Mosaic <b><i>GLUD1</i></b> Mutations Associated with Hyperinsulinism Hyperammonemia Syndrome
Kara E. Boodhansingh, Elizabeth Rosenfeld, Katherine Lord, N. Scott Adzick, Tricia Bhatti, Arupa Ganguly, Diva D. De León, Charles A. Stanley
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&#x3e;t/p.Ser445Leu and c.820c&#x3e;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.