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Transient Neonatal Diabetes, ZFP57, and Hypomethylation of Multiple Imprinted Loci: A detailed follow-up

Transient Neonatal Diabetes, ZFP57, and Hypomethylation of Multiple Imprinted Loci: A detailed follow-up
Transient Neonatal Diabetes, ZFP57, and Hypomethylation of Multiple Imprinted Loci: A detailed follow-up
OBJECTIVE Transient neonatal diabetes mellitus 1 (TNDM1) is the most common cause of diabetes presenting at birth. Approximately 5% of the cases are due to recessive ZFP57 mutations, causing hypomethylation at the TNDM locus and other imprinted loci (HIL). This has consequences for patient care, because it has impact on the phenotype and recurrence risk for families. We have determined the genotype, phenotype, and epigenotype of the first 10 families to alert health professionals to this newly described genetic subgroup of diabetes.

RESEARCH DESIGN AND METHODS The 10 families (14 homozygous/compound heterozygous individuals) with ZFP57 mutations were ascertained through TNDM1 diagnostic testing. ZFP57 was sequenced in probands and their relatives, and the methylation levels at multiple maternally and paternally imprinted loci were determined. Medical and family histories were obtained, and clinical examination was performed.

RESULTS The key clinical features in probands were transient neonatal diabetes, intrauterine growth retardation, macroglossia, heart defects, and developmental delay. However, the finding of two homozygous relatives without diabetes and normal intelligence showed that the phenotype could be very variable. The epigenotype always included total loss of methylation at the TNDM1 locus and reproducible combinations of differential hypomethylation at other maternally imprinted loci, including tissue mosaicism.

CONCLUSIONS There is yet no clear genotype–epigenotype–phenotype correlation to explain the variable clinical presentation, and this results in difficulties predicting the prognosis of affected individuals. However, many cases have a more severe phenotype than seen in other causes of TNDM1. Further cases and global epigenetic testing are needed to clarify this.
1935-5548
505-512
Boonen, Susanne E.
635ea5a0-76e3-4b60-bd4e-b9dd8998022c
Mackay, Deborah J. G.
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Hahnemann, Johanne M. D.
b477148f-c5de-42e8-bdcb-8b8297d5017c
Docherty, Louise E.
4accb565-e53b-400f-8d62-83935e2ae410
Grønskov, Karen
42b6747d-9009-499a-a70e-121137dbc83e
Lehmann, Anna
ad4759af-7698-43f3-a177-e22b43c37877
Larsen, Lise G.
ba44e842-f767-4cc7-a8e7-fcb9d3f42c46
Haemers, Andreas P.
9ddca0f9-f39f-4e35-bead-c152072b7cae
Kockaerts, Yves
4a8bd06d-55e4-4061-a157-a2e642b8b908
Dooms, Lutgarde
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Vũ, Dũng Chí
af41477b-b494-40d5-a41d-a070d898e3a3
Ngoc, C. T. Bich
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Nguyen, Phuong Bich
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Kordonouri, Olga
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Sundberg, Frida
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Dayanikli, Pinar
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Puthi, Vijith
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Acerini, Carlo
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Massoud, Ahmed F.
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Tümer, Zeynep
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Temple, I. Karen
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Boonen, Susanne E.
635ea5a0-76e3-4b60-bd4e-b9dd8998022c
Mackay, Deborah J. G.
588a653e-9785-4a00-be71-4e547850ee4a
Hahnemann, Johanne M. D.
b477148f-c5de-42e8-bdcb-8b8297d5017c
Docherty, Louise E.
4accb565-e53b-400f-8d62-83935e2ae410
Grønskov, Karen
42b6747d-9009-499a-a70e-121137dbc83e
Lehmann, Anna
ad4759af-7698-43f3-a177-e22b43c37877
Larsen, Lise G.
ba44e842-f767-4cc7-a8e7-fcb9d3f42c46
Haemers, Andreas P.
9ddca0f9-f39f-4e35-bead-c152072b7cae
Kockaerts, Yves
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Dooms, Lutgarde
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Vũ, Dũng Chí
af41477b-b494-40d5-a41d-a070d898e3a3
Ngoc, C. T. Bich
d185e1e7-c0f6-4887-899f-131e2f0a802a
Nguyen, Phuong Bich
ec151056-9b62-40b8-a719-73b6c8a6b01a
Kordonouri, Olga
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Sundberg, Frida
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Dayanikli, Pinar
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Puthi, Vijith
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Acerini, Carlo
d7e3b7bd-d84d-4751-a182-5be581bb4041
Massoud, Ahmed F.
d2d53d66-d7fa-45ad-8a0c-e9206014d252
Tümer, Zeynep
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Temple, I. Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226

Boonen, Susanne E., Mackay, Deborah J. G., Hahnemann, Johanne M. D., Docherty, Louise E., Grønskov, Karen, Lehmann, Anna, Larsen, Lise G., Haemers, Andreas P., Kockaerts, Yves, Dooms, Lutgarde, Vũ, Dũng Chí, Ngoc, C. T. Bich, Nguyen, Phuong Bich, Kordonouri, Olga, Sundberg, Frida, Dayanikli, Pinar, Puthi, Vijith, Acerini, Carlo, Massoud, Ahmed F., Tümer, Zeynep and Temple, I. Karen (2013) Transient Neonatal Diabetes, ZFP57, and Hypomethylation of Multiple Imprinted Loci: A detailed follow-up. Diabetes Care, 36 (3), 505-512. (doi:10.2337/dc12-0700). (PMID:23150280)

Record type: Article

Abstract

OBJECTIVE Transient neonatal diabetes mellitus 1 (TNDM1) is the most common cause of diabetes presenting at birth. Approximately 5% of the cases are due to recessive ZFP57 mutations, causing hypomethylation at the TNDM locus and other imprinted loci (HIL). This has consequences for patient care, because it has impact on the phenotype and recurrence risk for families. We have determined the genotype, phenotype, and epigenotype of the first 10 families to alert health professionals to this newly described genetic subgroup of diabetes.

RESEARCH DESIGN AND METHODS The 10 families (14 homozygous/compound heterozygous individuals) with ZFP57 mutations were ascertained through TNDM1 diagnostic testing. ZFP57 was sequenced in probands and their relatives, and the methylation levels at multiple maternally and paternally imprinted loci were determined. Medical and family histories were obtained, and clinical examination was performed.

RESULTS The key clinical features in probands were transient neonatal diabetes, intrauterine growth retardation, macroglossia, heart defects, and developmental delay. However, the finding of two homozygous relatives without diabetes and normal intelligence showed that the phenotype could be very variable. The epigenotype always included total loss of methylation at the TNDM1 locus and reproducible combinations of differential hypomethylation at other maternally imprinted loci, including tissue mosaicism.

CONCLUSIONS There is yet no clear genotype–epigenotype–phenotype correlation to explain the variable clinical presentation, and this results in difficulties predicting the prognosis of affected individuals. However, many cases have a more severe phenotype than seen in other causes of TNDM1. Further cases and global epigenetic testing are needed to clarify this.

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More information

e-pub ahead of print date: 12 November 2012
Published date: March 2013
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 345397
URI: http://eprints.soton.ac.uk/id/eprint/345397
ISSN: 1935-5548
PURE UUID: b59a8e0d-629c-4f3d-9e3f-73c7c5698c19
ORCID for Deborah J. G. Mackay: ORCID iD orcid.org/0000-0003-3088-4401
ORCID for I. Karen Temple: ORCID iD orcid.org/0000-0002-6045-1781

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Date deposited: 20 Nov 2012 11:11
Last modified: 23 Jul 2022 01:44

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Contributors

Author: Susanne E. Boonen
Author: Johanne M. D. Hahnemann
Author: Louise E. Docherty
Author: Karen Grønskov
Author: Anna Lehmann
Author: Lise G. Larsen
Author: Andreas P. Haemers
Author: Yves Kockaerts
Author: Lutgarde Dooms
Author: Dũng Chí Vũ
Author: C. T. Bich Ngoc
Author: Phuong Bich Nguyen
Author: Olga Kordonouri
Author: Frida Sundberg
Author: Pinar Dayanikli
Author: Vijith Puthi
Author: Carlo Acerini
Author: Ahmed F. Massoud
Author: Zeynep Tümer
Author: I. Karen Temple ORCID iD

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