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Transient neonatal diabetes, a disorder of imprinting
1Wessex Clinical Genetics Service, Southampton University Hospitals NHS Trust, Coxford Road, Southampton SO16 5YA, UK. ikt@soton.ac.uk
Insights
Transient neonatal diabetes (TND) is a rare condition causing growth retardation and diabetes in newborns. While symptoms remit by 3 months, later-life diabetes is common, linked to genetic factors at 6q24.
Area of Science:
- Genetics
- Endocrinology
- Pediatrics
Background:
- Transient neonatal diabetes (TND) is a rare endocrine disorder presenting in newborns.
- Affected infants exhibit growth retardation and hyperglycemia within the first week of life.
- While TND typically remits by three months, there's an increased risk of developing diabetes later in life.
Purpose of the Study:
- To investigate the genetic underpinnings of transient neonatal diabetes.
- To identify candidate genes and mechanisms responsible for TND.
- To elucidate the genetic etiology of TND for improved diagnosis and management.
Main Methods:
- Analysis of genetic data from TND patients.
- Identification and characterization of imprinted genes in the 6q24 region.
- Investigation of genetic mechanisms including uniparental isodisomy, duplication, and methylation defects.
Main Results:
- Evidence points to the overexpression of imprinted genes in the TND critical region at 6q24.
- Candidate genes ZAC and HYMAI were identified.
- Three primary genetic mechanisms leading to TND were confirmed: paternal uniparental isodisomy of chromosome 6, paternally inherited duplication of 6q24, and methylation defects at the ZAC/HYMAI CpG island.
Conclusions:
- TND is primarily caused by genetic alterations affecting imprinted gene expression at 6q24.
- Understanding these genetic mechanisms is crucial for diagnosing and potentially treating TND.
- Further research into imprinted gene regulation may offer insights into other forms of diabetes.
Abstract:
Transient neonatal diabetes (TND) is a rare but distinct type of diabetes. Classically, neonates present with growth retardation and diabetes in the first week of life. Apparent remission occurs by 3 months but there is a tendency for children to develop diabetes in later life. Evidence suggests it is the result of overexpression of an imprinted and paternally expressed gene/s within the TND critical region at 6q24. Two imprinted genes, ZAC (zinc finger protein associated with apoptosis and cell cycle arrest) and HYMAI (imprinted in hydatidiform mole) have been identified as potential candidates. Three genetic mechanisms have been shown to result in TND, paternal uniparental isodisomy of chromosome 6, paternally inherited duplication of 6q24, and a methylation defect at a CpG island overlapping exon 1 of ZAC/HYMAI.