A novel deep intronic EIF2AK3 variant disrupts splicing and causes Wolcott-Rallison syndrome

EIF2AK3

The deep intronic EIF2AK3 variant c.1651-180G>T creates a cryptic donor splice site within intron 9, leading to inclusion of a 79-nucleotide pseudoexon, a frameshift and a premature stop codon

A cohort of 116 individuals referred to the Exeter Genomics Laboratory for diabetes diagnosed at or before age 2 with at least one additional feature consistent with Wolcott-Rallison syndrome, and unsolved after testing all known early-onset diabetes genes, was screened in genome sequencing data for rare homozygous intronic EIF2AK3 variants. Two rare homozygous intronic variants were identified in two siblings born to consanguineous parents, only one of which, c.1651-180G>T, was predicted by SpliceAI to disrupt splicing. Both children had diabetes diagnosed at 1 year and 21 weeks, hepatic dysfunction, skeletal abnormalities, developmental delay, thyroid dysfunction, hip dysplasia and gait abnormalities. A minigene exon-trapping assay confirmed creation of a cryptic donor site in intron 9 and inclusion of a 79-nucleotide pseudoexon, allowing reclassification of the variant as likely pathogenic under ACMG/ACGS guidelines.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This is a textbook approach to a clinically typical but genetically unsolved case: targeted intronic screening of a candidate gene, SpliceAI prediction, then functional confirmation by minigene assay. The yield remains low — two siblings among 116 screened individuals — which honestly frames the size of the deep intronic reservoir in this indication. The transferable lesson is methodological: the genome has already been sequenced in many of these patients, and what is missing is intronic analysis, not additional data generation.

Analysis by Dr Thibaut Benquey