Transient neonatal diabetes, ZFP57, and hypomethylation of multiple imprinted loci: a detailed follow-up

Susanne E Boonen; Deborah J G Mackay; Johanne M D Hahnemann; Louise Docherty; Karen Grønskov; Anna Lehmann; Lise G Larsen; Andreas P Haemers; Yves Kockaerts; Lutgarde Dooms; Dung Chí Vu; C T Bich Ngoc; Phuong Bich Nguyen; Olga Kordonouri; Frida Sundberg; Pinar Dayanikli; Vijith Puthi; Carlo Acerini; Ahmed F Massoud; Zeynep Tümer; I Karen Temple

doi:10.2337/dc12-0700

Transient neonatal diabetes, ZFP57, and hypomethylation of multiple imprinted loci: a detailed follow-up

Susanne E Boonen, Deborah J G Mackay, Johanne M D Hahnemann, Louise Docherty, Karen Grønskov, Anna Lehmann, Lise G Larsen, Andreas P Haemers, Yves Kockaerts, Lutgarde Dooms, Dung Chí Vu, C T Bich Ngoc, Phuong Bich Nguyen, Olga Kordonouri, Frida Sundberg, Pinar Dayanikli, Vijith Puthi, Carlo Acerini, Ahmed F Massoud, Zeynep TümerI Karen Temple

Medical Genetics Program

39 Citationer (Scopus)

Abstract

OBJECTIVEdTransient neonatal diabetes mellitus 1 (TNDM1) is the most common cause of diabetes presenting at birth. Approximately 5%of the cases are due to recessive ZFP57mutations, 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 METHODSdThe 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. RESULTSdThe 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. CONCLUSIONSdThere 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.

Originalsprog	Engelsk
Tidsskrift	Diabetes Care
Vol/bind	36
Udgave nummer	3
Sider (fra-til)	505-12
Antal sider	8
ISSN	0149-5992
DOI	https://doi.org/10.2337/dc12-0700
Status	Udgivet - mar. 2013

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Boonen, S. E., Mackay, D. J. G., Hahnemann, J. M. D., Docherty, L., Grønskov, K., Lehmann, A., Larsen, L. G., Haemers, A. P., Kockaerts, Y., Dooms, L., Vu, D. C., Ngoc, C. T. B., Nguyen, P. B., Kordonouri, O., Sundberg, F., Dayanikli, P., Puthi, V., Acerini, C., Massoud, A. F., ... Temple, I. K. (2013). Transient neonatal diabetes, ZFP57, and hypomethylation of multiple imprinted loci: a detailed follow-up. Diabetes Care, 36(3), 505-12. https://doi.org/10.2337/dc12-0700

Boonen, SE, Mackay, DJG, Hahnemann, JMD, Docherty, L, Grønskov, K, Lehmann, A, Larsen, LG, Haemers, AP, Kockaerts, Y, Dooms, L, Vu, DC, Ngoc, CTB, Nguyen, PB, Kordonouri, O, Sundberg, F, Dayanikli, P, Puthi, V, Acerini, C, Massoud, AF, Tümer, Z & Temple, IK 2013, 'Transient neonatal diabetes, ZFP57, and hypomethylation of multiple imprinted loci: a detailed follow-up', Diabetes Care, bind 36, nr. 3, s. 505-12. https://doi.org/10.2337/dc12-0700

@article{3c38fa680be8437c94e8ba70f5121896,

title = "Transient neonatal diabetes, ZFP57, and hypomethylation of multiple imprinted loci: a detailed follow-up",

abstract = "OBJECTIVEdTransient neonatal diabetes mellitus 1 (TNDM1) is the most common cause of diabetes presenting at birth. Approximately 5%of the cases are due to recessive ZFP57mutations, 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 METHODSdThe 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. RESULTSdThe 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. CONCLUSIONSdThere 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.",

author = "Boonen, {Susanne E} and Mackay, {Deborah J G} and Hahnemann, {Johanne M D} and Louise Docherty and Karen Gr{\o}nskov and Anna Lehmann and Larsen, {Lise G} and Haemers, {Andreas P} and Yves Kockaerts and Lutgarde Dooms and Vu, {Dung Ch{\'i}} and Ngoc, {C T Bich} and Nguyen, {Phuong Bich} and Olga Kordonouri and Frida Sundberg and Pinar Dayanikli and Vijith Puthi and Carlo Acerini and Massoud, {Ahmed F} and Zeynep T{\"u}mer and Temple, {I Karen}",

year = "2013",

month = mar,

doi = "10.2337/dc12-0700",

language = "English",

volume = "36",

pages = "505--12",

journal = "Diabetes Care",

issn = "0149-5992",

publisher = "American Diabetes Association",

number = "3",

}

TY - JOUR

T1 - Transient neonatal diabetes, ZFP57, and hypomethylation of multiple imprinted loci

T2 - a detailed follow-up

AU - Boonen, Susanne E

AU - Mackay, Deborah J G

AU - Hahnemann, Johanne M D

AU - Docherty, Louise

AU - Grønskov, Karen

AU - Lehmann, Anna

AU - Larsen, Lise G

AU - Haemers, Andreas P

AU - Kockaerts, Yves

AU - Dooms, Lutgarde

AU - Vu, Dung Chí

AU - Ngoc, C T Bich

AU - Nguyen, Phuong Bich

AU - Kordonouri, Olga

AU - Sundberg, Frida

AU - Dayanikli, Pinar

AU - Puthi, Vijith

AU - Acerini, Carlo

AU - Massoud, Ahmed F

AU - Tümer, Zeynep

AU - Temple, I Karen

PY - 2013/3

Y1 - 2013/3

N2 - OBJECTIVEdTransient neonatal diabetes mellitus 1 (TNDM1) is the most common cause of diabetes presenting at birth. Approximately 5%of the cases are due to recessive ZFP57mutations, 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 METHODSdThe 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. RESULTSdThe 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. CONCLUSIONSdThere 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.

AB - OBJECTIVEdTransient neonatal diabetes mellitus 1 (TNDM1) is the most common cause of diabetes presenting at birth. Approximately 5%of the cases are due to recessive ZFP57mutations, 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 METHODSdThe 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. RESULTSdThe 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. CONCLUSIONSdThere 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.

U2 - 10.2337/dc12-0700

DO - 10.2337/dc12-0700

M3 - Journal article

C2 - 23150280

SN - 0149-5992

VL - 36

SP - 505

EP - 512

JO - Diabetes Care

JF - Diabetes Care

IS - 3

ER -

Transient neonatal diabetes, ZFP57, and hypomethylation of multiple imprinted loci: a detailed follow-up

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