de novo 12q24.31 MODY3 diagnosis

Molecular diagnosis of MODY3 reveals a de novo 12q24.31 deletion explaining a complex phenotype in a young diabetic patient

Monogenic diabetes is present in 2-6% of pediatric patients and maturity onset diabetes of the young (MODY) is the most common form. MODY includes a number of heterogeneous disorders where the symptoms do not involve autoimmune issues. It is important to do genetic testing to find the molecular diagnosis of MODY to both clarify the progress of the disease and to choose the appropriate treatment.

The authors discuss the case of a female patient, who at 10 years of age developed diabetes mellitus, characterized by excessive urination, excessive thirst, hyperglycemia, elevated hemoglobin A1c and ketoacidosis. Autoimmune diabetes markers were negative and the patient did not show clinical signs of insulin resistance, poor nutrition status or poor kidney function. However, the patient had Hashimoto’s thyroiditis, atrial septal defect, a history of seizures, psychomotor delay, autism spectrum disorder and other minor physical characteristics often linked to chromosome abnormalities.

Genetic tests for monogenic diabetes were performed. An analysis showed no pathogenic mutations in several of the genes often linked to monogenic diabetes (HNF1A, HNF4A and GCK). However, a de novo heterozygous deletion of the patient’s entire HNF1A gene was found, suggesting a MODY3 diagnosis. A high resolution comparative genomic hybridization array revealed deletion of 1.04 Mb on chromosome 12q24.31, encompassing 20 OMIM genes.

Three cases with a similar deletion on 12q24.31 have previously been reported and these individuals shared similar clinical features to the patient discussed. In these patients the observed deletions included ACADS, SPPL3, HNF1A, OASL, P2RX7, P2RX4, CAMKK2, ANAPC5 and RNF34 genes, which could explain some of the similar clinical signs in all four patients.

The HNF1A gene helps to regulate the expression of multiple genes in the pancreatic islet cells and in the liver, and mutations can be linked to insulin deficiency and severe hyperglycemia associated with ketoacidosis similar to type 1 diabetes. HNF1A mutation carriers usually respond to sulfonylureas (oral hypoglycemic agents stimulating insulin production). After confirming the MODY3 diagnosis in the patient, insulin therapy was replaced with oral sulfonylureas, showing a significant improvement.

Additional cases of 12q24.31 deletion involving a shorter common region not including the HNF1A gene had previously been reported in other patients. As expected, the clinical manifestations in these patients were different: they did not have a MODY3 diagnosis and showed different facial dysmorphisms.

Iafusco F. et al. “Molecular diagnosis of MODY3 permitted to reveal a de novo 12q24.31 deletion and to explain a complex phenotype in a young diabetic patient.” Clin Chem Lab Med. 2019, v. 57 (12), e306-e310.