Mosaic GLUD1 Mutations Associated with Hyperinsulinism Hyperammonemia Syndrome

Area of Science:

• Genetics
• Pediatrics
• Endocrinology

Background:

• Hyperinsulinemia-hyperammonemia syndrome (HIHA) is a common cause of congenital hyperinsulinism, typically due to GLUD1 gene mutations.
• Most HIHA cases result from de novo GLUD1 mutations, with genetic testing usually performed on peripheral blood DNA.
• Some patients present with HIHA symptoms but have negative genetic testing for known hyperinsulinism genes.

Purpose of the Study:

• To investigate the potential role of mosaic GLUD1 mutations in patients with clinical features of HIHA and negative genetic testing.
• To identify the underlying genetic cause in cases of congenital hyperinsulinism that are genetically unexplained by standard testing.

Main Methods:

• Next-generation sequencing (NGS) was employed on peripheral blood DNA from three patients with suspected HIHA.
• Pancreas tissue from one patient was also subjected to NGS to assess mutation presence.
• NGS was performed on a woman with a history of infantile HI and a child with HIHA due to a presumed de novo GLUD1 mutation.

Main Results:

• Mosaic GLUD1 mutations were detected in all three patients, with mosaicism levels ranging from 2.7% to 10.4% in peripheral blood.
• In one case, mosaic mutations were found at higher percentages (17.9% and 28.9%) in different pancreas tissue sections.
• Two distinct GLUD1 mutations, previously reported, were identified in these patients.

Conclusions:

• Low-level mosaic mutations in known hyperinsulinism genes can be the cause of congenital hyperinsulinism in patients with negative genetic testing in peripheral blood.
• Mosaicism should be considered in the genetic evaluation of unexplained congenital hyperinsulinism.
• Advanced sequencing techniques can uncover low-level mosaic mutations missed by standard genetic analyses.