Uniparental Disomy Causing Myoclonus Dystonia Associated with Russell Silver Syndrome.
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ABSTRACT:
SUBMITTER: Shpiner DS
PROVIDER: S-EPMC6592828 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC3657309 | biostudies-literature
Project description: Not available
| S-EPMC4643854 | biostudies-literature
Project description:We describe a patient presenting with argininosuccinic aciduria and Silver-Russell syndrome (SRS). SRS was caused by maternal uniparental disomy of chromosome 7 (UPD(7)mat). UPD(7)mat also unmasked a maternally inherited splicing variant in ASL on chromosome 7, leading to the onset of argininosuccinic aciduria. The phenotype of the present case was more severe than that of a previous case, demonstrating a phenotypic variation in the combination of argininosuccinic aciduria and SRS.
| S-EPMC9468177 | biostudies-literature
Project description:ObjectiveSilver-Russell syndrome (SRS) is a clinically and genetically heterogeneous syndrome which is characterized by severe intrauterine and postnatal growth retardation, and typical characteristic facial dysmorphisms. It has been associated with maternal uniparental disomy (UPD) for chromosome 7 and hypomethylation of imprinting control region 1 (IGF2/H19) in 11p15. UPD refers to the situation in which both copies of a chromosome pair have originated from one parent. UPD can be presented both as partial heterodisomy and isodisomy. The aim of this study was to determine the maternal UPD7 (matUPD7) in 13 Turkish SRS patients.MethodsGenotyping for matUPD7 was performed with microsatellite markers by polymerase chain reaction.FindingsThe maternal UPD7 including the entire chromosome was identified in 1/13 (7.6%) of individuals within SRS patients. There were no significant differences between clinical features of matUPD7 case and other SRS cases except congenital heart defects.ConclusionIt is often difficult to establish diagnosis of a child with intrauterine growth retardation (IUGR), growth failure and dysmorphic features. Thus, screening for matUPD7 in IUGR children with growth failure and mild SRS features might be a valuable diagnostic tool.
| S-EPMC3533142 | biostudies-literature
Project description:Maternal uniparental disomy of chromosome 7 (matUPD7), the inheritance of both chromosomes from only the mother, is observed in approximately 10% of patients with Silver-Russell syndrome (SRS). It has been suggested that at least one imprinted gene that regulates growth and development resides on human chromosome 7. To date, three imprinted genes-PEG1/MEST, gamma2-COP, and GRB10-have been identified on chromosome 7, but their role in the etiology of SRS remains uncertain. In a systematic screening with microsatellite markers, for matUPD7 cases among patients with SRS, we identified a patient who had a small segment of matUPD7 and biparental inheritance of the remainder of chromosome 7. Such a pattern may be explained by somatic recombination in the zygote. The matUPD7 segment at 7q31-qter extends for 35 Mb and includes the imprinted gene cluster of PEG1/MEST and gamma2-COP at 7q32. GRB10 at 7p11.2-p12 is located within a region of biparental inheritance. Although partial UPD has previously been reported for chromosomes 6, 11, 14, and 15, this is the first report of a patient with SRS who has segmental matUPD7. Our findings delimit a candidate imprinted region sufficient to cause SRS.
| S-EPMC1234921 | biostudies-literature
Project description:BackgroundSilver-Russell syndrome (SRS) is a growth retardation disorder with a very broad molecular and clinical spectrum. Whereas the association of SRS with imprinting disturbances of chromosomes 11p15.5 and 7 is generally accepted, there are controversial discussions on the involvement of other molecular changes. The recent reports on the occurrence of maternal uniparental disomies of chromosomes 6, 16 and 20 (upd(6, 16, 20)mat), as well as 14q32 imprint alterations in patients with SRS phenotypes raise the question on the involvement of these mutations in the etiology of SRS.MethodsA cohort of 54 growth retarded patients with SRS features was screened for aberrant methylation patterns of chromsomes 6, 14, 16 and 20.ResultsOne carrier of a 14q32 epimutation was identified whereas epimutations and maternal UPD for chromosomes 6, 16 and 20 were excluded.ConclusionsOur data and those from the literature confirm that 14q32 disturbances significantly contribute to the mutation spectrum in this cohort. Furthermore, maternal uniparental disomy of chromosomes 6, 16 and 20 can be observed, but are rare. In case they occur they can be regarded as causative for clinical features.
| S-EPMC4787016 | biostudies-literature
Project description:Silver Russell Syndrome (SRS, MIM #180860) is a rare growth retardation disorder in which clinical diagnosis is based on six features: pre- and postnatal growth failure, relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties (Netchine-Harbison clinical scoring system (NH-CSS)). The molecular mechanisms consist in (epi)genetic deregulations at multiple loci: the loss of methylation (LOM) at the paternal H19/IGF2:IG-DMR (chr11p15.5) (50%) and the maternal uniparental disomy of chromosome 7 (UPD(7)mat) (10%) are the most frequent causes. Thus far, about 40% of SRS remains undiagnosed, pointing to the need to define the rare mechanisms in such a consistent fraction of unsolved patients. Within a cohort of 176 SRS with an NH-CSS ≥ 3, a molecular diagnosis was disclosed in about 45%. Among the remaining patients, we identified in 3 probands (1.7%) with UPD(20)mat (Mulchandani-Bhoj-Conlin syndrome, OMIM #617352), a molecular mechanism deregulating the GNAS locus and described in 21 cases, characterized by severe feeding difficulties associated with failure to thrive, preterm birth, and intrauterine/postnatal growth retardation. Our patients share prominent forehead, feeding difficulties, postnatal growth delay, and advanced maternal age. Their clinical assessment and molecular diagnostic flowchart contribute to better define the characteristics of this rare imprinting disorder and to rank UPD(20)mat as the fourth most common pathogenic molecular defect causative of SRS.
| S-EPMC8073552 | biostudies-literature
Project description:BACKGROUND:Pathogenic CDKN1C gain-of-function variants on the maternal allele were initially reported as a cause of IMAGe syndrome characterized by intrauterine growth retardation, metaphyseal dysplasia, primary adrenal insufficiency and genital anomalies. Recently, a maternally inherited CDKN1C missense mutation (p.Arg279Leu) was identified in several members of a single family clinically diagnosed with Silver-Russell syndrome (SRS) but without adrenal insufficiency. Thereafter, two half siblings from UK with familial SRS were described who carried the same mutation. This specific amino acid change is located within a narrow functional region containing the mutations previously associated with IMAGe syndrome. RESULTS:Here, we describe a third familial case with maternally inherited SRS due to a missense variant affecting the same amino acid position 279 but leading to a different amino acid substitution (p. (Arg279Ser)). The two affected family members (mother and son) presented with the complete SRS phenotype (both Netchine-Harbison CSS score 5 of 6) but without body asymmetry or adrenal insufficiency. CONCLUSIONS:In comparison with loss-of-function genomic IGF2 mutations, CDKN1C gain-of-function mutations are a less frequent cause of SRS and seem to affect a cluster of few amino acids.
| S-EPMC7574352 | biostudies-literature
Project description:Robertsonian translocations (ROBs) are whole arm rearrangements involving the acrocentric chromosomes 13-15 and 21-22 and carriers are at increased risk for aneuploidy and thus uniparental disomy (UPD). Chromosomes 14 and 15 are imprinted with expression of genes dependent on the parental origin of the chromosome. Correction of a trisomic or monosomic conceptus for chromosomes 14 or 15 would lead to one of the established UPD 14mat/pat or UPD 15 (Prader-Willi/Angelman) syndromes (PWS/AS). In view of this, prenatal UPD testing should be considered for balanced carriers of a ROB, fetuses with a familial or de novo balanced ROB that contains chromosome 14 or 15 or with a normal karyotype when a parent is a carrier of a balanced ROB with a 14 or 15. Individuals with congenital anomalies and an abnormal phenotype and carry a ROB involving the two imprinted chromosomes should also be UPD tested.
| S-EPMC4729106 | biostudies-literature
Project description:BackgroundMany cases of myoclonus-dystonia (M-D) are due to mutations in SGCE (DYT11). For the majority of patients, myoclonus is relatively more severe than dystonia and can lead to significant functional disability. Deep brain stimulation has been chosen as a treatment option in some patients given that M-D often responds poorly to oral pharmacotherapy.MethodsTwo siblings with M-D due to the same SGCE deletion mutation were evaluated with the Global Dystonia Rating Scale (GDRS), Fahn-Marsden Rating Scale (FM) and Unified Myoclonus Rating Scale (UMRS) on and off tetrabenazine.ResultsBoth subjects showed marked improvement in myoclonus and mild-to-moderate improvement in dystonia with tetrabenazine. In addition, the response to tetrabenazine has been sustained for years.ConclusionsA therapeutic trial of tetrabenazine should be considered in patients with M-D, especially before consideration of deep brain stimulation. An adequately powered multi-center, double-blind study of tetrabenazine will be required to determine the relative contributions of tetrabenazine therapy to myoclonus, dystonia, quality of life, and activities of daily living in patients with M-D.
| S-EPMC4254189 | biostudies-literature