Abstract
<b><i>Introduction:</i></b> The hyperinsulinemia-hyperammonemia syndrome (HIHA) is the second most common cause of congenital hyperinsulinism and is caused by activating heterozygous missense mutations in <i>GLUD1</i>. In the majority of HIHA cases, the <i>GLUD1</i> mutation is found to be de novo. We have identified 3 patients in whom clinical evaluation was suggestive of HIHA but with negative mutation analysis in peripheral blood DNA for <i>GLUD1</i> as well as other known HI genes. <b><i>Methods:</i></b> We performed next-generation sequencing (NGS) on peripheral blood DNA from two children with clinical features of HIHA in order to look for mosaic mutations in <i>GLUD1</i>. Pancreas tissue was also available in one of these cases for NGS. In addition, NGS was performed on peripheral blood DNA from a woman with a history of HI in infancy whose child had HIHA due to a presumed de novo <i>GLUD1</i> mutation. <b><i>Results:</i></b> Mosaic <i>GLUD1</i> mutations were identified in these 3 cases at percent mosaicism ranging from 2.7% to 10.4% in peripheral blood. In one case with pancreas tissue available, the mosaic <i>GLUD1</i> mutation was present at 17.9% and 28.9% in different sections of the pancreas. Two unique GLUD1 mutations were identified in these cases, both of which have been previously reported (c.1493c>t/p.Ser445Leu and c.820c>t/p.Arg221Cys). <b><i>Conclusion:</i></b> The results suggest that low-level mosaic mutations in known HI genes may be the underlying molecular mechanism in some children with HI who have negative genetic testing in peripheral blood DNA.
Subject
Endocrinology,Endocrinology, Diabetes and Metabolism,Pediatrics, Perinatology and Child Health
Cited by
3 articles.
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