Loss of imprinting of the human-specific imprinted gene ZNF597 causes prenatal growth retardation and dysmorphic features: implications for phenotypic overlap with Silver-Russell syndrome

BackgroundZNF597, encoding a zinc-finger protein, is the human-specific maternally expressed imprinted gene located on 16p13.3. The parent-of-origin expression of ZNF597 is regulated by the ZNF597:TSS-DMR, of which only the paternal allele acquires methylation during postimplantation period. Overexpression of ZNF597 may contribute to some of the phenotypes associated with maternal uniparental disomy of chromosome 16 (UPD(16)mat), and some patients with UPD(16)mat presenting with Silver-Russell syndrome (SRS) phenotype have recently been reported.MethodsA 6-year-old boy presented with prenatal growth restriction, macrocephaly at birth, forehead protrusion in infancy and clinodactyly of the fifth finger. Methylation, expression, microsatellite marker, single nucleotide polymorphism array and trio whole-exome sequencing analyses were conducted.ResultsIsolated hypomethylation of the ZNF597:TSS-DMR and subsequent loss of imprinting and overexpression of ZNF597 were confirmed in the patient. Epigenetic alterations, such as UPD including UPD(16)mat and other methylation defects, were excluded. Pathogenic sequence or copy number variants affecting his phenotypes were not identified, indicating that primary epimutation occurred postzygotically.ConclusionWe report the first case of isolated ZNF597 imprinting defect, showing phenotypic overlap with SRS despite not satisfying the clinical SRS criteria. A novel imprinting disorder entity involving the ZNF597 imprinted domain can be speculated.

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

Clinical Epigenetics ◽

10.1186/s13148-021-01020-w ◽

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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Mice Lacking Paternally Expressed Pref-1/Dlk1 Display Growth Retardation and Accelerated Adiposity

Molecular and Cellular Biology ◽

10.1128/mcb.22.15.5585-5592.2002 ◽

2002 ◽

Vol 22 (15) ◽

pp. 5585-5592 ◽

Cited By ~ 295

Author(s):

Yang Soo Moon ◽

Cynthia M. Smas ◽

Kichoon Lee ◽

Josep A. Villena ◽

Kee-Hong Kim ◽

...

Keyword(s):

Human Chromosome ◽

Growth Retardation ◽

Uniparental Disomy ◽

Chromosome 14 ◽

Tissue Mass ◽

Imprinted Gene ◽

Maternal Uniparental Disomy ◽

Skeletal Malformation

ABSTRACT Preadipocyte factor 1 (Pref-1/Dlk1) inhibits in vitro adipocyte differentiation and has been recently reported to be a paternally expressed imprinted gene at human chromosome 14q32. Studies on human chromosome 14 deletions and maternal uniparental disomy (mUPD) 14 suggest that misexpression of a yet-to-be-identified imprinted gene or genes present on chromosome 14 causes congenital disorders. We generated Pref-1 knockout mice to assess the role of Pref-1 in growth and in vivo adipogenesis and to determine the contribution of Pref-1 in mUPD. Pref-1-null mice display growth retardation, obesity, blepharophimosis, skeletal malformation, and increased serum lipid metabolites. Furthermore, the phenotypes observed in Pref-1-null mice are present in heterozygotes that harbor a paternally inherited, but not in those with a maternally inherited pref-1-null allele. Our results demonstrate that Pref-1 is indeed paternally expressed and is important for normal development and for homeostasis of adipose tissue mass. We also suggest that Pref-1 is responsible for most of the symptoms observed in mouse mUPD12 and human mUPD14. Pref-1-null mice may be a model for obesity and other pathologies of human mUPD14.

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DNA demethylase ROS1 negatively regulates the imprinting of DOGL4 and seed dormancy in Arabidopsis thaliana

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1812847115 ◽

2018 ◽

Vol 115 (42) ◽

pp. E9962-E9970 ◽

Cited By ~ 15

Author(s):

Haifeng Zhu ◽

Wenxiang Xie ◽

Dachao Xu ◽

Daisuke Miki ◽

Kai Tang ◽

...

Keyword(s):

Gene Expression ◽

Seed Dormancy ◽

Genomic Imprinting ◽

Dna Demethylation ◽

Paternal Allele ◽

Maternal Allele ◽

Imprinted Gene ◽

Differential Gene ◽

Parent Of Origin ◽

Dna Demethylase

Genomic imprinting is a form of epigenetic regulation resulting in differential gene expression that reflects the parent of origin. In plants, imprinted gene expression predominantly occurs in the seed endosperm. Maternal-specific DNA demethylation by the DNA demethylase DME frequently underlies genomic imprinting in endosperm. Whether other more ubiquitously expressed DNA demethylases regulate imprinting is unknown. Here, we found that the DNA demethylase ROS1 regulates the imprinting of DOGL4. DOGL4 is expressed from the maternal allele in endosperm and displays preferential methylation and suppression of the paternal allele. We found that ROS1 negatively regulates imprinting by demethylating the paternal allele, preventing its hypermethylation and complete silencing. Furthermore, we found that DOGL4 negatively affects seed dormancy and response to the phytohormone abscisic acid and that ROS1 controls these processes by regulating DOGL4. Our results reveal roles for ROS1 in mitigating imprinted gene expression and regulating seed dormancy.

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