Congenital disorder of glycosylation with defective fucosylation 2 (FCSK gene defect): The third report in the literature with a mild phenotype

Abstract

Background Congenital disorders of glycosylation (CDG) are a group of heterogeneous disorders caused by abnormal lipid or protein glycosylation. Variants in the FCSK gene have been reported to cause CDG. Defective FCSK‐induced CDG (FCSK–CDG) has only been reported previously in three unrelated children. Methods In this study, we genetically and clinically examined a 3‐year‐old proband with resolved infantile spasms and normal development. Standard whole‐exome sequencing (WES) and Sanger sequencing were performed to identify the functional impact of the variant. Results WES revealed a rare biallelic missense variant (c.3013G>C; p.Val1005Leu) in FCSK . RT‐qPCR showed a significant depletion in FCSK gene expression in the affected individual. Western blotting revealed reduced FCSK expression at the protein level compared to that in the control. Furthermore, 3D protein modeling suggested changes in the secondary structure, which might affect the overall FCSK protein function. Conclusion This study broadens the mutation and phenotypic spectrum of FCSK‐associated developmental disorders.

Novel insight into FCSK‐congenital disorder of glycosylation through a CRISPR‐generated cell model

“…have confirmed the significant decrease of fucokinase, FCSK ‐encoded protein, in patients and the created CRISPR/Cas9 FCSK knockout HAP1 cell line, they have not seen any detectable fucosylation change in the fibroblast and serum samples of patients, and FCSK knockout cells (Ng, Rosenfeld, et al., 2018 ). Their two reported cases and the subsequent reported ones, FCSK‐CDG patients, manifested intellectual disability, developmental delay, seizure, epilepsy, gait problems, hypotonia, contractures, abnormal brain MRI, feeding difficulty, and ophthalmological disorders (Al Tuwaijri et al., 2023 ; Manoochehri et al., 2022 ; Ng, Rosenfeld, et al., 2018 ; Ozgun & Sahin, 2022 ).…”

“…(Hullen et al., 2021 ; Lefeber et al., 2011 ) It is notable that four of the five known types of fucosylation defects have been discovered quite recently, (Hullen et al., 2021 ) and it cannot be ignored that more cases will be identified after describing a disorder. Given FCSK‐CDG specifically, it is noteworthy that three of the five reported patients have Middle Eastern ancestry, (Al Tuwaijri et al., 2023 ; Manoochehri et al., 2022 ; Ng, Rosenfeld, et al., 2018 ; Ozgun & Sahin, 2022 ) which is well explainable by the recessive inheritance nature of this disease and the high rate of consanguineous marriage in some nations in the Middle East and Western Asia (Piedade et al., 2022 ). Since these are generally less‐developed countries, a high underdiagnosis of FCSK‐CDG and other fucosylation‐related CDGs with autosomal recessive inheritance is expected.…”

“…in two unrelated patients with severe multisystem manifestations such as brain anomalies, intellectual disability, developmental delay, intractable seizures accompanied by epileptic encephalopathy, muscle contractures, hypotonia, walking disability, poor feeding, difficulty in gastric emptying, and ocular disorders (Ng, Rosenfeld, et al., 2018 ). Subsequently, three other patients with different pathogenic variants in the FCSK gene have been reported, including one by our team (Al Tuwaijri et al., 2023 ; Manoochehri et al., 2022 ; Ozgun & Sahin, 2022 ). Table 1 displays the characteristics of all FCSK‐CDG patients documented thus far (Al Tuwaijri et al., 2023 ; Manoochehri et al., 2022 ; Ng, Rosenfeld, et al., 2018 ; Ozgun & Sahin, 2022 ).…”

“…T A B L E 1 Molecular and clinical characterization of CDGF2 patients (Al Tuwaijri et al, 2023;Manoochehri et al, 2022;Ng, Rosenfeld, et al, 2018;Ozgun & Sahin, 2022). U-87 MG cells were seeded in a 6-well cell culture plate, and 80% confluency was achieved after 24 h; they were co-transfected by guide-1 and guide-2 CRISPR/Cas9 constructs utilizing Lipofectamine 3000 (Thermo Fisher Scientific) according to the manufacturer's instruction.…”

“…Subsequently, three other patients with different pathogenic variants in the FCSK gene have been reported, including one by our team (Al Tuwaijri et al, 2023;Manoochehri et al, 2022;Ozgun & Sahin, 2022). Table 1 displays the characteristics of all FCSK-CDG patients documented thus far (Al Tuwaijri et al, 2023;Manoochehri et al, 2022;Ng, Rosenfeld, et al, 2018;Ozgun & Sahin, 2022).…”