Expanding the mutational spectrum of GCK in Turkish pediatric population

Abstract

Heterozygous loss-of-function variants in GCK cause persistent, mildly elevated plasma glucose beginning at birth. Recently, clinical phenotype created by deleterious variants in GCK is called GCK-MODY, although currently registered as "MODY, type 2" (maturity-onset diabetes of the young type 2, MODY2, MIM # 125851) in OMIM. The hyperglycemia of GCK-MODY is a benign and non-progressive condition, usually suspected upon detection of hyperglycemia in adulthood. Medication is not essential, nevertheless, pregnant females may require special attention. Here, we report recurrent and novel GCK variants detected in 43 pediatric patients who were investigated for hyperglycemia by the referring pediatric endocrinologist. Electronic medical records (EMR) of the patients were collected and reviewed retrospectively. All patients applied to Ankara City Hospital between April 2019 and June 2022. GCK variants were screened on NovaSeq 6000 next-generation sequencing platform (Illumina). Variants detected in GCK were checked with recent literature for a proper pathogenicity classification. In 43 patients, 28 distinct GCK variants were identified. Of these variants, 25 were classified as likely pathogenic/pathogenic variants (c.1342G>A, c.112C>T, c.1178T>C, c.130G>A, c.565A>G, c.208+3A>T, c.349G>C, c.863+5G>A, c.214G>A, c.1292C>A, c.830_831delTG, c.106C>T, c.572G>A, c.107G>C, c.454T>C, c.793G>A, c.645C>A, c.377T>A, c.667G>A, c.46-1G>A, c.149A>C, c.1079C>G, c.401T>C, c.758T>G, c.467_483+6del; NM_000162.5), while remaining 3 variants (c.950A>C, c.186G>T, c.188G>A; NM_000162.5) were classified as variant of uncertain significance. According to the variant effect, missense variants accounted for the majority (71%; 20/28), followed by splice junction (14%; 4/28), premature termination (7%; 2/28), frameshift (4%; 1/28), and synonymous (4%; 1/28) alterations. There were 3 novel variants: c.830_831del, c.377T>A, c.467_483+6del.