Recombinant Chromosome 7 Driven by Maternal Chromosome 7 Pericentric Inversion in a Girl with Features of Silver-Russell Syndrome

Maternal uniparental disomy of chromosome 7 is present in 5–10% of patients with Silver-Russell syndrome (SRS), and duplication of 7p including GRB10 (Growth Factor Receptor-Bound Protein 10), an imprinted gene that affects pre-and postnatal growth retardation, has been associated with the SRS phenotype. Here, we report on a 17 year old girl referred to array-CGH analysis for short stature, psychomotor delay, and relative macrocephaly. Array-CGH analysis showed two copy number variants (CNVs): a ~12.7 Mb gain in 7p13-p11.2, involving GRB10 and an ~9 Mb loss in 7q11.21-q11.23. FISH experiments performed on the proband’s mother showed a chromosome 7 pericentric inversion that might have mediated the complex rearrangement harbored by the daughter. Indeed, we found that segmental duplications, of which chromosome 7 is highly enriched, mapped at the breakpoints of both the mother’s inversion and the daughter’s CNVs. We postulate that pairing of highly homologous sequences might have perturbed the correct meiotic chromosome segregation, leading to unbalanced outcomes and acting as the putative meiotic mechanism that was causative of the proband’s rearrangement. Comparison of the girl’s phenotype to those of patients with similar CNVs supports the presence of 7p in a locus associated with features of SRS syndrome.

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

Clinical Genetics ◽

10.1111/cge.12075 ◽

2013 ◽

Vol 84 (4) ◽

pp. 368-372 ◽

Cited By ~ 6

Author(s):

MB Sheridan ◽

A Bytyci Telegrafi ◽

V Stinnett ◽

CC Umeh ◽

Z Mari ◽

...

Keyword(s):

Uniparental Disomy ◽

Chromosome 7 ◽

Maternal Uniparental Disomy ◽

Myoclonus Dystonia ◽

Silver Russell Syndrome

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Detection of maternal uniparental disomy at the two imprinted genes on chromosome 7, GRB10 and PEG1/MEST, in a Silver-Russell syndrome patient using methylation-specific PCR assays

Clinical Genetics ◽

10.1111/j.1399-0004.2004.00387.x ◽

2004 ◽

Vol 67 (3) ◽

pp. 267-269 ◽

Cited By ~ 2

Keyword(s):

Uniparental Disomy ◽

Chromosome 7 ◽

Imprinted Genes ◽

Syndrome Patient ◽

Maternal Uniparental Disomy ◽

Methylation Specific Pcr ◽

Specific Pcr ◽

Pcr Assays ◽

Silver Russell Syndrome

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Silver-Russell syndrome due to maternal uniparental disomy of chromosome 7

10.32388/9i7ywc ◽

2020 ◽

Author(s):

Keyword(s):

Uniparental Disomy ◽

Chromosome 7 ◽

Maternal Uniparental Disomy ◽

Silver Russell Syndrome

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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 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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