AUTHOR=Martínez Duncker Ivan , Mata-Salgado Denisse , Shammas Ibrahim , Ranatunga Wasantha , Daniel Earnest James Paul , Cruz Muñoz Mario E. , Abreu Melania , Mora-Montes Héctor , He Miao , Morava Eva , Zafra de la Rosa Gildardo 

TITLE=Case report: Novel genotype of ALG2-CDG and confirmation of the heptasaccharide glycan (NeuAc-Gal-GlcNAc-Man2-GlcNAc2) as a specific diagnostic biomarker

JOURNAL=Frontiers in Genetics

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2024.1363558

DOI=10.3389/fgene.2024.1363558

ISSN=1664-8021

ABSTRACT=<p>This report outlines the case of a child affected by a type of congenital disorder of glycosylation (CDG) known as ALG2-CDG (<ext-link ext-link-type="uri" xlink:href="https://www.omim.org/entry/607906" xmlns:xlink="http://www.w3.org/1999/xlink">OMIM 607906</ext-link>), presenting as a congenital myasthenic syndrome (CMS) caused by variants identified in <italic>ALG2</italic>, which encodes an α1,3-mannosyltransferase (<ext-link ext-link-type="uri" xlink:href="https://enzyme.expasy.org/EC/2.4.1.132" xmlns:xlink="http://www.w3.org/1999/xlink">EC 2.4.1.132</ext-link>) involved in the early steps of N-glycosylation. To date, fourteen cases of ALG2-CDG have been documented worldwide. From birth, the child experienced perinatal asphyxia, muscular weakness, feeding difficulties linked to an absence of the sucking reflex, congenital hip dislocation, and hypotonia. Over time, additional complications emerged, such as inspiratory stridor, gastroesophageal reflux, low intake, recurrent seizures, respiratory infections, an inability to maintain the head upright, and a global developmental delay. Whole genome sequencing (WGS) revealed the presence of two <italic>ALG2</italic> variants in compound heterozygosity: a novel variant c.1055_1056delinsTGA p.(Ser352Leufs*3) and a variant of uncertain significance (VUS) c.964C&gt;A p.(Pro322Thr). Additional studies, including determination of carbohydrate-deficient transferrin (CDT) revealed a mild type I CDG pattern and the presence of an abnormal transferrin glycoform containing a linear heptasaccharide consisting of one sialic acid, one galactose, one N-acetyl-glucosamine, two mannoses and two N-acetylglucosamines (NeuAc-Gal-GlcNAc-Man2-GlcNAc2), ALG2-CDG diagnostic biomarker, confirming the pathogenicity of these variants.</p>