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Temple syndrome and Kagami-Ogata syndrome: clinical presentations, genotypes, models and mechanisms.Human Molecular Genetics Sep 2020Temple syndrome (TS) and Kagami-Ogata syndrome (KOS) are imprinting disorders caused by absence or overexpression of genes within a single imprinted cluster on human... (Review)
Review
Temple syndrome (TS) and Kagami-Ogata syndrome (KOS) are imprinting disorders caused by absence or overexpression of genes within a single imprinted cluster on human chromosome 14q32. TS most frequently arises from maternal UPD14 or epimutations/deletions on the paternal chromosome, whereas KOS most frequently arises from paternal UPD14 or epimutations/deletions on the maternal chromosome. In this review, we describe the clinical symptoms and genetic/epigenetic features of this imprinted region. The locus encompasses paternally expressed protein-coding genes (DLK1, RTL1 and DIO3) and maternally expressed lncRNAs (MEG3/GTL2, RTL1as and MEG8), as well as numerous miRNAs and snoRNAs. Control of expression is complex, with three differentially methylated regions regulating germline, placental and tissue-specific transcription. The strong conserved synteny between mouse chromosome 12aF1 and human chromosome 14q32 has enabled the use of mouse models to elucidate imprinting mechanisms and decipher the contribution of genes to the symptoms of TS and KOS. In this review, we describe relevant mouse models and highlight their value to better inform treatment options for long-term management of TS and KOS patients.
Topics: Abnormalities, Multiple; Animals; Chromosome Disorders; Chromosomes, Human, Pair 14; Disease Models, Animal; Genomic Imprinting; Hallux; Humans; Intellectual Disability; Mice; Nails, Malformed; Phenotype; Thumb; Uniparental Disomy
PubMed: 32592473
DOI: 10.1093/hmg/ddaa133 -
Journal of Clinical Medicine Oct 2022Temple syndrome (TS14) is an imprinting disorder caused by a maternal uniparental disomy of chromosome 14 (UPD(14)mat), paternal deletion of 14q32 or an isolated...
BACKGROUND
Temple syndrome (TS14) is an imprinting disorder caused by a maternal uniparental disomy of chromosome 14 (UPD(14)mat), paternal deletion of 14q32 or an isolated methylation defect of the MEG3-DMR. Studies on phenotypical characteristics in TS14 are scarce and patients with TS14 often experience delay in diagnosis, which has adverse effects on their health. TS14 is often characterized as either Prader-Willi-like, Silver-Russell-like or as a Silver-Russell spectrum disorder.
METHODS
This study describes 15 patients with TS14 who visited the Dutch Reference Center for Prader-Willi-like from December 2018 to January 2022.
RESULTS
Eight patients had UPD(14)mat and seven a methylation defect. The most common symptoms were intra-uterine growth retardation (IUGR) (100%), hypotonia (100%), precocious puberty (89%), small for gestational age (SGA) birth (67%), tube feeding after birth (53%) and psycho-behavioral problems (53%). Median (interquartile range (IQR)) IQ was 91.5 (84.25; 100.0), whilst many patients were enrolled in special education (54%). The median (IQR) fat mass % (FM%) SDS was 2.53 (2.26; 2.90) and lean body mass (LBM) SDS -2.03 (-3.22; -1.28). There were no significant differences in clinical characteristics between patients with a UPD(14)mat and a methylation defect.
CONCLUSIONS
Our patients share a distinct phenotype consisting of IUGR, SGA birth, precocious puberty, hypotonia, tube feeding after birth, psycho-behavioral problems and abnormal body composition with a high FM% and low LBM. Whilst similarities with Prader-Willi syndrome (PWS) and Silver-Russell syndrome (SRS) exist, TS14 is a discernible syndrome, deserving a tailored clinical approach. Testing for TS14 should be considered in patients with a PWS or SRS phenotype in infancy if PWS/SRS testing is negative.
PubMed: 36362517
DOI: 10.3390/jcm11216289 -
Clinical Epigenetics Oct 2020Imprinting disorders (IDs) show overlapping phenotypes, particularly in Silver-Russell syndrome (SRS), Temple syndrome (TS14), and Prader-Willi syndrome (PWS). These...
BACKGROUND
Imprinting disorders (IDs) show overlapping phenotypes, particularly in Silver-Russell syndrome (SRS), Temple syndrome (TS14), and Prader-Willi syndrome (PWS). These three IDs include fetal and postnatal growth failure, feeding difficulty, and muscular hypotonia as major clinical features. However, the mechanism that causes overlapping phenotypes has not been clarified. To investigate the presence or absence of methylation signatures associated with overlapping phenotypes, we performed genome-wide methylation analysis (GWMA).
RESULTS
GWMA was carried out on 36 patients with three IDs (SRS [n = 16], TS14 [n = 7], PWS [n = 13]) and 11 child controls using HumanMethylation450 BeadChip including 475,000 CpG sites across the human genome. To reveal an aberrantly methylated region shared by SRS, TS14, and PWS groups, we compared genome-wide methylation data of the three groups with those of control subjects. All the identified regions were known as SRS-, TS14-, and PWS-related imprinting-associated differentially methylated regions (iDMRs), and there was no hypermethylated or hypomethylated region shared by different ID groups. To examine the methylation pattern shared by SRS, TS14, and PWS groups, we performed clustering analysis based on GWMA data. The result focusing on 620 probes at the 62 known iDMRs (except for SRS-, TS14-, and PWS-related iDMRs) classified patients into two categories: (1) category A, grossly normal methylation patterns mainly consisting of SRS group patients; and (2) category B, broad and mild hypermethylation patterns mainly consisting of TS14 and PWS group patients. However, we found no obvious relationship between these methylation patterns and phenotypes of patients.
CONCLUSIONS
GWMA in three IDs found no methylation signatures shared by SRS, TS14, and PWS groups. Although clustering analysis showed similar mild hypermethylation patterns in TS14 and PWS groups, further study is needed to clarify the effect of methylation patterns on the overlapping phenotypes.
Topics: Case-Control Studies; CpG Islands; DNA Methylation; Genome, Human; Genome-Wide Association Study; Genomic Imprinting; Hallux; High-Throughput Nucleotide Sequencing; Humans; Intellectual Disability; Nails, Malformed; Phenotype; Prader-Willi Syndrome; Silver-Russell Syndrome; Thumb
PubMed: 33092629
DOI: 10.1186/s13148-020-00949-8 -
Clinical Epigenetics May 2021ZNF445, as well as ZFP57, is involved in the postfertilization methylation maintenance of multiple imprinting-associated differentially methylated regions (iDMRs). Thus,...
BACKGROUND
ZNF445, as well as ZFP57, is involved in the postfertilization methylation maintenance of multiple imprinting-associated differentially methylated regions (iDMRs). Thus, ZNF445 pathogenic variants are predicted to cause multilocus imprinting disturbances (MLIDs), as do ZFP57 pathogenic variants. In particular, the MEG3/DLK1:IG-DMR would be affected, because the postzygotic methylation imprint of the MEG3/DLK1:IG-DMR is maintained primarily by ZNF445, whereas that of most iDMRs is preserved by both ZFP57 and ZNF445 or primarily by ZFP57.
RESULTS
We searched for a ZNF445 variant(s) in six patients with various imprinting disorders (IDs) caused by epimutations and MLIDs revealed by pyrosequencing for nine iDMRs, without a selection for the original IDs. Re-analysis of the previously obtained whole exome sequencing data identified a homozygous ZNF445 variant (NM_181489.6:c.2803C>T:p.(Gln935*)) producing a truncated protein missing two of 14 zinc finger domains in a patient with Temple syndrome and MLID. In this patient, array-based genomewide methylation analysis revealed severe hypomethylation of most CpGs at the MEG3:TSS-DMR, moderate hypomethylation of roughly two-thirds of CpGs at the H19/IGF2:IG-DMR, and mild-to-moderate hypomethylation of a few CpGs at the DIRAS3:TSS-DMR, MEST:alt-TSS-DMR, IGF2:Ex9-DMR, IGF2:alt-TSS, and GNAS-AS1:TSS-DMR. Furthermore, bisulfite sequencing analysis for the MEG3/DLK1:IG-DMR delineated a markedly hypomethylated segment (CG-A). The heterozygous parents were clinically normal and had virtually no aberrant methylation pattern.
CONCLUSIONS
We identified a ZNF445 pathogenic variant for the first time. Since ZNF445 binds to the MEG3/DLK1:IG-DMR and other iDMRs affected in this patient, the development of Temple syndrome and MLID would primarily be explained by the ZNF445 variant. Furthermore, CG-A may be the target site for ZNF445 within the MEG3/DLK1:IG-DMR.
Topics: Child, Preschool; Epigenesis, Genetic; Female; Genomic Imprinting; Hallux; Humans; Intellectual Disability; Multilocus Sequence Typing; Nails, Malformed; Repressor Proteins; Thumb; Zinc Fingers
PubMed: 34039421
DOI: 10.1186/s13148-021-01106-5 -
Genome-wide multilocus imprinting disturbance analysis in Temple syndrome and Kagami-Ogata syndrome.Genetics in Medicine : Official Journal... Apr 2017Recent studies have identified multilocus imprinting disturbances (MLIDs) in a subset of patients with imprinting diseases (IDs) caused by epimutations. We examined...
PURPOSE
Recent studies have identified multilocus imprinting disturbances (MLIDs) in a subset of patients with imprinting diseases (IDs) caused by epimutations. We examined MLIDs in patients with Temple syndrome (TS14) and Kagami-Ogata syndrome (KOS14).
METHODS
We studied four TS14 patients (patients 1-4) and five KOS14 patients (patients 5-9) with epimutations. We performed HumanMethylation450 BeadChip (HM450k) analysis for 43 differentially methylated regions (DMRs) (753 CpG sites) and pyrosequencing for 12 DMRs (62 CpG sites) using leukocyte genomic DNA (Leu-gDNA) of patients 1-9, and performed HM450k analysis for 43 DMRs (a slightly different set of 753 CpG sites) using buccal cell gDNA (Buc-gDNA) of patients 1, 3, and 4. We also performed mutation analysis for six causative and candidate genes for MLIDs and quantitative expression analysis using immortalized lymphocytes in MLID-positive patients.
RESULTS
Methylation analysis showed hypermethylated ZDBF2-DMR and ZNF597/NAA60-DMR, hypomethylated ZNF597-DMR in both Leu-gDNA and Buc-gDNA, and hypomethylated PPIEL-DMR in Buc-gDNA of patient 1, and hypermethylated GNAS-A/B-DMR in Leu-gDNA of patient 3. No mutations were detected in the six genes for MLIDs. Expression patterns of ZDBF2, ZNF597, and GNAS-A/B were consistent with the identified MLIDs.
CONCLUSION
This study indicates the presence of MLIDs in TS14 patients but not in KOS14 patients.Genet Med 19 4, 476-482.
Topics: Chromosomes, Human, Pair 14; CpG Islands; DNA Methylation; DNA-Binding Proteins; Genetic Testing; Genomic Imprinting; Humans; Mutation; Transcription Factors; Uniparental Disomy
PubMed: 27632690
DOI: 10.1038/gim.2016.123 -
Seminars in Reproductive Medicine Jul 2019The factors that trigger human puberty are among the central mysteries of reproductive biology. Several approaches, including mutational analysis of candidate genes,... (Review)
Review
The factors that trigger human puberty are among the central mysteries of reproductive biology. Several approaches, including mutational analysis of candidate genes, large-scale genome-wide association studies, whole exome sequencing, and whole genome sequencing have been performed in attempts to identify novel genetic factors that modulate the human hypothalamic-pituitary-gonadal axis to result in premature sexual development. Genetic abnormalities involving excitatory and inhibitory pathways regulating gonadotropin-releasing hormone secretion, represented by the kisspeptin ( and ) and makorin ring finger 3 () systems, respectively, have been associated with sporadic and familial cases of central precocious puberty (CPP). More recently, paternally inherited genetic defects of were identified in four families with nonsyndromic CPP and a metabolic phenotype. encodes a transmembrane protein that is important for adipose tissue homeostasis and neurogenesis and is located in the imprinted chromosome 14q32 region associated with Temple syndrome. In this review, we highlight the clinical and genetic features of patients with CPP caused by mutations and explore the involvement of Notch signaling and DLK1 in the control of pubertal onset.
Topics: Age Factors; Calcium-Binding Proteins; Genome-Wide Association Study; Humans; Membrane Proteins; Puberty; Receptors, Notch; Sexual Maturation; Signal Transduction; Time Factors
PubMed: 31972862
DOI: 10.1055/s-0039-3400963 -
Genetics in Medicine : Official Journal... Dec 2017PurposeTemple syndrome (TS14) is a rare imprinting disorder caused by aberrations at the 14q32.2 imprinted region. Here, we report comprehensive molecular and clinical...
PurposeTemple syndrome (TS14) is a rare imprinting disorder caused by aberrations at the 14q32.2 imprinted region. Here, we report comprehensive molecular and clinical findings in 32 Japanese patients with TS14.MethodsWe performed molecular studies for TS14 in 356 patients with variable phenotypes, and clinical studies in all TS14 patients, including 13 previously reported.ResultsWe identified 19 new patients with TS14, and the total of 32 patients was made up of 23 patients with maternal uniparental disomy (UPD(14)mat), six patients with epimutations, and three patients with microdeletions. Clinical studies revealed both Prader-Willi syndrome (PWS)-like marked hypotonia and Silver-Russell syndrome (SRS)-like phenotype in 50% of patients, PWS-like hypotonia alone in 20% of patients, SRS-like phenotype alone in 20% of patients, and nonsyndromic growth failure in the remaining 10% of patients in infancy, and gonadotropin-dependent precocious puberty in 76% of patients who were pubescent or older.ConclusionThese results suggest that TS14 is not only a genetically diagnosed entity but also a clinically recognizable disorder. Genetic testing for TS14 should be considered in patients with growth failure plus both PWS-like hypotonia and SRS-like phenotypes in infancy, and/or precocious puberty, as well as a familial history of Kagami-Ogata syndrome due to maternal microdeletion at 14q32.2.
Topics: Adolescent; Adult; Child; Child, Preschool; Chromosome Aberrations; Chromosome Disorders; Chromosomes, Human, Pair 14; Facies; Female; Genetic Association Studies; Genetic Testing; Genomic Imprinting; Growth Charts; Humans; Infant; Japan; Male; Middle Aged; Phenotype; Pregnancy; Young Adult
PubMed: 28640239
DOI: 10.1038/gim.2017.53 -
Genes Apr 2021Intrauterine and postnatal growth disturbances are major clinical features of imprinting disorders, a molecularly defined group of congenital syndromes caused by... (Review)
Review
Intrauterine and postnatal growth disturbances are major clinical features of imprinting disorders, a molecularly defined group of congenital syndromes caused by molecular alterations affecting parentally imprinted genes. These genes are expressed monoallelically and in a parent-of-origin manner, and they have an impact on human growth and development. In fact, several genes with an exclusive expression from the paternal allele have been shown to promote foetal growth, whereas maternally expressed genes suppress it. The evolution of this correlation might be explained by the different interests of the maternal and paternal genomes, aiming for the conservation of maternal resources for multiple offspring versus extracting maximal maternal resources. Since not all imprinted genes in higher mammals show the same imprinting pattern in different species, the findings from animal models are not always transferable to human. Therefore, human imprinting disorders might serve as models to understand the complex regulation and interaction of imprinted loci. This knowledge is a prerequisite for the development of precise diagnostic tools and therapeutic strategies for patients affected by imprinting disorders. In this review we will specifically overview the current knowledge on imprinting disorders associated with growth retardation, and its increasing relevance in a personalised medicine direction and the need for a multidisciplinary therapeutic approach.
Topics: DNA Methylation; Female; Fetal Growth Retardation; Gene Regulatory Networks; Genetic Predisposition to Disease; Genomic Imprinting; Humans; Phenotype; Precision Medicine; Pregnancy
PubMed: 33920525
DOI: 10.3390/genes12040585 -
Epigenetics 2018Temple syndrome (TS14) is a rare imprinting disorder caused by genetic and epigenetic alterations on chromosome 14q32. A subset of these patients shows an imprinting...
Temple syndrome (TS14) is a rare imprinting disorder caused by genetic and epigenetic alterations on chromosome 14q32. A subset of these patients shows an imprinting defect (ID) where the paternal allele harbors a maternal epigenotype thus silencing the paternally expressed genes and leading to an increased expression of the maternally expressed genes. We investigated the grandparental origin of the incorrectly imprinted chromosome 14 in a cohort of 13 TS14 ID patients and their families. In seven families grandmaternal and, in six families, grandpaternal inheritance was observed. These results indicate that the ID occurred after imprint erasure in the paternal germ line. While the complete lack of methylation as observed in the majority of TS14 ID patients may be due to an imprint establishment error in the paternal germ line, cases with methylation mosaicism suggest that in general many IDs (TS14, AS, BWS, and SRS) are in fact of somatic origin in the early or late embryo.
Topics: Abnormalities, Multiple; Adult; Aged; Child; Chromosomes, Human, Pair 14; DNA Methylation; Female; Genomic Imprinting; Germ Cells; Grandparents; Humans; Male; Middle Aged; Muscle Hypotonia; Obesity; Pedigree; Syndrome
PubMed: 30227764
DOI: 10.1080/15592294.2018.1514233 -
Clinical Epigenetics Dec 2022Parental imprinting is an epigenetic mechanism that leads to monoallelic expression of a subset of genes depending on their parental origin. Imprinting disorders (IDs),...
BACKGROUND
Parental imprinting is an epigenetic mechanism that leads to monoallelic expression of a subset of genes depending on their parental origin. Imprinting disorders (IDs), caused by disturbances of imprinted genes, are a set of rare congenital diseases that mainly affect growth, metabolism and development. To date, there is no accurate model to study the physiopathology of IDs or test therapeutic strategies. Human induced pluripotent stem cells (iPSCs) are a promising cellular approach to model human diseases and complex genetic disorders. However, aberrant hypermethylation of imprinting control regions (ICRs) may appear during the reprogramming process and subsequent culture of iPSCs. Therefore, we tested various conditions of reprogramming and culture of iPSCs and performed an extensive analysis of methylation marks at the ICRs to develop a cellular model that can be used to study IDs.
RESULTS
We assessed the methylation levels at seven imprinted loci in iPSCs before differentiation, at various passages of cell culture, and during chondrogenic differentiation. Abnormal methylation levels were found, with hypermethylation at 11p15 H19/IGF2:IG-DMR and 14q32 MEG3/DLK1:IG-DMR, independently of the reprogramming method and cells of origin. Hypermethylation at these two loci led to the loss of parental imprinting (LOI), with biallelic expression of the imprinted genes IGF2 and DLK1, respectively. The epiPS™ culture medium combined with culturing of the cells under hypoxic conditions prevented hypermethylation at H19/IGF2:IG-DMR (ICR1) and MEG3/DLK1:IG-DMR, as well as at other imprinted loci, while preserving the proliferation and pluripotency qualities of these iPSCs.
CONCLUSIONS
An extensive and quantitative analysis of methylation levels of ICRs in iPSCs showed hypermethylation of certain ICRs in human iPSCs, especially paternally methylated ICRs, and subsequent LOI of certain imprinted genes. The epiPS™ culture medium and culturing of the cells under hypoxic conditions prevented hypermethylation of ICRs in iPSCs. We demonstrated that the reprogramming and culture in epiPS™ medium allow the generation of control iPSCs lines with a balanced methylation and ID patient iPSCs lines with unbalanced methylation. Human iPSCs are therefore a promising cellular model to study the physiopathology of IDs and test therapies in tissues of interest.
Topics: Humans; DNA Methylation; Induced Pluripotent Stem Cells; Genomic Imprinting; Epigenesis, Genetic; RNA, Long Noncoding
PubMed: 36578048
DOI: 10.1186/s13148-022-01410-8