
Clinical Genetics, 2013Co-Authors: Molly Sheridan, Bytyci A Telegrafi, V Stinnett, Cc Umeh, Zoltan Mari, Ted M Dawson, Joann N Bodurtha, Denise A S BatistaAbstract:Myoclonus-dystonia (M-D) is a movement disorder that is often associated with mutations in epsilon-sarcoglycan (SGCE), a maternally imprinted gene at 7q21.3. We report a 24-year-old male with short stature (<5th percentile) and a movement disorder clinically consistent with M-D. Single nucleotide polymorphism (SNP) array did not identify significant copy number changes, but revealed three long continuous stretches of homozygosity on chromosome 7 suggestive of Uniparental Disomy. Parental SNP arrays confirmed that the proband had maternal Uniparental Disomy of chromosome 7 (mUPD7) with regions of heteroDisomy and isoDisomy. mUPD7 is the cause of approximately 5–10% of Silver–Russell syndrome (SRS), a disorder characterized by prenatal and postnatal growth retardation. Although SRS was not suspected in our patient, these findings explain his short stature. SGCE methylation testing showed loss of the unmethylated paternal allele. Our findings provide a unifying diagnosis for his short stature and M-D and help to optimize his medication regimen. In conclusion, we show that M-D is a clinical feature that may be associated with SRS due to mUPD7. Individuals with mUPD7 should be monitored for the development of movement disorders. Conversely, individuals with M-D and short stature should be evaluated for SRS.
