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Maternal Uniparental Disomy of Chromosome 20 (UPD(20)mat) as Differential Diagnosis of Silver Russell Syndrome: Identification of Three New Cases.

ABSTRACT: 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.

SUBMITTER: Tannorella P

PROVIDER: S-EPMC8073552 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Maternal uniparental disomy of chromosome 7 underlying argininosuccinic aciduria and Silver-Russell syndrome.

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

The maternal uniparental disomy of chromosome 6 (upd(6)mat) "phenotype": result of placental trisomy 6 mosaicism?

Project description:BACKGROUND:Maternal uniparental disomy of chromosome 6 (upd(6)mat) is a rare finding and its clinical relevance is currently unclear. Based on clinical data from two new cases and patients from the literature, the pathogenetic significance of upd(6)mat is delineated. METHODS:Own cases were molecularly characterized for isodisomic uniparental regions on chromosome 6. For further cases with upd(6)mat, a literature search was conducted and genetic and clinical data were ascertained. RESULTS:Comparison of isodisomic regions between the new upd(6)mat cases and those from four reports did not reveal any common isodisomic region. Among the patients with available cytogenetic data, five had a normal karyotype in lymphocytes, whereas a trisomy 6 (mosaicism) was detected prenatally in four cases. A common clinical picture was not obvious in upd(6)mat, but intrauterine growth restriction (IUGR) and preterm delivery were frequent. CONCLUSION:A common upd(6)mat phenotype is not obvious, but placental dysfunction due to trisomy 6 mosaicism probably contributes to IUGR and preterm delivery. In fact, other clinical features observed in upd(6)mat patients might be caused by homozygosity of recessive mutations or by an undetected trisomy 6 cell line. Upd(6)mat itself is not associated with clinical features, and can rather be regarded as a biomarker. In case upd(6)mat is detected, the cause for the phenotype is identified indirectly, but the UPD is not the basic cause.

| S-EPMC5702562 | biostudies-literature

Myoclonus-dystonia and Silver-Russell syndrome resulting from maternal uniparental disomy of chromosome 7.

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

Mosaic Segmental and Whole-Chromosome Upd(11)mat in Silver-Russell Syndrome.

Project description:Molecular defects altering the expression of the imprinted genes of the 11p15.5 cluster are responsible for the etiology of two congenital disorders characterized by opposite growth disturbances, Silver-Russell syndrome (SRS), associated with growth restriction, and Beckwith-Wiedemann syndrome (BWS), associated with overgrowth. At the molecular level, SRS and BWS are characterized by defects of opposite sign, including loss (LoM) or gain (GoM) of methylation at the H19/IGF2:intergenic differentially methylated region (H19/IGF2:IG-DMR), maternal or paternal duplication (dup) of 11p15.5, maternal (mat) or paternal (pat) uniparental disomy (upd), and gain or loss of function mutations of CDKN1C. However, while upd(11)pat is found in 20% of BWS cases and in the majority of them it is segmental, upd(11)mat is extremely rare, being reported in only two SRS cases to date, and in both of them is extended to the whole chromosome. Here, we report on two novel cases of mosaic upd(11)mat with SRS phenotype. The upd is mosaic and isodisomic in both cases but covers the entire chromosome in one case and is restricted to 11p14.1-pter in the other case. The segmental upd(11)mat adds further to the list of molecular defects of opposite sign in SRS and BWS, making these two imprinting disorders even more specular than previously described.

| S-EPMC8073375 | biostudies-literature

First genetic screening for maternal uniparental disomy of chromosome 7 in Turkish silver-russell syndrome patients.

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

Examinations of maternal uniparental disomy and epimutations for chromosomes 6, 14, 16 and 20 in Silver-Russell syndrome-like phenotypes.

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

Mosaic UPD(7q)mat in a patient with silver Russell syndrome.

Project description:BACKGROUND:Silver-Russell syndrome (SRS) is one of the imprinting disorders characterized by prenatal and postnatal growth restriction, relative macrocephaly, body asymmetry and characteristic facial features. ~ 10% of SRS cases are known to be associated with maternal uniparental disomy of chromosome 7 (UPD(7)mat). Mosaic maternal segmental UPD of 7q (UPD(7q)mat) is very rare, had only been described in one case before. CASE PRESENTATION:We reported a second case of mosaic segmental UPD involving 7q. The patient presented with dysmorphic features including thin and short stature, triangular face, moderate protruding forehead, relative macrocephaly, fifth toe clinodactyly and irregular teeth, meeting the clinical diagnosed criteria of SRS. This case indicated that ~ 80% of mosaic UPD(7q)mat lead to the manifestation of main phenotypes of Silver-Russell syndrome. CONCLUSIONS:Our case support the notion that there are genes control postnatal growth on long arm of chromosome 7 and indicate that ~ 80% of UPD(7q)mat mosaicism level was contributed to the SRS phenotype.

| S-EPMC5645907 | biostudies-literature

A narrow segment of maternal uniparental disomy of chromosome 7q31-qter in Silver-Russell syndrome delimits a candidate gene region.

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.

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Uniparental Disomy Causing Myoclonus Dystonia Associated with Russell Silver Syndrome.

Project description: Not available

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Cytogenetic contribution to uniparental disomy (UPD).

Project description:Uniparental disomy (UPD) is often considered as an event to be characterized exclusively by molecular genetic or epigenetic approaches. This review shows that at least one third of UPD cases emerge in connection with or due to a chromosomal rearrangement. Thus, additional (molecular) cytogenetic characterization of UPD cases is essential. Up to now > 1,100 UPD cases detected in clinical, non-tumor cases are reported in the literature. Recently, these cases were summarized in a regularly updated, freely available online database http://www.med.uni-jena.de/fish/sSMC/00START-UPD.htm. Based of this, here the presently known imprinting syndromes, the chromosomal contribution to UPD phenomenon, and the cytogenetic subgroups of UPD, including cases with normal, abnormal balanced or unbalanced karyotype (like e.g. small supernumerary marker chromosomes and Robertsonian translocations) and segmental UPD are reviewed. Furthermore, chromosome fragmentation as a possible mechanism of trisomic rescue is discussed, which might help to explain the observed 1:9 rate of maternal versus paternal UPD present in cases with original trisomic karyotypes. Overall, as UPD is more but an interesting rarity, the genetic background of each "UPD-patient" needs to be characterized besides by molecular methods, also by molecular cytogenetics in detail.

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