Mother holding the hand of her newborn baby

First polygenic cause found for neonatal diabetes

A new study has found the first ever polygenic cause for diabetes in children younger than six months of age

Diabetes is a condition that can affect all age groups, and it can present in children as young as six months old. Previously, the onset of diabetes in very young children was attributed to variants in single genes, but recent research has found a new, polygenic cause.

Type 1 and neonatal diabetes

Type 1 diabetes is an autoimmune condition where the body attacks and destroys the beta cells in the pancreas that manufacture insulin. Only around 8% of diabetic people have type 1, but the condition accounts for most cases of diabetes in children.

In children under six months of age, the cause of diabetes is presumed to be genetic. This condition is called neonatal diabetes and is not an autoimmune disease. Instead, it is caused by variants in the genes that affect insulin production.

Although there are 26 gene variants known to cause neonatal diabetes, they don’t tell the whole story: 10-15% of those diagnosed with the condition carry none of these variants.

It had been presumed that neonatal diabetes was always caused by a variant in a single gene, and so the 10-15% of uncertain cases were attributed to unidentified rare variants, rather than a different type of diabetes.

A new study, published in Diabetologia, has identified a rare, polygenic subtype of type 1 diabetes that affects children under six months old, suggesting that the cause is not always monogenic, as previously thought.

Finding the cause

Researchers at the University of Exeter and King’s College London compared two groups of infants who appeared to have neonatal diabetes: one group consisting of infants who had one of the 26 known diabetes-causing gene variants and one group of infants without. A third group, of children between 6 and 24 months of age, who presented with type 1 diabetes, was also included in the study.

As no polygenic autoimmune conditions had been identified in children younger than six months old before, the researchers wanted to confirm that the infants without diabetes-causing variants did indeed have diabetes. To do this, they checked for markers of autoimmunity and beta cell loss, and found that the results were comparable to those from the other two groups.

The researchers then generated a polygenic risk scoring system using the top 30 risk alleles for type 1 diabetes at any age. 38% of the infants without a previously-identified diabetes-causing variant placed in the top 5% of the population for risk of the condition. If all cases of neonatal diabetes were indeed monogenic, as had been thought, the number of individuals with this high risk score would be expected to mirror the population average of 5%.

A new subtype

The researchers concluded that the cause was a subtype of polygenic type 1 diabetes, which could account for around 4% of neonatal diabetes cases. It is the first autoimmune condition not caused by a monogenic variant to be found in children younger than six months old.

The researchers also identified that the children who presented with polygenic diabetes aged under six months were more likely to have lower birth weight than those diagnosed between six months and two years old. The difference was even greater when looking at infants who presented with diabetes before three months of age. As insulin is needed for fetal growth, these findings suggest that, in some cases, the body had started attacking the beta cells before the child was born.