Single‐center experience of N‐linked Congenital Disorders of Glycosylation with a Summary of Molecularly Characterized Cases in Arabs

Abstract

Congenital disorders of glycosylation (CDG) represent an expanding group of conditions that result from defects in protein and lipid glycosylation. Different subgroups of CDG display considerable clinical and genetic heterogeneity due to the highly complex nature of cellular glycosylation. This is further complicated by ethno-geographic differences in the mutational landscape of each of these subgroups. Ten Arab CDG patients from Latifa Hospital in Dubai, United Arab Emirates, were assessed using biochemical (glycosylation status of transferrin) and molecular approaches (next-generation sequencing [NGS] and Sanger sequencing). In silico tools including CADD and PolyPhen-2 were used to predict the functional consequences of uncovered mutations. In our sample of patients, five novel mutations were uncovered in the genes: MPDU1, PMM2, MAN1B1, and RFT1. In total, 9 mutations were harbored by the 10 patients in 7 genes. These are missense and nonsense mutations with deleterious functional consequences. This article integrates a single-center experience within a list of reported CDG mutations in the Arab world, accompanied by full molecular and clinical details pertaining to the studied cases. It also sheds light on potential ethnic differences that were not noted before in regards to CDG in the Arab world.

International clinical guidelines for the management of phosphomannomutase 2‐congenital disorders of glycosylation: Diagnosis, treatment and follow up

“…Mutation analysis of PMM2 has been reported in 475 patients, with mutations mostly identified by direct Sanger sequencing. In addition, three patients have been molecularly diagnosed by whole exome sequencing, one by autozygocyty mapping, and four by gene panel targeted sequencing …”

RFT1-CDG: Absence of Epilepsy and Deafness in Two Patients with Novel Pathogenic Variants

“…Of note are that the siblings with a mild phenotype reported by Ondruskova et al (2012) had variants located in the transmembrane domain and that our patient 2 also had a variant in the transmembrane domain (Haeuptle and Hennet 2009). Table 1 summarizes the clinical findings of the 14 previously reported and the present patients (Imtiaz et al 2000;Haeuptle et al 2008;Clayton and Grunewald 2009;Haeuptle and Hennet 2009;Jaeken et al 2009;Vleugels et al 2009Vleugels et al , 2011Ondruskova et al 2012;Aeby et al 2016;Barba et al 2016;Bastaki et al 2018;Monies et al 2017;Pérez-Cerdá et al 2017). Common to all 16 patients is a psychomotor disability, which is mostly severe.…”

“…It is a defect in the assembly of N-glycans since RFT1 is a putative flippase (Haeuptle et al 2008) involved in the transfer of Man5GlcNAc2-PP-Dol from the cytoplasmic to the luminal side of the endoplasmic reticulum. To date, 14 RFT1-CDG cases have been reported, and the phenotype is characterized mainly by encephalopathy including epilepsy (n ¼ 14) and hearing impairment (n ¼ 11), both hallmarks of the disease, as well as variable feeding problems, dysmorphism, and hypotonia (Imtiaz et al 2000;Haeuptle et al 2008;Clayton and Grunewald 2009;Haeuptle and Hennet 2009;Jaeken et al 2009;Vleugels et al 2009Vleugels et al , 2011Ondruskova et al 2012;Aeby et al 2016;Barba et al 2016;Bastaki et al 2018;Monies et al 2017;Pérez-Cerdá et al 2017).…”

Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions

“…8 To date, 24 individuals have been identified with pathogenic de novo variants in ALG13 resulting in a neurodevelopmental disorder primarily characterized by early infantile epileptic encephalopathy. [1][2][3][4][5][10][11][12][13][14][15][16][17][18][19][20] Most of these cases were identified in sequencing studies where clinical and variant information is summarized in the supplemental material. Nearly all reported affected persons are female and harbor an apparently recurrent de novo variant (c.320G>A; p.N107S).…”

“…Within the LLO pathway, at least 35 genes have been identified to cause a glycosylation related disorder 8 . To date, 24 individuals have been identified with pathogenic de novo variants in ALG13 resulting in a neurodevelopmental disorder primarily characterized by early infantile epileptic encephalopathy 1‐5,10‐20 . Most of these cases were identified in sequencing studies where clinical and variant information is summarized in the supplemental material.…”