Temple syndrome in a patient with variably methylated CpGs at the primary  MEG3/DLK1 :IG-DMR and severely hypomethylated CpGs at the secondary  MEG3 :TSS-DMR

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Abstract

Background

The human chromosome 14q32.2 imprinted region harbors the primary MEG3/DLK1:IG-differentially methylated region (DMR) and secondary MEG3:TSS-DMR. The MEG3:TSS-DMR can remain unmethylated only in the presence of unmethylated MEG3/DLK1:IG-DMR in somatic tissues, but not in the placenta, because of a hierarchical regulation of the methylation pattern between the two DMRs.

Methods

We performed molecular studies in a 4-year-old Japanese girl with Temple syndrome (TS14).

Results

Pyrosequencing analysis showed extremely low methylation levels of five CpGs at the MEG3:TSS-DMR and grossly normal methylation levels of four CpGs at the MEG3/DLK1:IG-DMR in leukocytes. HumanMethylation450 BeadChip confirmed marked hypomethylation of the MEG3:TSS-DMR and revealed multilocus imprinting disturbance (MLID) including mild hypomethylation of the H19/IGF2:IG-DMR and mild hypermethylation of the GNAS A/B:TSS-DMR in leukocytes. Bisulfite sequencing showed markedly hypomethylated CpGs at the MEG3:TSS-DMR and irregularly and non-differentially methylated CpGs at the MEG3/DLK1:IG-DMR in leukocytes and apparently normal methylation patterns of the two DMRs in the placenta. Maternal uniparental disomy 14 and a deletion involving this imprinted region were excluded.

Conclusions

Such a methylation pattern of the MEG3/DLK1:IG-DMR has not been reported in patients with TS14. It may be possible that a certain degree of irregular hypomethylation at the MEG3/DLK1:IG-DMR has prevented methylation of the MEG3:TSS-DMR in somatic tissues and that a hypermethylation type MLID has occurred at the MEG3/DLK1:IG-DMR to yield the apparently normal methylation pattern in the placenta.

Electronic supplementary material

The online version of this article (10.1186/s13148-019-0640-2) contains supplementary material, which is available to authorized users.

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Human genetic variation database, a reference database of genetic variations in the Japanese population

Koichiro Higasa, Noriko Miyake, Jun-ichi Yoshimura … (2016)

Whole-genome and -exome resequencing using next-generation sequencers is a powerful approach for identifying genomic variations that are associated with diseases. However, systematic strategies for prioritizing causative variants from many candidates to explain the disease phenotype are still far from being established, because the population-specific frequency spectrum of genetic variation has not been characterized. Here, we have collected exomic genetic variation from 1208 Japanese individuals through a collaborative effort, and aggregated the data into a prevailing catalog. In total, we identified 156 622 previously unreported variants. The allele frequencies for the majority (88.8%) were lower than 0.5% in allele frequency and predicted to be functionally deleterious. In addition, we have constructed a Japanese-specific major allele reference genome by which the number of unique mapping of the short reads in our data has increased 0.045% on average. Our results illustrate the importance of constructing an ethnicity-specific reference genome for identifying rare variants. All the collected data were centralized to a newly developed database to serve as useful resources for exploring pathogenic variations. Public access to the database is available at http://www.genome.med.kyoto-u.ac.jp/SnpDB/.

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The changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria.

M Aygün, Brittany S. Cassidy, Rachel S. Schwartz … (2001)

Prader-Willi syndrome (PWS) is a complex, multisystem disorder. Its major clinical features include neonatal hypotonia, developmental delay, short stature, behavioral abnormalities, childhood-onset obesity, hypothalamic hypogonadism, and characteristic appearance. The genetic basis of PWS is also complex. It is caused by absence of expression of the paternally active genes in the PWS critical region on 15q11-q13. In approximately 70% of cases this is the result of deletion of this region from the paternal chromosome 15. In approximately 28%, it is attributable to maternal uniparental disomy (UPD; inheritance of 2 copies of a chromosome from the mother and no copies from the father, as opposed to the normal 1 copy from each parent) of chromosome 15, and in 97% of the patients. Feeding problems in infancy, excessive weight gain after 1 year, hypogonadism, and hyperphagia were all present in 93% or more of patients. Sensitivities of the minor criteria ranged form 37% (sleep disturbance and apneas) to 93% (speech and articulation defects). Interestingly, the sensitivities of 8 of the minor criteria were higher than the sensitivity of characteristic facial features, which is a major criterion. Fifteen out of 90 patients with molecular diagnosis did not meet the clinical diagnostic criteria retrospectively. When definitive diagnostic testing is not available, as was the case for PWS when the 1993 criteria were developed, diagnostic criteria are important to avoid overdiagnosis and to ensure that diagnostic test development is performed on appropriate samples. When diagnostic testing is available, as is now the case for PWS, diagnostic criteria should serve to raise diagnostic suspicion, ensure that all appropriate people are tested, and avoid the expense of testing unnecessarily. Our results indicate that the sensitivities of most of the published criteria are acceptable. However, 16.7% of patients with molecular diagnosis did not meet the 1993 clinical diagnostic criteria retrospectively, suggesting that the published criteria may be too exclusive. A less strict scoring system may ensure that all appropriate people are tested. Accordingly, we suggest revised clinical criteria to help identify the appropriate patients for DNA testing for PWS. The suggested age groupings are based on characteristic phases of the natural history of PWS. Some of the features (eg, neonatal hypotonia, feeding problems in infancy) serve to diagnose the syndrome in the first few years of life, whereas others (eg, excessive eating) are useful during early childhood. Similarly, hypogonadism is most useful during and after adolescence. Some of the features like neonatal hypotonia and infantile feeding problems are less likely to be missed, whereas others such as characteristic facial features and hypogonadism (especially in prepubertal females) may require more careful and/or expert examination. The issue of who should have diagnostic testing is distinct from the determination of features among confirmed patients. Based on the sensitivities of the published criteria and our experience, we suggest testing all newborns/infants with otherwise unexplained hypotonia with poor suck. For children between 2 and 6 years of age, we consider hypotonia with history of poor suck associated with global developmental delay sufficient criteria to prompt testing. Between 6 and 12 years of age, we suggest testing those with hypotonia (or history of hypotonia with poor suck), global developmental delay, and excessive eating with central obesity (if uncontrolled). At the ages of 13 years and above, we recommend testing patients with cognitive impairment, excessive eating with central obesity (if uncontrolled), and hypogonadotropic hypogonadism and/or typical behavior problems (including temper tantrums and obsessive-compulsive features). Thus, we propose a lower threshold to prompt diagnostic DNA testing, leading to a higher likelihood of diagnosis of this disorder in which anticipatory guidance and intervention can significantly influence outcome.

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Recommendations for a nomenclature system for reporting methylation aberrations in imprinted domains.

David Monk, Joannella Morales, Johan T. den Dunnen … (2018)

The analysis of DNA methylation has become routine in the pipeline for diagnosis of imprinting disorders, with many publications reporting aberrant methylation associated with imprinted differentially methylated regions (DMRs). However, comparisons between these studies are routinely hampered by the lack of consistency in reporting sites of methylation evaluated. To avoid confusion surrounding nomenclature, special care is needed to communicate results accurately, especially between scientists and other health care professionals. Within the European Network for Human Congenital Imprinting Disorders we have discussed these issues and designed a nomenclature for naming imprinted DMRs as well as for reporting methylation values. We apply these recommendations for imprinted DMRs that are commonly assayed in clinical laboratories and show how they support standardized database submission. The recommendations are in line with existing recommendations, most importantly the Human Genome Variation Society nomenclature, and should facilitate accurate reporting and data exchange among laboratories and thereby help to avoid future confusion.

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Author and article information

Contributors

Masayo Kagami:

ORCID: http://orcid.org/0000-0003-3020-455X

kagami-ms@ncchd.go.jp

Atsuhiro Yanagisawa: atsyanagi@yahoo.co.jp

Miyuki Ota: miyuki.hashimoto2112@gmail.com

Kentaro Matsuoka: kenta-ma@dokkyomed.ac.jp

Akie Nakamura: akieda@med.hokudai.ac.jp

Keiko Matsubara: matsubara-k@ncchd.go.jp

Kazuhiko Nakabayashi: nakabaya-k@ncchd.go.jp

Shuji Takada: takada-s@ncchd.go.jp

Maki Fukami: fukami-m@ncchd.go.jp

Tsutomu Ogata: tomogata@hama-med.ac.jp

Journal

Journal ID (nlm-ta): Clin Epigenetics

Journal ID (iso-abbrev): Clin Epigenetics

Title: Clinical Epigenetics

Publisher: BioMed Central (London )

ISSN (Print): 1868-7075

ISSN (Electronic): 1868-7083

Publication date (Electronic): 7 March 2019

Publication date PMC-release: 7 March 2019

Publication date Collection: 2019

Volume: 11

Electronic Location Identifier: 42

Affiliations

[1 ]ISNI 0000 0004 0377 2305, GRID grid.63906.3a, Department of Molecular Endocrinology, , National Research Institute for Child Health and Development, ; 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535 Japan

[2 ]Department of Pediatrics, Yaizu City Hospital, 1000 Doubara, Yaizu, Shizuoka 425-8505 Japan

[3 ]ISNI 0000 0004 1764 7265, GRID grid.414768.8, Department of Pediatrics, , JR Tokyo General Hospital, ; 2-1-3 Yoyogi, Shibuya-ku, Tokyo, 151-8528 Japan

[4 ]ISNI 0000 0004 0467 0255, GRID grid.415020.2, Department of Pathology, , Dokkyo Medical University, Saitama Medical Center, ; 2-1-50 Minami-Koshigaya, Koshigaya, Saitama 343-8555 Japan

[5 ]ISNI 0000 0001 2173 7691, GRID grid.39158.36, Department of Pediatrics, , Hokkaido University Graduate School of Medicine, ; Kita 15, Nishi 7, Kita-ku, Sapporo, 060-8638 Japan

[6 ]ISNI 0000 0004 0377 2305, GRID grid.63906.3a, Department of Maternal-Fetal Biology, , National Research Institute for Child Health and Development, ; 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535 Japan

[7 ]ISNI 0000 0004 0377 2305, GRID grid.63906.3a, Department of Systems BioMedicine, , National Research Institute for Child Health and Development, ; 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535 Japan

[8 ]ISNI 0000 0004 1762 0759, GRID grid.411951.9, Department of Pediatrics, , Hamamatsu University School of Medicine, ; 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192 Japan

Author information

Masayo Kagami http://orcid.org/0000-0003-3020-455X

Article

Publisher ID: 640

DOI: 10.1186/s13148-019-0640-2

PMC ID: 6407230

PubMed ID: 30846001

SO-VID: ad8e1b85-d042-4e91-a78e-8adbb2abfcb4

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 27 December 2018

Date accepted : 28 February 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100009619, Japan Agency for Medical Research and Development;

Award ID: JP17ek0109141

Award ID: JP18ek0109373

Award Recipient : Masayo Kagami

Funded by: National Center for Child Health and Development

Award ID: 28-3

Award Recipient : Masayo Kagami

Funded by: Japan Society for the Promotion of Science

Award ID: 15K15096

Award Recipient : Masayo Kagami

Funded by: FundRef http://dx.doi.org/10.13039/100007449, Takeda Science Foundation;

Award ID: No number

Award Recipient : Masayo Kagami

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: temple syndrome,multilocus imprinting disturbance,primary dmr,secondary dmr

Data availability:

ScienceOpen disciplines: Genetics

Keywords: temple syndrome, multilocus imprinting disturbance, primary dmr, secondary dmr

Temple syndrome in a patient with variably methylated CpGs at the primary MEG3/DLK1:IG-DMR and severely hypomethylated CpGs at the secondary MEG3:TSS-DMR

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

Related collections

Genomic Prediction

Most cited references 11

Human genetic variation database, a reference database of genetic variations in the Japanese population

The changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria.

Recommendations for a nomenclature system for reporting methylation aberrations in imprinted domains.

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