SLC35A2‐CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals

Abstract

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo NG ET AL. | 909

Congenital disorders of glycosylation and the challenge of rare diseases

“…Unlike the previous case, there is not a simple consistent link between the mutation and the final observed phenotype (i.e., altered glycosylation). In contrast to the classical presentation of a disease as seen in Himmelreich et al (), in the case of Ng et al (), we have a nonclassical or “occult” presentation of a disease where it is often difficult to demonstrate a difference in glycosylation. This nonclassical presentation had been observed previously in other studies of individuals carrying mutations in SLC35A2 and other types of CDG.…”

“…If the X‐chromosomes carrying the mutation are inactivated preferentially in the liver, then the glycoforms of transferrin, being synthesized in the liver, would demonstrate a normal pattern. Of the 30 patients in the study of Ng et al (), only one was male and, in fact, exhibited altered CDT, while the females had either normal or abnormal CDT. At least some of the difficulties in identification of individuals may be ameliorated with improvement of mass spectrometry technology (Chen et al, ; Huang, Cathy, Pollard, & Wood, ).…”

“…In contrast, in the study of Ng et al (), patients with an extreme phenotype (neurological impairments with and without skeletal abnormalities) were the subject of whole exome or selected panel sequencing and variants were identified in SLC35A2 (SLC35A2‐CDG). The SLC35A2 gene codes for a UDP‐galactose transporter.…”

“…By definition, CDGs are rare diseases so these associations are lacking, as their rare variants are not found in the databases. For example, many of the mutations seen by Ng et al () are novel. Consequently, mutations are often classified as variants of unknown significance when even to the casual observer the amino acid substitution is potentially disruptive to the protein structure (e.g., insertion/deletion of a proline residue).…”

“…The expression of the variant may occur only in specific tissues or in specific locations or at specific times. For example, the variant identified by Ng et al () is X‐linked. As X‐chromosomes are inactivated randomly in females, the degree and distribution of inactivation of the normal X‐chromosome could affect disease severity.…”