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- Title
<italic>FOXP3</italic> mutations causing early‐onset insulin‐requiring diabetes but without other features of immune dysregulation, polyendocrinopathy, enteropathy, X‐linked syndrome.
- Authors
Hwang, Jessica L.; Park, Soo‐Young; Ye, Honggang; Sanyoura, May; Pastore, Ashley N.; Carmody, David; del Gaudio, Daniela; Wilson, Janna F.; Hanis, Craig L.; Liu, Xiaoming; Atzmon, Gil; Glaser, Benjamin; Philipson, Louis H.; Greeley, Siri Atma W.; T2D‐Genes Consortium
- Abstract
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. <italic>FOXP3</italic> 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 <italic>FOXP3</italic>. 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 <italic>FOXP3</italic> 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 <italic>FOXP3</italic> mutations can cause early‐onset insulin‐requiring diabetes with or without other features of IPEX syndrome.
- Subjects
GENETICS of diabetes; TYPE 2 diabetes diagnosis; AGE factors in disease; AUTOIMMUNE diseases; GENOMES; IMMUNE system; INSULIN; INTESTINAL diseases; X-linked genetic disorders; GENETIC mutation; POLYMERASE chain reaction; RNA; TRANSCRIPTION factors; PHENOTYPES; REVERSE transcriptase polymerase chain reaction; SEQUENCE analysis; GENOTYPES; CHILDREN
- Publication
Pediatric Diabetes, 2018, Vol 19, Issue 3, p388
- ISSN
1399-543X
- Publication type
Article
- DOI
10.1111/pedi.12612