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Genetic and epigenetic defects at the 6q24 imprinted locus in a cohort of 13 patients with transient neonatal diabetes: new hypothesis raised by the finding of a unique case with hemizygotic deletion in the critical region

¹ Inserm U781, Université Paris 5, Paris, France
² Département de Cytogénétique, Université Pierre et Marie Curie, AP-HP Saint Antoine, Paris, France
³ Faculté de Médecine Paris 5, Fédération de Pédiatrie, Hôpital Necker-Enfants Malades, Paris, France

Correspondence to:
Dr C Diatloff-Zito
Inserm U781 Groupe Hospitalier Necker Enfants-Malades, 149-161 rue de Sèvres 75743, Paris Cedex 15, France;diatloff{at}necker.fr] Background: Transient neonatal diabetes (TND) is a rare form of diabetes usually present in the first few days after birth that resolves within 1 year but that has a tendency to recur later in life. It can be associated with chromosome 6 paternal uniparental disomy (UPD), paternal duplications or loss of maternal methylation at the 6q24 imprinted locus.

Objective: To report on a cohort of 13 sporadic TND cases, including five with birth defects (congenital abnormalities of heart, brain and bone) and eight without.

Results: The hallmarks of diabetes were similar in patients with or without 6q24 defects. The chromosome 6 abnormalities in our patients (n = 13) included 2 of 13 (approximately 15.4%) cases of paternal UPD6, 2 of 11 (approximately 18%) cases of complete and 3 of 11 (approximately 27%) cases of partial loss of the maternal methylation signature upstream of ZAC1-HYMAI imprinted genes in non-UPD cases, and 1 of 13 (approximately 7.7%) cases of hemizygotic deletion.

Conclusion: The deletion was found in a patient with severe congenital abnormalities. This genetic lesion was not reported previously. The hypothesis of an effect on regulatory elements critical for imprinting and tissue-specific gene expression in early development by the deletion is raised. The data presented here may contribute to the diagnosis and the understanding of imprinting in the region.

Abbreviations: CGi, CpG islands; DMR, differentially methylated region; ICE, imprinting control element; PCR, polymerase chain reaction; TND, transient neonatal diabetes; UPD, uniparental disomy

Keywords: transient neonatal diabetes; genetics; imprinting; methylation; deletion