GATA4 – Neonatal Diabetes Mellitus

GATA4 encodes a zinc-finger transcription factor essential for cardiac and endodermal development; it has been included in neonatal diabetes mellitus (NDM) gene panels but lacks definitive pathogenic variants in diabetic cohorts. Sequencing of GATA4 in three isolated cases of permanent NDM with pancreatic hypoplasia and congenital heart defects revealed no deleterious variants across exons and splice sites (PMID:20082465). In a large Egyptian cohort of 29 PNDM patients from 26 families, targeted NGS failed to identify GATA4 mutations among the 59% mutation-positive cases, underscoring its minimal contribution to classical NDM (PMID:34426871). A solitary heterozygous p.Pro407Gln variant was reported in two siblings with DEND syndrome, but this variant did not segregate with diabetes independently and remains of uncertain significance (PMID:35703918).

No functional studies have demonstrated a role for GATA4 in pancreatic β-cell development or insulin secretion. The absence of pathogenic alleles and lack of experimental support indicate limited clinical validity of GATA4 in NDM. Larger studies or mechanistic data would be required to further assess its role.

Key Take-home: Although critical for cardiac development, GATA4 currently shows limited genetic or functional evidence in neonatal diabetes mellitus, suggesting it is not a primary diagnostic target for NDM.

References

• American journal of medical genetics. Part A • 2010 • Pancreatic hypoplasia presenting with neonatal diabetes mellitus in association with congenital heart defect and developmental delay. PMID:20082465
• Acta diabetologica • 2021 • Genetic and clinical heterogeneity of permanent neonatal diabetes mellitus: a single tertiary centre experience. PMID:34426871
• American journal of medical genetics. Part A • 2022 • Compound heterozygous variants of the NARS2 gene in siblings with developmental delay, epilepsy, and neonatal diabetes syndrome. PMID:35703918

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