NSD1duplication in Silver-Russell syndrome (SRS): molecular karyotyping in patients with SRS features

2016 ◽  
Vol 91 (1) ◽  
pp. 73-78 ◽  
Author(s):  
J. Sachwitz ◽  
R. Meyer ◽  
G. Fekete ◽  
S. Spranger ◽  
A. Matulevičienė ◽  
...  
Keyword(s):  
Molecular Karyotyping ◽  
Silver Russell Syndrome

Growing up with Silver Russell Syndrome

2018 ◽  
Author(s):  
Jenny Child ◽  
Nick Child ◽  
Georgia Child
Keyword(s):  
Growing Up ◽  
Silver Russell Syndrome

Cochlear malformation and sensorineural hearing loss in the Silver-Russell Syndrome

2018 ◽  
Vol 70 (6) ◽  
Author(s):  
Stefania Bigoni ◽  
Antonio Mauro ◽  
Alessandra Ferlini ◽  
Virginia Corazzi ◽  
Andrea Ciorba ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Sensorineural Hearing ◽  
Cochlear Malformation ◽  
Silver Russell Syndrome

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

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.

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

Genes ◽  
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.

scholarly journals Mosaic Segmental and Whole-Chromosome upd(11)mat in Silver-Russell Syndrome

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 581
Author(s):  
Laura Pignata ◽  
Angela Sparago ◽  
Orazio Palumbo ◽  
Elena Andreucci ◽  
Elisabetta Lapi ◽  
...  
Keyword(s):  
Molecular Level ◽  
Opposite Sign ◽  
Uniparental Disomy ◽  
Differentially Methylated Region ◽  
Imprinted Genes ◽  
Loss Of Function ◽  
Growth Disturbances ◽  
Molecular Defects ◽  
Entire Chromosome ◽  
Silver Russell Syndrome

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.

scholarly journals Unusual deletion of the maternal 11p15 allele in Beckwith–Wiedemann syndrome with an impact on both imprinting domains

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Thomas Eggermann ◽  
Matthias Begemann ◽  
Lutz Pfeiffer
Keyword(s):  
Clinical Signs ◽  
Gene Content ◽  
Paternal Inheritance ◽  
Maternal Allele ◽  
Heterozygous Deletion ◽  
First Case ◽  
Clinical Consequences ◽  
Regulation Mechanisms ◽  
Silver Russell Syndrome ◽  
Deletion Carrier

Abstract Background Whereas duplications in 11p15.5 covering both imprinting centers (ICs) and their subordinated genes account for up to 1% of Beckwith–Wiedemann and Silver–Russell syndrome patients (BWS, SRS), the deletions in 11p15.5 reported so far only affect one of the ICs. In these cases, not only the size and gene content had an impact on the phenotype, but also the sex of the contributing parent influences the clinical signs of the deletion carrier. Results We here report on the first case with a heterozygous deletion within the maternal allele affecting genes which are regulated by both ICs in 11p15.5 in a BWS patient, and describe the molecular and clinical consequences in case of its maternal or paternal inheritance. Conclusions The identification of a unique deletion affecting both 11p15.5 imprinting domains in a BWS patient illustrates the complexity of the regulation mechanisms in these key imprinting regions.

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