The application of precision medicine in monogenic diabetes

ABSTRACT

Introduction

Monogenic diabetes, a form of diabetes mellitus, is caused by a mutation in a single gene and may account for 1–2% of all clinical forms of diabetes. To date, more than 40 loci have been associated with either isolated or syndromic monogenic diabetes.

Areas covered

While the request of a genetic test is mandatory for cases with diabetes onset in the first 6 months of life, a decision may be difficult for childhood or adolescent diabetes. In an effort to assist the clinician in this task, we have grouped monogenic diabetes genes according to the age of onset (or incidental discovery) of hyperglycemia and described the additional clinical features found in syndromic diabetes. The therapeutic options available are reviewed.

Expert opinion

Technical improvements in DNA sequencing allow for rapid, simultaneous analysis of all genes involved in monogenic diabetes, progressively shrinking the area of unsolved cases. However, the complexity of the analysis of genetic data requires close cooperation between the geneticist and the diabetologist, who should play a proactive role by providing a detailed clinical phenotype that might match a specific disease gene.

KEYWORDS:

• B cell
• genetics
• monogenic diabetes
• neonatal diabetes
• syndromic diabetes

Article highlights

• Pathogenic variants in more than 40 loci cause monogenic diabetes.

• Most cases of Maturity Onset Diabetes of the Young (MODY) are caused by mutations in 2 genes: GCK (heterozygous, loss-of-function) and HNF1A.

• Most cases of permanent neonatal diabetes mellitus (PNDM) in non consanguineous families are caused by pathogenic variants in KCNJ11, INS, and ABCC8 ((heterozygous, gain-of-function in all 3 genes), while most frequent genes in consanguineous families are EIF2AK3, INS (homozygous, loss-of-function), PTF1A (enhancer), and GCK (biallelic, loss-of-function).

• Specific clinical MODY phenotype (e.g.: GCK, HNF1B) may help to decide whether a novel genetic variant can be considered a causative mutation.

• Age at onset of diabetes may guide to decide whether a novel genetic variant can be considered a causative mutation.