Biallelic SLC25A36 mutation causes hyperinsulinism/hyperammonemia syndrome

Hyperinsulinism/Hyperammonemia (HIHA) syndrome, the second most common form of congenital hyperinsulinism, is characterized by recurrent symptomatic hypoglycemia combined with persistently elevated serum ammonia levels. HIHA syndrome has been shown to be caused by dominant activating mutations in GLUD1, encoding the intra-mitochondrial enzyme glutamate dehydrogenase (GDH1). In this study, we present four children from consanguineous Bedouin kindred that were diagnosed with an autosomal recessive consistent HIHA syndrome phenotype with no mutations in GLUD1. Genome-wide linkage analysis of ten family members was performed using 750K SNP arrays, HomozigosityMapper and SuperLink softwares. Whole exome sequencing was performed for one affected individual and analyzed using the Qiagen Clinical Insight software and our in-house database of ~700 samples. A single ~16 Mbp homozygous disease-associated locus was identified on chromosome 3 (maximal LOD score of 2.65). Using our filtering analysis pipeline only one homozygous variant was found within the locus: a highly conserved SLC25A36 c.284+3A>T splice site mutation. The variant was validated by Sanger sequencing and segregated as expected within the family. The mutation changes the 5` splice site consensus sequence and leads to exon 3 skipping. In parallel to two recent independent studies, we report a homozygous mutation in SLC25A36 as causing HIHA syndrome phenotype. The SLC25A36/PNC2 encodes a mitochondrial transporter that imports/exports pyrimidine and guanine nucleotides. Our study reinforces the involvement of SLC25A36 in the development of the HIHA syndrome through a recessive mode of inheritance.