6q24 Transient Neonatal Diabetes
There are two genes that are thought to be responsible for 6q24 TND: these genes are called PLAGL1 and HYMAI. They are both located on chromosome 6 (at position 6q24).
These genes are regulated through a process called parental imprinting: the copies of these genes inherited from the mum are switched off through a mechanism called methylation (represented as yellow circles in the figure below). The copy inherited from dad is not switched off (not methylated) and it is therefore active. This imprinting is set around the time when a baby is conceived.
In patients with 6q24 TND, too much PLAGL1 and HYMAI are made, and this can be for one of three reasons.
SCENARIO A – Loss of maternal methylation:
There was an error when the imprinting was reset in the baby at the very early stages of pregnancy. This resulted in the maternal copy of chromosome 6 not being switched off. This is called ‘loss of maternal methylation’ and it is a rare event that usually happens randomly. Since it is usually a random event, it is unlikely that the parents will have another affected baby. Furthermore, it is very unlikely that a baby with TND caused by this defect will have a child with TND (see Q&A below). About 1 in 5 patients with TND who have this defect also have mutations in both copies of a gene called ZFP57. This gene is one of the regulators that reset imprinting just after conception, and when ZFP57 doesn’t work, the re-setting of imprinting is defective. If a child inherits mutations in ZFP57 from both parents, there is a 1 in 4 chance that future children will inherit these same mutations and also have TND (see Q&A below).
Q. I have a child with 6q24 TND; what is the risk that my next child will also have 6q24 TND?
A. Does the baby have mutations in both copies of ZFP57?
Yes = 1 in 4
No = LOW RISK
Q. I have 6q24 TND; what is the risk that my child will have 6q24 TND?
A. Do you have a mutation in ZFP57?
Yes = It depends on whether your partner also has a mutation or not
No = LOW RISK
SCENARIO B – Uniparental disomy:
There was an error when the chromosomes were separated in the baby at the very early stages of pregnancy. This resulted in the baby inheriting both copies of chromosome 6 from their dad and none from their mum. This means that both copies of the genes at 6q24 are unmethylated, and both switched on; and this causes TND. When a baby inherits both chromosomes from the same parent it is called uniparental disomy. This is a rare, random event, and the chances that the baby’s parents will have another child with TND are very low (<1%). Furthermore, it is very unlikely that a baby with TND caused by uniparental disomy will have a child with TND (see Q&A below).
Q. I have a child with 6q24 TND; what is the risk that my next child will also have 6q24 TND?
A. VERY LOW (<1%)
Q. I have 6q24 TND; what is the risk that my child will have 6q24 TND?
A. VERY LOW (<1%)
SCENARIO C – Duplication on the paternal copy of the genes on 6q24
A baby normally inherits one copy of PLAGL1 and HYMAI from mum, and one from dad. If the baby inherits an extra copy, this is called a duplication. If the extra copies of PLAGL1 and HYMAI come from dad, they are unmethylated and therefore active. This results in too many copies of the genes at 6q24 being active, and causes TND. If the father of the baby also carries the duplication, he has a 1 in 2 chance of passing it on to each of his children (see Q&A below). If a 6q24 duplication is inherited from the mother it does not result in 6q24 TND because both maternal copies of the genes on 6q24 (the ‘normal’ and the ‘duplicated’ copy) would be methylated and therefore inactive.
A baby with TND and paternal duplication of PLAGL1 and HYMAI will have a 1 in 2 chance of passing this duplication on to their offspring. If the affected baby is male, he will pass on unmethylated copies of PLAGL1 and HYMAI, and children inheriting the duplicated DNA will develop TND. If the baby is female, her offspring will still have a 1 in 2 chance of inheriting the duplicated genes – but they will be methylated and inactive. Therefore her children will not develop TND (see Q&A below).
Q. I have a child with 6q24 TND; what is the risk that my next child will also have 6q24 TND?
A. Does the baby’s father also have the duplication?
Yes = 1 in 2
No = LOW RISK
Q. I have 6q24 TND; what is the risk that my child will have 6q24 TND?
A. Are you male?
Yes = 1 in 2
No = There is 1 in 2 chance that the baby will inherit the duplication but they will NOT have 6q24 TND