P-233: Neonatal diabetes and congenital anomalies associated with a de novo GATA6 variant: a case report
P Konecna, J Vyzralkova, K Slaba, P Pokorna, T Kramarova, D ProchazkovaAbstract
Introduction
GATA6 is a transcription factor essential for the development of endoderm-derived organs, particularly the pancreas and heart. Pathogenic variants in GATA6 can impair beta-cell function, leading to reduced insulin secretion and early-onset diabetes. In addition to diabetes, GATA6 variants are frequently associated with additional abnormalities, most commonly congenital heart defects, pancreatic agenesis, congenital diaphragmatic hernia, and developmental delay.
Objectives
We report a case of a newborn from a pregnancy monitored prenatally for congenital heart defect and intrauterine growth restriction. The infant was delivered at 36 weeks of gestation with a birth weight of 1,460 g and a birth length of 39 cm.
Methods
Postnatal echocardiography revealed multiple cardiac malformations: subaortic ventricular septal defect, atrial septal defect, pulmonary stenosis, and patent ductus arteriosus. On day 3 of life, the patient developed severe hyperglycemia (32.4 mmol/L) with glycosuria and no ketonemia. C-peptide was markedly reduced (<33 pmol/L), and pancreatic autoantibodies were negative, consistent with neonatal diabetes mellitus. Insulin therapy was initiated immediately. Abdominal ultrasound demonstrated pancreatic hypoplasia, gallbladder aplasia, and uterus duplex.
Results
Singleton whole-exome sequencing (WES) identified a heterozygous intronic variant of uncertain significance in the GATA6 gene (NM_005257.6: c.1516+34_1517-30del; p.?). De novo origin of the variant was confirmed by Sanger sequencing of the proband and both parents.To evaluate the functional impact of this variant, RNA analysis from cultured fibroblasts is planned, given insufficient GATA6 expression in peripheral blood leukocytes, with the aim of assessing its effect on pre-mRNA splicing.
Conclusions
The combination of a de novo GATA6 variant and a compatible multisystem clinical phenotype strongly suggests a possible underlying monogenic etiology; however, definitive pathogenicity remains to be confirmed by functional studies.