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Thomas Eggermann - One of the best experts on this subject based on the ideXlab platform.

  • Epigenetic and genetic diagnosis of Silver–Russell Syndrome
    Expert Review of Molecular Diagnostics, 2020
    Co-Authors: Thomas Eggermann, Matthias Begemann, Sabrina Spengler, Magdalena Gogiel, Miriam Elbracht
    Abstract:

    Silver–Russell Syndrome (SRS) is a congenital imprinting disorder characterized by intrauterine and postnatal growth restriction and further characteristic features. SRS is genetically heterogenous: 7–10% of patients carry a maternal uniparental disomy of chromosome 7; >38% show a hypomethylation in imprinting control region 1 in 11p15; and a further class of mutations are copy number variations affecting different chromosomes, but mainly 11p15 and 7. The diagnostic work-up should thus aim to detect these three molecular subtypes. Numerous techniques are currently applied in genetic SRS testing, but none of them covers all known (epi)mutations, and they should therefore be used synergistically. However, future next-generation sequencing approaches will allow a comprehensive analysis of all types of alterations in SRS.

  • Diagnostic proceeding in Silver-Russell Syndrome.
    Molecular Diagnosis, 2020
    Co-Authors: Thomas Eggermann, Esther Meyer, Michael B. Ranke, Martin Holder, Stefanie Spranger, Klaus Zerres, Hartmut A. Wollmann
    Abstract:

    Background: Silver-Russell Syndrome (SRS) describes a uniform malformation Syndrome characterized by pre- and postnatal growth restriction (

  • microdeletions of the 7q32 2 imprinted region are associated with Silver Russell Syndrome features
    American Journal of Medical Genetics Part A, 2016
    Co-Authors: Ignacio Arroyo Carrera, Matthias Begemann, María Solo De Zaldívar, Rebeca Martín, Lukas Soellner, Thomas Eggermann
    Abstract:

    The association of maternal uniparental disomy of human chromosome 7 (upd(7) mat) and the growth retardation disorder Silver–Russell Syndrome (SRS) is well established, but the causative gene or region is currently unknown. However, several observations indicate that molecular alterations of the genomically imprinted MEST region in 7q32.2 are associated with growth retardation and a phenotype reminiscent to SRS. We now report on a second patient with a similar phenotype and a de novo 7q32.2 microdeletion including MEST affecting the paternal allele. This confirms the central role of imprinted genes in 7q32.2 in the etiology of a growth retardation phenotype associated with SRS features. © 2015 Wiley Periodicals, Inc.

  • Microdeletions of the 7q32.2 imprinted region are associated with Silver–Russell Syndrome features
    American Journal of Medical Genetics Part A, 2015
    Co-Authors: Ignacio Arroyo Carrera, Matthias Begemann, María Solo De Zaldívar, Rebeca Martín, Lukas Soellner, Thomas Eggermann
    Abstract:

    The association of maternal uniparental disomy of human chromosome 7 (upd(7) mat) and the growth retardation disorder Silver–Russell Syndrome (SRS) is well established, but the causative gene or region is currently unknown. However, several observations indicate that molecular alterations of the genomically imprinted MEST region in 7q32.2 are associated with growth retardation and a phenotype reminiscent to SRS. We now report on a second patient with a similar phenotype and a de novo 7q32.2 microdeletion including MEST affecting the paternal allele. This confirms the central role of imprinted genes in 7q32.2 in the etiology of a growth retardation phenotype associated with SRS features. © 2015 Wiley Periodicals, Inc.

  • epigenetic and genetic diagnosis of Silver Russell Syndrome
    Expert Review of Molecular Diagnostics, 2012
    Co-Authors: Thomas Eggermann, Matthias Begemann, Sabrina Spengler, Magdalena Gogiel, Miriam Elbracht
    Abstract:

    Silver–Russell Syndrome (SRS) is a congenital imprinting disorder characterized by intrauterine and postnatal growth restriction and further characteristic features. SRS is genetically heterogenous: 7–10% of patients carry a maternal uniparental disomy of chromosome 7; >38% show a hypomethylation in imprinting control region 1 in 11p15; and a further class of mutations are copy number variations affecting different chromosomes, but mainly 11p15 and 7. The diagnostic work-up should thus aim to detect these three molecular subtypes. Numerous techniques are currently applied in genetic SRS testing, but none of them covers all known (epi)mutations, and they should therefore be used synergistically. However, future next-generation sequencing approaches will allow a comprehensive analysis of all types of alterations in SRS.

Horacio Rivera - One of the best experts on this subject based on the ideXlab platform.

  • Severe Silver‐Russell Syndrome and translocation (17;20) (q25;q13)
    Clinical Genetics, 2008
    Co-Authors: M. L. Ramirez-dueñas, C. Medina, R. Ocampo-campos, Horacio Rivera
    Abstract:

    Ramirez-Duenas ML, Medina C, Ocampo-Campos R, Rivera H. Severe Silver-Russell Syndrome and translocation (17;20)(q25;q13). Clin Genet 1992:41: 51–53. An 8-year-8-month-old girl with Silver-Russell Syndrome (SRS) and a paternally inherited balanced t(17;20)(q25;q13) is described. This observation suggests that an SRS gene(s) maps on chromosome 17 or 20 and that the patient phenotype resulted from either unmasking of heteroz-ygosity or genomic imprinting via paternal disomy.

  • severe Silver Russell Syndrome and translocation 17 20 q25 q13
    Clinical Genetics, 2008
    Co-Authors: M L Ramirezduenas, C. Medina, R Ocampocampos, Horacio Rivera
    Abstract:

    Ramirez-Duenas ML, Medina C, Ocampo-Campos R, Rivera H. Severe Silver-Russell Syndrome and translocation (17;20)(q25;q13). Clin Genet 1992:41: 51–53. An 8-year-8-month-old girl with Silver-Russell Syndrome (SRS) and a paternally inherited balanced t(17;20)(q25;q13) is described. This observation suggests that an SRS gene(s) maps on chromosome 17 or 20 and that the patient phenotype resulted from either unmasking of heteroz-ygosity or genomic imprinting via paternal disomy.

Emma L Wakeling - One of the best experts on this subject based on the ideXlab platform.

  • Silver–Russell Syndrome
    Archives of Disease in Childhood, 2011
    Co-Authors: Emma L Wakeling
    Abstract:

    Silver–Russell Syndrome (SRS) is characterised by intrauterine growth restriction, poor postnatal growth, relative macrocephaly, triangular face, asymmetry and feeding difficulties. As many of these features are non-specific, clinical diagnosis of SRS remains difficult. Hypomethylation of the imprinting control region (ICR) 1 on chromosome 11p15 and maternal uniparental disomy (mUPD) for chromosome 7 are found in up to 60% and around 5–10% of patients with SRS, respectively. Patients with ICR1 hypomethylation are more likely to have classical features of SRS, including asymmetry; patients with mUPD7 are more likely to have learning difficulties, particularly speech problems, although these are usually mild. As features vary widely in severity, clinicians should have a low threshold for genetic investigation of patients with features suggestive of SRS.

  • Silver Russell Syndrome
    Archives of Disease in Childhood, 2011
    Co-Authors: Emma L Wakeling
    Abstract:

    Silver–Russell Syndrome (SRS) is characterised by intrauterine growth restriction, poor postnatal growth, relative macrocephaly, triangular face, asymmetry and feeding difficulties. As many of these features are non-specific, clinical diagnosis of SRS remains difficult. Hypomethylation of the imprinting control region (ICR) 1 on chromosome 11p15 and maternal uniparental disomy (mUPD) for chromosome 7 are found in up to 60% and around 5–10% of patients with SRS, respectively. Patients with ICR1 hypomethylation are more likely to have classical features of SRS, including asymmetry; patients with mUPD7 are more likely to have learning difficulties, particularly speech problems, although these are usually mild. As features vary widely in severity, clinicians should have a low threshold for genetic investigation of patients with features suggestive of SRS.

  • epigenotype phenotype correlations in Silver Russell Syndrome
    Journal of Medical Genetics, 2010
    Co-Authors: Emma L Wakeling, Deborah J.g. Mackay, Abu S Amero, Marielle Alders, Jet Bliek, E Forsythe, Sudhesh Kumar, Fiona Macdonald, Eamonn R Maher
    Abstract:

    Background Silver-Russell Syndrome (SRS) is characterised by intrauterine growth restriction, poor postnatal growth, relative macrocephaly, triangular face and asymmetry. Maternal uniparental disomy (mUPD) of chromosome 7 and hypomethylation of the imprinting control region (ICR) 1 on chromosome 11p15 are found in 5-10% and up to 60% of patients with SRS, respectively. As many features are non-specific, diagnosis of SRS remains difficult. Studies of patients in whom the molecular diagnosis is confirmed therefore provide valuable clinical information on the condition. Methods A detailed, prospective study of 64 patients with mUPD7 (n=20) or ICR1 hypomethylation (n=44) was undertaken. Results and conclusions The considerable overlap in clinical phenotype makes it difficult to distinguish these two molecular subgroups reliably. ICR1 hypomethylation was more likely to be scored as 'classical' SRS. Asymmetry, fifth finger clinodactyly and congenital anomalies were more commonly seen with ICR1 hypomethylation, whereas learning difficulties and referral for speech therapy were more likely with mUPD7. Myoclonus-dystonia has been reported previously in one mUPD7 patient. The authors report mild movement disorders in three further cases. No correlation was found between clinical severity and level of ICR1 hypomethylation. Use of assisted reproductive technology in association with ICR1 hypomethylation seems increased compared with the general population. ICR1 hypomethylation was also observed in affected siblings, although recurrence risk remains low in the majority of cases. Overall, a wide range of severity was observed, particularly with ICR1 hypomethylation. A low threshold for investigation of patients with features suggestive, but not typical, of SRS is therefore recommended.

  • Epigenotype–phenotype correlations in Silver–Russell Syndrome
    Journal of Medical Genetics, 2010
    Co-Authors: Emma L Wakeling, Deborah J.g. Mackay, Marielle Alders, Jet Bliek, E Forsythe, Sudhesh Kumar, Fiona Macdonald, S Abu Amero, Eamonn R Maher
    Abstract:

    Background Silver-Russell Syndrome (SRS) is characterised by intrauterine growth restriction, poor postnatal growth, relative macrocephaly, triangular face and asymmetry. Maternal uniparental disomy (mUPD) of chromosome 7 and hypomethylation of the imprinting control region (ICR) 1 on chromosome 11p15 are found in 5-10% and up to 60% of patients with SRS, respectively. As many features are non-specific, diagnosis of SRS remains difficult. Studies of patients in whom the molecular diagnosis is confirmed therefore provide valuable clinical information on the condition. Methods A detailed, prospective study of 64 patients with mUPD7 (n=20) or ICR1 hypomethylation (n=44) was undertaken. Results and conclusions The considerable overlap in clinical phenotype makes it difficult to distinguish these two molecular subgroups reliably. ICR1 hypomethylation was more likely to be scored as 'classical' SRS. Asymmetry, fifth finger clinodactyly and congenital anomalies were more commonly seen with ICR1 hypomethylation, whereas learning difficulties and referral for speech therapy were more likely with mUPD7. Myoclonus-dystonia has been reported previously in one mUPD7 patient. The authors report mild movement disorders in three further cases. No correlation was found between clinical severity and level of ICR1 hypomethylation. Use of assisted reproductive technology in association with ICR1 hypomethylation seems increased compared with the general population. ICR1 hypomethylation was also observed in affected siblings, although recurrence risk remains low in the majority of cases. Overall, a wide range of severity was observed, particularly with ICR1 hypomethylation. A low threshold for investigation of patients with features suggestive, but not typical, of SRS is therefore recommended.

  • epigenetic signatures of Silver Russell Syndrome
    Journal of Medical Genetics, 2010
    Co-Authors: Sayeda Abuamero, Philip Stanier, Emma L Wakeling, Mike Preece, John C Whittaker, G.E. Moore
    Abstract:

    Silver–Russell Syndrome (SRS) (OMIM 180860) has been recognised as a clinical entity since the 1950s; however, a molecular genetic cause remained unknown until 1997 when maternal uniparental disomy for chromosome 7 (mUPD7) was found in approximately 10% of affected individuals. The focus then turned to the identification of causative imprinted genes on chromosome 7. Over the next 10 years many of the potential candidate genes identified on chromosome 7 as well as many imprinted loci elsewhere were excluded.1–13 However, in 2006, Gicquel et al identified a major role in the aetiology of SRS for the chromosome 11p15.5 region.14–16 This work, and a succession of comparative, detailed and confirmatory studies, demonstrated an epigenetic signature of hypomethylation at the 11p15.5 imprinting control region 1 (ICR1) in 30–60% of SRS probands (table 1). Here the H19 differentially methylated domain ( H19 DMD) regulates the methylation and therefore respective maternal or paternal expression of H19 and insulin-like growth factor 2 ( IGF2 ) genes. View this table: Table 1 Summary of literature on hypomethylation status in SRS patients Hypomethylation at ICR1 causes epigenetic dysregulation of H19 and IGF2 , ultimately resulting in reduced expression of IGF2 and potentially phenotypic growth restriction. Interestingly, the degree of hypomethylation was also found to correlate with the severity of the growth phenotype as well as additional SRS diagnostic features. In comparison, patients with mUPD7 were clinically distinguishable displaying a noticeably milder phenotype. Since then, the literature includes a number of detailed clinical evaluations with the aim of developing a clinical scoring system to help characterise specific subgroups of SRS caused by mUPD7, hypomethylation of 11p15.5 or those with an …

Nadine Schonherr - One of the best experts on this subject based on the ideXlab platform.

  • Molecular Analyses of the BORIS Gene in Children with Silver-Russell Syndrome
    International Journal of Human Genetics, 2009
    Co-Authors: Magdalena Gogiel, Gerhard Binder, Sabrina Spengler, Nadine Schonherr, Isabelle Leisten, Gesa Schwanitz, Alina T. Midro, Thomas Eggermann
    Abstract:

    KEYWORDS Silver-Russell Syndrome. Hypomethylation. Imprinting. ICR.BORIS ABSTRACT Silver-Russell Syndrome (SRS) is a heterogeneous disorder associated with intrauterine and postnatal growth retardation, skeletal asymmetry and facial dysmorphisms. In 7-10% of patients maternal uniparental disomy for chromosome 7 can be observed, nearly 50% of patients carry an epimutation resulting in hypomethylation of the imprinting center region 1 (ICR1) in 11p15. This leaves 40% of patients with unknown genetic aetiology. Based on the observation that the CTCF homologue BORIS is involved in imprinted gene expression and that it binds to methylated alleles we assumed that loss-of-function mutations in BORIS might have similar functional consequences as an ICR1 hypomethylation. On the other hand, there is evidence that BORIS mutations may disturb the methylation process and therefore cause hypomethylation in the ICR1. In our study we searched for BORIS gene mutations in a mixed cohort of SRS patients with and without 11p15 hypomethylation to determine whether this gene is involved in SRS aetiology. Mutation analyses revealed eight genomic variants but pathogenic mutations were not observed. Thus we conclude that alterations of the BORIS gene are probably not associated with SRS.

  • broad clinical spectrum in Silver Russell Syndrome and consequences for genetic testing in growth retardation
    Pediatrics, 2009
    Co-Authors: Thomas Eggermann, Gerhard Binder, Daniela Gonzalez, Sabrina Spengler, Mine Arslankirchner, Nadine Schonherr
    Abstract:

    OBJECTIVE. Silver-Russell Syndrome is a heterogenous disorder characterized by severe intrauterine growth restriction, lack of catch-up after birth, and specific dysmorphisms. In ∼10% of patients, maternal uniparental disomy of chromosome 7 is detectable, but hypomethylation of the imprinting in 11p15 is the major epigenetic disturbance in Silver-Russell Syndrome. The use of strict clinical criteria, indeed, results in relatively high detection rates for the 11p15 epimutation, but we feel that the application of a strict clinical scoring system is not useful in clinical workaday life because of the broad clinical spectrum in 11p15 epimutation and maternal uniparental disomy of chromosome 7 carriers. PATIENTS AND METHODS. We report on our experience of molecular testing in 188 patients referred for routine diagnostics of Silver-Russell Syndrome and in a group of 20 patients with isolated intrauterine growth restriction/postnatal growth retardation. RESULTS. The molecular genetic results in both groups of data showed that 11p15 epimutation and maternal uniparental disomy of chromosome 7 carriers did not always show the unambiguous Silver-Russell Syndrome phenotype. CONCLUSIONS. In addition to patients with the classical Silver-Russell Syndrome phenotype fulfilling the Silver-Russell Syndrome-specific scores, genetic testing for the 11p15 epimutation and/or maternal uniparental disomy of chromosome 7 should also be considered in case of “Silver-Russell Syndrome-like” phenotypes, for example, mild intrauterine growth restriction and postnatal growth retardation associated with a prominent forehead and triangular face or asymmetry as the only clinical signs. In particular, the lack of intrauterine growth restriction in patients with a Silver-Russell Syndrome-like phenotype should not automatically result in exclusion from molecular testing.

  • growth retardation versus overgrowth Silver Russell Syndrome is genetically opposite to beckwith wiedemann Syndrome
    Trends in Genetics, 2008
    Co-Authors: Thomas Eggermann, Katja Eggermann, Nadine Schonherr
    Abstract:

    Human growth is a complex process that requires the appropriate interaction of many players. Central members in the growth pathways are regulated epigenetically and thereby reflect the profound significance of imprinting for correct mammalian ontogenesis. In this review, we show that the growth retardation disorder Silver-Russell Syndrome (SRS) is a suitable model to decipher the role of imprinting in growth. As we will show, SRS should not only be regarded as the genetically (and clinically) opposite disease to Beckwith-Wiedemann Syndrome, but it also represents the first human disorder with imprinting disturbances that affect two different chromosomes (i.e. chromosomes 7 and 11). Thus, a functional interaction between factors encoded by chromosomes 7 and 11 is likely.

Flavia Cerrato - One of the best experts on this subject based on the ideXlab platform.