LAUSR

Diabetes occurs in 1/90 000 to 1/160 000 births and when diagnosed under 6 months of age is very likely to have a primary genetic cause. FOXP3 encodes a transcription factor critical for T regulatory cell function and mutations are known to cause “immune dysregulation, polyendocrinopathy (including insulin‐requiring diabetes), enteropathy, X‐linked” (IPEX) syndrome. This condition is often fatal unless patients receive a bone‐marrow transplant. Here we describe the phenotype of male neonates and infants who had insulin‐requiring diabetes without other features of IPEX syndrome and were found to have mutations in FOXP3. Whole‐exome or next generation sequencing of genes of interest was carried out in subjects with isolated neonatal diabetes without a known genetic cause. RT‐PCR was carried out to investigate the effects on RNA splicing of a novel intronic splice‐site variant. Four male subjects were found to have FOXP3 variants in the hemizygous state: p.Arg114Trp, p.Arg347His, p.Lys393Met, and c.1044+5G>A which was detected in 2 unrelated probands and in a brother diagnosed with diabetes at 2.1 years of age. Of these, p.Arg114Trp is likely a benign rare variant found in individuals of Ashkenazi Jewish ancestry and p.Arg347His has been previously described in patients with classic IPEX syndrome. The p.Lys393Met and c.1044+5G>A variants are novel to this study. RT‐PCR studies of the c.1044+5G>A splice variant confirmed it affected RNA splicing by generating both a wild type and truncated transcript. We conclude that FOXP3 mutations can cause early‐onset insulin‐requiring diabetes with or without other features of IPEX syndrome.