Glutaminase Deficiency Caused by Short Tandem Repeat Expansion in <i>GLS</i>

Abstract

We report an inborn error of metabolism caused by an expansion of a GCA-repeat tract in the 5' untranslated region of the gene encoding glutaminase (<i>GLS</i>) that was identified through detailed clinical and biochemical phenotyping, combined with whole-genome sequencing. The expansion was observed in three unrelated patients who presented with an early-onset delay in overall development, progressive ataxia, and elevated levels of glutamine. In addition to ataxia, one patient also showed cerebellar atrophy. The expansion was associated with a relative deficiency of <i>GLS</i> messenger RNA transcribed from the expanded allele, which probably resulted from repeat-mediated chromatin changes upstream of the <i>GLS</i> repeat. Our discovery underscores the importance of careful examination of regions of the genome that are typically excluded from or poorly captured by exome sequencing.