A maternal hypomethylation syndrome presenting as transient neonatal diabetes mellitus

Mackay, Deborah J G; Boonen, Susanne E.; Clayton‐Smith, Jill; Goodship, Judith A.; Hahnemann, Johanne M D; Kant, S. G.; Njølstad, Pål R.; Robin, Nathaniel H.; Robinson, David; Siebert, Reiner; Shield, Julian P H; White, Helen; Temple, I. Karen

doi:10.1007/s00439-006-0205-2

Cited by 146 publications

(119 citation statements)

References 33 publications

(35 reference statements)

Supporting

Mentioning

104

Contrasting

Unclassified

Order By: Relevance

“…These findings underline the lower birthweight and earlier presentation in 6q24 TNDM that is caused by potassium channel mutations (<1st vs 12th centile, and <1 week vs 4 weeks, respectively). However, the relatively low birthweight previously reported in duplication patients [8] was not supported by this study. While birthweight (adjusted for gestation) was normally distributed, the ages of presentation and remission of diabetes were markedly skewed, with modes at 1 day and 2 months, but means of 8 days and 4.5 months.…”

Section: Discussioncontrasting

confidence: 99%

Clinical presentation of 6q24 transient neonatal diabetes mellitus (6q24 TNDM) and genotype–phenotype correlation in an international cohort of patients

et al. 2013

Self Cite

View full text Add to dashboard Cite

Aims/hypothesis 6q24 transient neonatal diabetes mellitus (TNDM) is a rare form of diabetes presenting in the neonatal period that remits during infancy but, in a proportion of cases, recurs in later life. We aim to describe the clinical presentation of 6q24 TNDM in the largest worldwide cohort of patients with defined molecular aetiology, in particular seeking differences in presentation or clinical history between aetiological groups. Methods One-hundred and sixty-three patients with positively diagnosed 6q24 TNDM were ascertained from Europe, the Americas, Asia and Australia. Clinical data from referrals were recorded and stratified by the molecular aetiology of patients. Results 6q24 TNDM patients presented at a modal age of one day, with growth retardation and hyperglycaemia, irrespective of molecular aetiology. There was a positive correlation between age of presentation and gestational age, and a negative correlation between adjusted birthweight SD and age of remission. Congenital anomalies were significantly more frequent in patients with paternal uniparental disomy of chromosome 6 or hypomethylation of multiple imprinted loci defects than in those with 6q24 duplication or isolated hypomethylation defects. Patients with hypomethylation had an excess representation of assisted conception at 15%. Conclusions/interpretation This, the largest case series of 6q24 TNDM published, refines and extends the clinical phenotype of the disorder and confirms its clinical divergence from other monogenic TNDM in addition to identifying previously unreported clinical differences between 6q24 subgroups.

show abstract

Section: Discussioncontrasting

confidence: 99%

Clinical presentation of 6q24 transient neonatal diabetes mellitus (6q24 TNDM) and genotype–phenotype correlation in an international cohort of patients

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…1 Similar dual LOM had previously been demonstrated in two patients by Arima et al 2 Subsequently, we showed that 6 out of 12 anonymised TNDM patients with LOM at TNDM DMR (6q24) in addition had a diverse spectrum of maternal hypomethylation at multiple imprinted loci including KCNQ1OT1 (11p15.5), and we suggested the existence of a maternal hypomethylation syndrome. 3 A similar spectrum of multiple maternal hypomethylation was found by Rossignol et al, 4 in 10 out of 40 LOM BWS patients.…”

Section: Introductionsupporting

confidence: 67%

“…[2][3][4][5][6][7][8][9][10][11][12], PEG1/MEST (7q32), KCNQ1OT1 and H19 (both 11p15.5), DLK1 (14q32), SNRPN (15q11-12), PEG3 (19q13), and NESPAS (20q13) by methylation-specific PCR (MS-PCR) following bisulphite treatment, as previously described. 1,3,5 Primer sequences for NESPAS were derived from Williamson et al 6 Aberrant results were confirmed by either pyrosequencing 7 or MS-PCR with another primer set. Control data were drawn from previous publications, 1,3 with supplementary MS-PCR at some loci to obtain an epigenotype of all 120 anonymised normal controls at all the loci.…”

Section: Laboratory Investigationsmentioning

confidence: 99%

“…1,3,5 Primer sequences for NESPAS were derived from Williamson et al 6 Aberrant results were confirmed by either pyrosequencing 7 or MS-PCR with another primer set. Control data were drawn from previous publications, 1,3 with supplementary MS-PCR at some loci to obtain an epigenotype of all 120 anonymised normal controls at all the loci. For the sisters, the MS-PCR was performed on genomic DNA extracted from EDTA-stabilised whole blood, cells from repeated buccal swabs, and skin fibroblasts.…”

Section: Laboratory Investigationsmentioning

confidence: 99%

See 1 more Smart Citation

Clinical characterisation of the multiple maternal hypomethylation syndrome in siblings

et al. 2008

View full text Add to dashboard Cite

We present the first clinical report of sibs with the multiple maternal hypomethylation syndrome. Both sisters presented with transient neonatal diabetes mellitus (TNDM). By methylation-specific PCR of bisulphite-treated DNA, we found a mosaic spectrum of hypomethylation at the following maternally methylated loci in both sibs:, and NESPAS (20q13). While the older sister has a milder phenotype, the younger one was severely ill and died at 11 months of age. Despite phenotypic differences, the sisters had several manifestations of both TNDM and BWS in common. The family is highly consanguineous, and the parents are first cousins. We suggest that the genetic defect in this family is a novel, most likely autosomal recessive defect of methylation mechanisms, either in the sisters or in their mother, affecting her oocyte imprinting. The recurrence with affected sibs as reported in this family has implications for genetic counselling.

show abstract

“…8 A subset of BWS patients with hypomethylation at the KCNQ1OT1 ICR (IC2 defect, ICD2) have loss of methylation at other imprinted loci. 9 Hypomethylation of multiple maternally methylated ICRs including KCNQ1OT1 has also been demonstrated in cases of transient neonatal diabetes 10,11 (TND, OMIM 601410). TND is a disease characterised by intrauterine growth retardation and transient hyperglycaemia that results from dysregulation of the imprinted growth inhibitor and antiapoptotic PLAGL1 (ZAC) gene located at chromosome 6q24.…”

Section: Introductionmentioning

confidence: 99%

Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith–Wiedemann syndrome

et al. 2008

View full text Add to dashboard Cite

Genomic imprinting is an epigenetic phenomenon restricting gene expression in a manner dependent on parent of origin. Imprinted gene products are critical regulators of growth and development, and imprinting disorders are associated with both genetic and epigenetic mutations, including disruption of DNA methylation within the imprinting control regions (ICRs) of these genes. It was recently reported that some patients with imprinting disorders have a more generalised imprinting defect, with hypomethylation at a range of maternally methylated ICRs. We report a cohort of 149 patients with a clinical diagnosis of Beckwith -Wiedemann syndrome (BWS), including 81 with maternal hypomethylation of the KCNQ1OT1 ICR. Methylation analysis of 11 ICRs in these patients showed that hypomethylation affecting multiple imprinted loci was restricted to 17 patients with hypomethylation of the KCNQ1OT1 ICR, and involved only maternally methylated loci. Both partial and complete hypomethylation was demonstrated in these cases, suggesting a possible postzygotic origin of a mosaic imprinting error. Some ICRs, including the PLAGL1 and GNAS/NESPAS ICRs implicated in the aetiology of transient neonatal diabetes and pseudohypoparathyroidism type 1b, respectively, were more frequently affected than others. Although we did not find any evidence for mutation of the candidate gene DNMT3L, these results support the hypotheses that trans-acting factors affect the somatic maintenance of imprinting at multiple maternally

show abstract

A maternal hypomethylation syndrome presenting as transient neonatal diabetes mellitus

Cited by 146 publications

References 33 publications

Clinical presentation of 6q24 transient neonatal diabetes mellitus (6q24 TNDM) and genotype–phenotype correlation in an international cohort of patients

Clinical presentation of 6q24 transient neonatal diabetes mellitus (6q24 TNDM) and genotype–phenotype correlation in an international cohort of patients

Clinical characterisation of the multiple maternal hypomethylation syndrome in siblings

Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith–Wiedemann syndrome

Contact Info

Product

Resources

About