Copy Number Variation in GCK in Patients With Maturity-Onset Diabetes of the Young.

Purpose: Next generation sequencing (NGS) methods to diagnose maturity-onset diabetes of the young (MODY), a monogenic autosomal dominant cause of diabetes, do not typically detect large-scale copy number variations (CNVs). New techniques may allow assessment for CNVs using output data from targeted NGS, without requiring additional sequencing. Using this technique, two kindreds of patients presenting with features of MODY were found to bear the same heterozygous large-scale deletion in GCK.

Methods: Patients suspected of having MODY but with negative targeted NGS pathogenic variant calling were reanalyzed using the CNV caller tool (VarSeq v1.4.3). Two patients were identified as having a possible heterozygous whole exon deletion affecting exon 1 of GCK. For confirmation and determination of the exact breakpoints, whole exome sequencing followed by Sanger sequencing were used. Familial samples from both affected and nonaffected first-degree relatives were then analyzed for each proband.

Results: A heterozygous whole-exon deletion spanning 4763 bp affecting the entire exon 1 of GCK was detected in two apparently unrelated patients with clinical features of MODY. This deletion showed segregation concordance across generations in affected and nonaffected family members.

Conclusions: Our findings confirm the utility of applying the CNV caller tool to screen for CNVs in GCK from NGS data. In so doing, we identified a deletion of exon 1 of GCK as likely causal for MODY. Our data indicate that incorporating CNV analysis routinely when assessing for MODY via targeted NGS may increase diagnostic yield and reduce false negative genetic testing rates.