A cohort of GFPT1 related congenital myasthenic syndrome in China: high frequency of c.331 c > t variant

Abstract

Background: Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is the key enzyme initiating protein O- and N-glycosylation at the postsynaptic membrane. Variants in GFPT1 gene cause congenital myasthenic (GFPT1-CMS). However, the understanding of the phenotype and genetic spectrum of GFPT1-CMS remains limited.

Methods: A total of 24 patients with GFPT1-CMS from 22 Han Chinese families across four neuromuscular disease centers were included in this study. Clinical assessments involved detailed medical histories, muscle biopsies, and electrophysiological studies. GFPT1 variants were identified using targeted next-generation sequencing or WES. Additionally, published GFPT1-CMS case data from 2011 to 2024 were compiled and combined with this cohort for genotype-phenotype correlation analysis.

Results: In addition to the limb girdle myasthenia pattern, our cohort presented with extraocular involvement including eyelid ptosis and mild ophthalmoparesis (25.0%), facial weakness (20.8%) and a relatively high prevalence of distal weakness (62.5%). Electrophysiological testing revealed myopathic changes in 95.0% of cases and decremental CMAPs in all cases during RNS. We found that c.331 C > T is a hotspot variant in GFPT1-CMS patients and may have a founder effect in the Chinese population. Patients with homozygous null variants presented a more severe phenotype, including earlier onset and more frequent bulbar involvement.

Conclusion: We have described the clinical features and variant spectrum in a cohort of 24 Chinese GFPT1-CMS patients. Our findings update the understanding of clinical manifestation, pathological features and mutational spectrum in GFPT1-CMS patients.

Keywords: Congenital myasthenic syndrome; Distal muscle weakness; Glutamine-fructose-6-phosphate transaminase 1; Tubular aggregates.

Fig. 1

Muscle pathology of GFPT1-CMS patients. Muscle pathology showed tubular aggregates (Pt. 9) (A-C) and vacuoles (Pt. 2) (D)

Fig. 2

Schematic representation of GFPT1 variants and haplotype analysis. (A) Schematic presentation of GFPT1 variants. Variants newly identified in this study are shown in bold black text. (B) Haplotype analysis. Red/pink triangles represent alleles with/without c. 331 C> T. Light blue triangles indicate references sequence, whereas blue triangles indicate the polymorphic variant

Fig. 3

Schematic representation of the distribution and frequency analysis of GFPT1 variants. (A) Age of onset distribution across different regions, categorized into birth, 0–10, 10–18, and over 18 years. (B) The distribution of variant types, with missense variants comprising 76.4% of the entire dataset, and within missense variants, c.331 C > T accounts for 28.7%. (C) Chord plot for the association between recurrent variants and ethnicity, where the thickness of the connecting bands represents the number of variants. (D) Allele frequency comparison of c.331 C > T between different populations. (E) The frequency of c.331 C > T variant between the Han Chinese and other populations. (F) Structural distribution of GFPT1 variants, highlighting the allele counts in global cohort, with a high frequency of c.331 C > T variant.