Identification of the ACTB p.Ser348Leu de novo variant in individuals with syndromic neonatal diabetes.

BACKGROUND

Identifying novel genetic causes of diabetes in the first 6 months of life (neonatal diabetes) can highlight genes and pathways essential for pancreatic beta-cell development and function in humans. Our aim was to uncover genetic aetiologies of neonatal diabetes.

METHODS

We performed genome sequencing in 38 probands diagnosed with neonatal diabetes without an identified genetic cause, and their unaffected parents. Genes with de novo coding variants in ≥2 probands were followed up. Replication was performed in a separate cohort of 288 genetically unresolved individuals diagnosed with neonatal diabetes.

FINDINGS: The de novo ACTB (p.Ser348Leu) variant was identified in two unrelated individuals. Both had diabetes onset soon after birth (1 and 8 days), low birthweight (-3.22SD and -3.98SD), and extra-pancreatic features (hearing loss and developmental delay in one; intestinal atresia in the other). The same ACTB (p.Ser348Leu) variant was reported in seven individuals in the literature; one individual had confirmed neonatal diabetes and a further two had hyperglycaemia. Extra-pancreatic features were similar to our probands (hearing loss in 3/7; neurodevelopmental features in 4/7; gastrointestinal atresia in 6/7). In total, 5/9 individuals with the ACTB (p.Ser348Leu) variant had neonatal diabetes or hyperglycaemia. None of the 96 cases with other ACTB pathogenic variants in the Human Gene Mutation Database had diabetes.

INTERPRETATION: The identification of 3 individuals (two in this report and one from the literature) with neonatal diabetes and a de novo ACTB p.(Ser348Leu) variant supports ACTB as a previously unrecognised neonatal diabetes aetiological gene, most likely through a variant-specific mechanism.

FUNDING: Diabetes UK; EFSD/NNF; NIHR, Wellcome Trust.