Clinical, laboratory and molecular features of glycogen storage disease type 1a and 1b patients from Turkey: novel mutations and phenotypes.

Unlabelled: Glycogen storage disease type 1 (GSD1), which is categorized into GSD1a and GSD1b, is caused by disease-causing genetic variants in G6PC or SLC37A4 genes, respectively. The aim of this study was to present clinical characteristics, novel phenotypic and molecular features as well as long-term complications of the largest cohort of patients in Turkey and one of the largest cohorts in the world. The demographic, clinical, and molecular data of GSD1a or 1b patients who were followed up between 2000 and 2024 were collected retrospectively from patients' medical records. A total of 39 GSD1a patients were enrolled, and four different variants in the G6PC gene, c.247C > T (p.R83C), c.809G > T (p.G270V), c.562G > C (p.G188R), c.480G > A (p.W160*) were revealed. The most common variant among Turkish GSD1a patients was the c.247C > T (p.R83C) variant with an allele frequency of about 90%. Some unusual clinical features such as stroke, cataract, and mental retardation were observed in some patients. Also, cardiac hypertrophy was detected in three patients. Six different variants in the SLC37A4 gene, c.1042_1043delCT (p.L348Vfs*53), c.892_905del (p.N298Pfs*23), c.1015G > T (p.G339C), c.817G > A (p.G273S), c.892A > G (p.N298D), and c.382 T > C (p.W128R) were detected in eight patients with GSD1b, of which c.892A > G (p.N298D) and c.892_905del (p.N298Pfs*23) were novel. The most prevalent variant was c.1042_1043delCT (p.L348Vfs*53). The patient with the novel variant c.892A > G (p.N298D) has shown a very mild clinical course and was diagnosed in adulthood. This patient also had a co-existing HNF1A variants causing hepatic adenomas and MODY Diabetes.

Conclusions: Based on our study with the largest cohort from Turkey, the c.247C > T (p.R83C) allele frequency was found to be 85% for GSD1a, resembling the Ashkenazi Jewish population. The most frequent pathogenic genetic variant for GSD1b was found to be c.1042_1043delCT (p.L348Vfs*53). There were patients with novel presentations and coexistent phenotypic features. The high frequency of consanguineous marriages, of course, significantly contributes to such molecular and clinical findings, but further studies are obviously needed to investigate other factors.

What Is Known: • Glycogen storage disease type 1 (GSD1), which is categorized into GSD1a and GSD1b, is an autosomal recessive inborn error of metabolism, caused by disease-causing genetic variants in G6PC or SLC37A4 genes. The allelic homogeneity of G6PC gene was described in some ethnic or geographical origin. • Without adequate treatments long term complications may present in both GSD1a and GSD1b.

What Is Known: • This study documented the genotypic background and showed that c.247C>T (p.R83C) pathogenic genetic variant allele frequency is very high in Turkey for GSD1a resembling the Ashkenazi Jewish population and the c.1042_1043delCT (p.L348Vfs*53) disease-causing genetic variant seems to be the most frequent one for GSD1b. • This study includes largest cohort from Turkey with a high frequency of consanguineous marriages, and also presents phenotypic and genotypic features, co-existent diseases or conditions that could modify the clinical course.