Role of Imprinting Disorders in Short Children Born SGA and Silver-Russell Syndrome Spectrum

Abstract Background (Epi)genetic disorders associated with small-for-gestational-age with short stature (SGA-SS) include imprinting disorders (IDs). Silver-Russell syndrome (SRS) is a representative ID in SGA-SS and has heterogenous (epi)genetic causes. Subjects and Methods To clarify the contribution of IDs to SGA-SS and the molecular and phenotypic spectrum of SRS, we recruited 269 patients with SGA-SS, consisting of 103 and 166 patients referred to us for genetic testing for SGA-SS and SRS, respectively. After excluding 20 patients with structural abnormalities detected by comparative genomic hybridization analysis using catalog array, 249 patients were classified into 3 subgroups based on the Netchine-Harbison clinical scoring system (NH-CSS), SRS diagnostic criteria. We screened various IDs by methylation analysis for differentially methylated regions (DMRs) related to known IDs. We also performed clinical analysis. Results These 249 patients with SGA-SS were classified into the “SRS-compatible group” (n = 148), the “non-SRS with normocephaly or relative macrocephaly at birth group” (non-SRS group) (n = 94), or the “non-SRS with relative microcephaly at birth group” (non-SRS with microcephaly group) (n = 7). The 44.6% of patients in the “SRS-compatible group,” 21.3% of patients in the “non-SRS group,” and 14.3% in the “non-SRS with microcephaly group” had various IDs. Loss of methylation of the H19/IGF2:intergenic-DMR and uniparental disomy chromosome 7, being major genetic causes of SRS, was detected in 30.4% of patients in the “SRS-compatible group” and in 13.8% of patients in the “non-SRS group.” Conclusion We clarified the contribution of IDs as (epi)genetic causes of SGA-SS and the molecular and phenotypic spectrum of SRS. Various IDs constitute underlying factors for SGA-SS, including SRS.

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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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MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Acta Endocrinologica ◽

10.1530/eje-15-0937 ◽

2016 ◽

Vol 174 (4) ◽

pp. R145-R173 ◽

Cited By ~ 65

Author(s):

Jan M Wit ◽

Wilma Oostdijk ◽

Monique Losekoot ◽

Hermine A van Duyvenvoorde ◽

Claudia A L Ruivenkamp ◽

...

Keyword(s):

Short Stature ◽

Hormone Deficiency ◽

Comparative Genomic ◽

Genetic Defects ◽

Pituitary Hormone ◽

Epiphyseal Growth Plate ◽

Paracrine Factors ◽

Imprinting Disorders ◽

Genetic Causes ◽

Cellular Processes

The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD areGH1andGHRHRdefects, but several novel causes have recently been found, such asGHSR,RNPC3, andIFT172mutations. Besides well-defined causes of GH insensitivity (GHR,STAT5B,IGFALS,IGF1defects), disorders of NFκB signalling,STAT3andIGF2have recently been discovered. HeterozygousIGF1Rdefects are a relatively frequent cause of prenatal and postnatal growth retardation.TRHAmutations cause a syndromic form of short stature with elevated T3/T4ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. HeterozygousNPR2orSHOXdefects may be found in ∼3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.

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Molecular testing for imprinting disorders

Medizinische Genetik ◽

10.1515/medgen-2020-2048 ◽

2020 ◽

Vol 32 (4) ◽

pp. 305-319

Author(s):

Jasmin Beygo ◽

Deniz Kanber ◽

Thomas Eggermann ◽

Matthias Begemann

Keyword(s):

New Technologies ◽

Molecular Genetic ◽

Gene Clusters ◽

Recurrence Risk ◽

Imprinted Genes ◽

Molecular Testing ◽

Imprinting Disorders ◽

Genetic Causes ◽

Phenotypic Spectrum ◽

Or Gene

Abstract Imprinting disorders are a group of rare diseases with a broad phenotypic spectrum caused by a wide variety of genetic and epigenetic disturbances of imprinted genes or gene clusters. The molecular genetic causes and their respective frequencies vary between the different imprinting disorders so that each has its unique requirements for the diagnostic workflow, making it challenging. To add even more complexity to this field, new molecular genetic causes have been identified over time and new technologies have enhanced the detectability e. g. of mosaic disturbances. The precise identification of the underlying molecular genetic cause is of utmost importance in regard to recurrence risk in the families, tumour risk, clinical management and conventional and in the future therapeutic managements. Here we give an overview of the imprinting disorders, their specific requirements for the diagnostic workup and the most common techniques used and point out possible pitfalls.

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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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A case report and mechanism analysis of a normal phenotype mosaic 47, XXY complicated by paternal iUPD (9) who had a normal PGD result

BMC Medical Genetics ◽

10.1186/s12881-019-0897-5 ◽

2019 ◽

Vol 20 (1) ◽

Author(s):

Dan Li ◽

Yun Wang ◽

Nan Zhao ◽

Liang Chang ◽

Ping Liu ◽

...

Keyword(s):

Case Report ◽

Karyotype Analysis ◽

Snp Array ◽

Uniparental Disomy ◽

Comparative Genomic ◽

Klinefelter’S Syndrome ◽

Mechanism Analysis ◽

Klinefelter's Syndrome ◽

Preimplantation Genetic Testing ◽

First Case

Abstract Background Uniparental disomy (UPD) refers to the situation in which two copies of homologous chromosomes or part of a chromosome originate from the one parent and no copy is supplied by the other parent. Case presentation Here, we reported a woman whose karyotype was 46, XX, t (1;17)(q42;q21), has obtained 5 embryos by intracytoplasmic sperm injection (ICSI) after one cycle of in vitro fertility (IVF). After microarray-based comparative genomic hybridization (array-CGH) for preimplantation genetic testing for chromosomal structural rearrangements (PGT-SR), two embryos were balanced, one balanced embryo was implanted and the patient successfully achieved pregnancy. Amniocentesis was performed at the 19th week of gestation for karyotype analysis and single nucleotide polymorphism (SNP)-array test. The result of karyotype analysis was: mos 47, XXY [19]/46, XY [81]; SNP-array results revealed 46, XY, iUPD (9) pat. After full genetic counseling for mosaic Klinefelter’s syndrome and paternal iUPD (9), the couple decided to continue pregnancy, and the patient gave birth to a healthy boy. The newborn is now 3.5 years old, and developed normally. This case will provide counseling evidences of paternal iUPD (9) for doctors. Conclusions This is the first case report of paternal iUPD9 with mosaic Klinefelter’s syndrome, and no abnormality has been observed during the 3.5-year follow-up. Further observation is required to determine whether the imprinted genes on the chromosomes are pathogenic and whether recessive pathogenetic genes are activated.

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

Genes ◽

10.3390/genes12040581 ◽

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.

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Multiplex ligation-dependent probe amplification – a short overview

Revista Romana de Medicina de Laborator ◽

10.2478/rrlm-2020-0016 ◽

2020 ◽

Vol 28 (2) ◽

pp. 123-131

Author(s):

Valeriu Moldovan ◽

Elena Moldovan

Keyword(s):

Copy Number ◽

Genetic Disorders ◽

Cost Effective ◽

Copy Number Variations ◽

Comparative Genomic ◽

Gene Deletions ◽

Conventional Cytogenetic Analysis ◽

Main Technique ◽

Cost Effective Technique ◽

Dependent Probe

AbstractMultiplex Ligation-dependent Probe Amplification is a technique proposed for the detection of deletions or duplications that may lead to copy number variations in genomic DNA, mainly due to its higher resolution, and shorter overall diagnosis time, when compared with techniques traditionally used, namely karyotyping, fluorescence in situ hybridization, and array comparative genomic hybridization. Multiplex Ligation-dependent Probe Amplification is a fast (about 2 days), useful and cost-effective technique, being suitable for the diagnosis of hereditary conditions caused by complete or partial gene deletions or duplications, as these conditions are either more difficult or impossible to be diagnosed by other techniques, such as PCR, Real-Time PCR, or sequencing (Sanger or Next Generation). Due to its numerous advantages over conventional cytogenetic analysis techniques, Multiplex Ligation-dependent Probe Amplification could be used in the near future as the main technique for the molecular investigation of genetic conditions caused by copy number variations, in both rare and complex genetic disorders.

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