Epigenotype, Genotype, and Phenotype Analysis of Taiwanese Patients with Silver–Russell Syndrome

Background: Silver–Russell syndrome (SRS) is a clinically and genetically heterogeneous disorder characterized by severe intrauterine growth retardation, poor postnatal growth, characteristic facial features, and body asymmetry. Hypomethylation of the imprinted genes of the chromosome 11p15.5 imprinting gene cluster and maternal uniparental disomy of chromosome 7 (mUPD7) are the major epigenetic disturbances. The aim of this study was to characterize the epigenotype, genotype, and phenotype of these patients in Taiwan. Methods: Two hundred and six subjects with clinically suspected SRS were referred for diagnostic testing, which was performed by profiling the methylation of H19-associated imprinting center (IC) 1 and the imprinted PEG1/MEST region using methylation-specific multiplex ligation-dependent probe amplification and high-resolution melting analysis with a methylation-specific polymerase chain reaction assay. We also applied a whole genome strategy to detect copy number changes and loss of heterozygosity. Clinical manifestations were recorded and analyzed according to the SRS scoring system proposed by Bartholdi et al. Results: Among the 206 referred subjects, 100 were classified as having a clinical diagnosis of SRS (score ≥ 8, maximum = 15) and 106 had an SRS score ≤ 7. Molecular lesions were detected in 45% (45/100) of the subjects with a clinical diagnosis of SRS, compared to 5% (5/106) of those with an SRS score ≤ 7. Thirty-seven subjects had IC1 hypomethylation, ten subjects had mUPD7, and three subjects had microdeletions. Several clinical features were found to be statistically different (p < 0.05) between the “IC1 hypomethylation” and “mUPD7” groups, including relative macrocephaly at birth (89% vs. 50%), triangular shaped face (89% vs. 50%), clinodactyly of the fifth finger (68% vs. 20%), and SRS score (11.4 ± 2.2 vs. 8.3 ± 2.5). Conclusions: The SRS score was positively correlated with the molecular diagnosis rate (p < 0.001). The SRS subjects with mUPD7 seemed to have fewer typical features and lower SRS scores than those with IC1 hypomethylation. Careful clinical observation and timely molecular confirmation are important to allow for an early diagnosis and multidisciplinary management of these patients.

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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

Genes ◽

10.3390/genes12040588 ◽

2021 ◽

Vol 12 (4) ◽

pp. 588

Author(s):

Pierpaola Tannorella ◽

Daniele Minervino ◽

Sara Guzzetti ◽

Alessandro Vimercati ◽

Luciano Calzari ◽

...

Keyword(s):

Growth Retardation ◽

Molecular Mechanisms ◽

Uniparental Disomy ◽

Postnatal Growth ◽

Molecular Diagnostic ◽

Growth Delay ◽

Molecular Defect ◽

Maternal Uniparental Disomy ◽

Feeding Difficulties ◽

Silver Russell Syndrome

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.

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Multiple Segmental Uniparental Disomy Associated with Abnormal DNA Methylation of Imprinted Loci in Silver-Russell Syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2012-1980 ◽

2012 ◽

Vol 97 (11) ◽

pp. E2188-E2193 ◽

Cited By ~ 11

Author(s):

Renuka P. Dias ◽

Irina Bogdarina ◽

Jean-Baptiste Cazier ◽

Charles Buchanan ◽

Malcolm C. Donaldson ◽

...

Keyword(s):

Dna Methylation ◽

Mrna Expression ◽

Single Nucleotide Polymorphism Array ◽

Uniparental Disomy ◽

Postnatal Growth ◽

Chromosome 7 ◽

Imprinted Genes ◽

Methylation Array ◽

Maternal Uniparental Disomy ◽

Silver Russell Syndrome

Background: Silver-Russell syndrome (SRS; online inheritance in man 180860) is a low-birth-weight syndrome characterized by postnatal growth restriction and variable dysmorphic features. Although maternal uniparental disomy (UPD) of chromosome 7 and hypomethylation of H19 have been reported in up to 50% of all cases, no unifying mechanism is apparent. Subjects and Methods: Ten patients and their parents were studied using the Illumina GoldenGate methylation array and the Illumina 370K HumHap single-nucleotide polymorphism array to identify aberrations in DNA methylation as well as genomic changes including copy number changes and uniparental disomy events. Results: We found evidence of UPD events outside chromosome 7 in all patients. In up to 30% of patients with SRS, DNA methylation changes occur in imprinted gene loci outside 11p15.5 (PEG3, PLAGL1, and GRB10), not previously consistently linked with SRS. Furthermore, hypermethylation of GRB10 was associated with increased mRNA expression. In addition, 20% of patients appear to have DNA methylation abnormalities within multiple loci. Not all the imprinted loci with methylation defects were affected directly by UPD. Conclusions: The association of widespread UPD associated with abnormal methylation and mRNA expression in imprinted genes in SRS is consistent with the concept of UPD as an initial genomic abnormality leading to unstable DNA methylation within the regulatory network of imprinted genes. Furthermore, disruption of any one of these genes may contribute to the heterogeneous clinical spectrum of SRS.

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Molecular and clinical analyses of two patients with UPD(16)mat detected by screening 94 patients with Silver-Russell syndrome phenotype of unknown aetiology

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105463 ◽

2018 ◽

Vol 56 (6) ◽

pp. 413-418 ◽

Cited By ~ 8

Author(s):

Takanobu Inoue ◽

Hideaki Yagasaki ◽

Junko Nishioka ◽

Akie Nakamura ◽

Keiko Matsubara ◽

...

Keyword(s):

Snp Array ◽

Uniparental Disomy ◽

Gene Mutations ◽

Growth Failure ◽

Postnatal Growth ◽

Differentially Methylated Region ◽

Unknown Aetiology ◽

Chromosome 16 ◽

Maternal Uniparental Disomy ◽

Silver Russell Syndrome

BackgroundRecently, a patient with maternal uniparental disomy of chromosome 16 (UPD(16)mat) presenting with Silver-Russell syndrome (SRS) phenotype was reported. SRS is characterised by growth failure and dysmorphic features.ObjectiveTo clarify the prevalence of UPD(16)mat in aetiology-unknown patients with SRS phenotype and phenotypic differences between UPD(16)mat and SRS.MethodsWe studied 94 patients with SRS phenotype of unknown aetiology. Sixty-three satisfied the Netchine-Harbison clinical scoring system (NH-CSS) criteria, and 25 out of 63 patients showed both protruding forehead and relative macrocephaly (clinical SRS). The remaining 31 patients met only three NH-CSS criteria, but were clinically suspected as having SRS. To detect UPD(16)mat, we performed methylation analysis for the ZNF597:TSS-differentially methylated region (DMR) on chromosome 16 and subsequently performed microsatellite, SNP array and exome analyses in the patients with hypomethylated ZNF597:TSS-DMR.ResultsWe identified two patients (2.1%) with a mixture of maternal isodisomy and heterodisomy of chromosome 16 in 94 aetiology-unknown patients with SRS phenotype. Both patients exhibited preterm birth and prenatal and postnatal growth failure. The male patient had ventricular septal defect and hypospadias. Whole-exome sequencing detected no gene mutations related to their phenotypes.ConclusionWe suggest considering genetic testing for UPD(16)mat in SRS phenotypic patients without known aetiology.

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The Diagnostic Value of IGF-2 and the IGF/IGFBP-3 System in Silver-Russell Syndrome

Hormone Research in Paediatrics ◽

10.1159/000477666 ◽

2017 ◽

Vol 88 (3-4) ◽

pp. 201-207 ◽

Cited By ~ 4

Author(s):

Gerhard Binder ◽

Thomas Eggermann ◽

Karin Weber ◽

Nawfel Ferrand ◽

Roland Schweizer

Keyword(s):

Uniparental Disomy ◽

Clinical Signs ◽

Growth Failure ◽

Postnatal Growth ◽

Diagnostic Value ◽

Maternal Uniparental Disomy ◽

Short Children ◽

Postnatal Growth Failure ◽

Silver Russell Syndrome ◽

Igfbp 3

Background/Aims: Recently, we have described a family of 4 members presenting with intrauterine and postnatal growth failure, low IGF-2 levels, and signs of Silver-Russell syndrome (SRS) who carried a genomic IGF2 mutation. Here, we assess the value of IGF-2 in relation to SRS. Methods: We collected data from 48 SRS children and 48 short children born small for gestational age (SGA) seen at our center. The SRS children were 4.6 ± 2.0 years of age, and the SGA children were 4.8 ± 1.8 years of age. All patients were prepubertal and growth hormone naive. An 11p15 ICR1 loss of methylation (11p15LOM) was present in 22, maternal uniparental disomy of chromosome 7 (upd(7)mat) in 7, and IGF2 genomic mutation (IGF2mut) in 3 patients. Growth factors were measured by in-house radioimmunoassays. Results: The median IGF-2 standard deviation scores (SDSs) were: IGF2mut –1.75, upd(7)mat –1.69, nonsyndromic SGA –1.52, 11p15LOM –0.61, and clinical (tested negative) –0.55. The median IGF-2:IGF-1 concentration ratio was 2.57 in IGF2mut compared to 5.44 in 11p15LOM (p = 0.036), 7.84 in clinical, and 7.98 in upd(7)mat. Upd(7)mat patients had significantly lower IGF-1 and IGFBP-3 SDSs than patients with 11p15LOM (p ≤ 0.002). Conclusion: Serum IGF-2 in combination with IGF-1 and IGFBP-3 can add to the clinical signs of SRS patients and help to perform targeted genetic testing. Further studies are needed.

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One test for all: whole exome sequencing significantly improves the diagnostic yield in growth retarded patients referred for molecular testing for Silver–Russell syndrome

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01683-x ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Robert Meyer ◽

Matthias Begemann ◽

Christian Thomas Hübner ◽

Daniela Dey ◽

Alma Kuechler ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Diagnostic Yield ◽

Uniparental Disomy ◽

Molecular Testing ◽

Main Body ◽

Comprehensive Overview ◽

Maternal Uniparental Disomy ◽

Whole Exome ◽

Silver Russell Syndrome

Abstract Background Silver-Russell syndrome (SRS) is an imprinting disorder which is characterised by severe primordial growth retardation, relative macrocephaly and a typical facial gestalt. The clinical heterogeneity of SRS is reflected by a broad spectrum of molecular changes with hypomethylation in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat) as the most frequent findings. Monogenetic causes are rare, but a clinical overlap with numerous other disorders has been reported. However, a comprehensive overview on the contribution of mutations in differential diagnostic genes to phenotypes reminiscent to SRS is missing due to the lack of appropriate tests. With the implementation of next generation sequencing (NGS) tools this limitation can now be circumvented. Main body We analysed 75 patients referred for molecular testing for SRS by a NGS-based multigene panel, whole exome sequencing (WES), and trio-based WES. In 21/75 patients a disease-causing variant could be identified among them variants in known SRS genes (IGF2, PLAG1, HMGA2). Several patients carried variants in genes which have not yet been considered as differential diagnoses of SRS. Conclusions WES approaches significantly increase the diagnostic yield in patients referred for SRS testing. Several of the identified monogenetic disorders have a major impact on clinical management and genetic counseling.

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Maternal uniparental disomy 7 and Silver–Russell syndrome – Clinical update and comparison with other subgroups

European Journal of Medical Genetics ◽

10.1016/j.ejmg.2008.06.001 ◽

2008 ◽

Vol 51 (5) ◽

pp. 444-451 ◽

Cited By ~ 36

Author(s):

Dieter Kotzot

Keyword(s):

Uniparental Disomy ◽

Maternal Uniparental Disomy ◽

Silver Russell Syndrome

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

BMC Medical Genetics ◽

10.1186/s12881-016-0280-8 ◽

2016 ◽

Vol 17 (1) ◽

Cited By ~ 13

Author(s):

Jana Sachwitz ◽

Getrud Strobl-Wildemann ◽

György Fekete ◽

Laima Ambrozaitytė ◽

Vaidutis Kučinskas ◽

...

Keyword(s):

Uniparental Disomy ◽

Maternal Uniparental Disomy ◽

Silver Russell Syndrome

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Silver-Russell syndrome due to maternal uniparental disomy 7 and a familial reciprocal translocation t(7;13)

Clinical Genetics ◽

10.1111/j.1399-0004.2011.01792.x ◽

2011 ◽

Vol 82 (5) ◽

pp. 494-498 ◽

Cited By ~ 7

Author(s):

A Behnecke ◽

K Hinderhofer ◽

A Jauch ◽

JWG Janssen ◽

U Moog

Keyword(s):

Reciprocal Translocation ◽

Uniparental Disomy ◽

Maternal Uniparental Disomy ◽

Silver Russell Syndrome

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Phenotype of genetically confirmed Silver-Russell syndrome beyond childhood

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106561 ◽

2020 ◽

Vol 57 (10) ◽

pp. 683-691 ◽

Cited By ~ 1

Author(s):

Oluwakemi Lokulo-Sodipe ◽

Lisa Ballard ◽

Jenny Child ◽

Hazel M Inskip ◽

Christopher D Byrne ◽

...

Keyword(s):

Quality Of Life ◽

Uniparental Disomy ◽

Scoring Systems ◽

Hormone Treatment ◽

Diagnostic Features ◽

Maternal Uniparental Disomy ◽

Feeding Difficulties ◽

Adult Growth ◽

Silver Russell Syndrome

BackgroundSilver-Russell syndrome is an imprinting disorder that restricts growth, resulting in short adult stature that may be ameliorated by treatment. Approximately 50% of patients have loss of methylation of the imprinting control region (H19/IGF2:IG-DMR) on 11p15.5 and 5%–10% have maternal uniparental disomy of chromosome 7. Most published research focuses on the childhood phenotype. Our aim was to describe the phenotypic characteristics of older patients with SRS.MethodsA retrospective cohort of 33 individuals with a confirmed molecular diagnosis of SRS aged 13 years or above were carefully phenotyped.ResultsThe median age of the cohort was 29.6 years; 60.6% had a height SD score (SDS) ≤−2 SDS despite 70% having received growth hormone treatment. Relative macrocephaly, feeding difficulties and a facial appearance typical of children with SRS were no longer discriminatory diagnostic features. In those aged ≥18 years, impaired glucose tolerance in 25%, hypertension in 33% and hypercholesterolaemia in 52% were noted. While 9/33 accessed special education support, university degrees were completed in 40.0% (>21 years). There was no significant correlation between quality of life and height SDS. 9/25 were parents and none of the 17 offsprings had SRS.ConclusionHistorical treatment regimens for SRS were not sufficient for normal adult growth and further research to optimise treatment is justified. Clinical childhood diagnostic scoring systems are not applicable to patients presenting in adulthood and SRS diagnosis requires molecular confirmation. Metabolic ill-health warrants further investigation but SRS is compatible with a normal quality of life including normal fertility in many cases.

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