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ALG13 X‐linked intellectual disability: New variants, glycosylation analysis, and expanded phenotypes
Author(s) -
Alsharhan Hind,
He Miao,
Edmondson Andrew C.,
Daniel Earnest J. P.,
Chen Jie,
Donald Tyhiesia,
Bakhtiari Somayeh,
Amor David J.,
Jones Elizabeth A.,
Vassallo Grace,
Vincent Marie,
Cogné Benjamin,
Deb Wallid,
Werners Arend H.,
Jin Sheng C.,
Bilguvar Kaya,
Christodoulou John,
Webster Richard I.,
Yearwood Katherine R.,
Ng Bobby G.,
Freeze Hudson H.,
Kruer Michael C.,
Li Dong,
Raymond Kimiyo M.,
Bhoj Elizabeth J.,
Sobering Andrew K.
Publication year - 2021
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1002/jimd.12378
Subject(s) - glycosylation , phenotype , transferrin , glycan , clinical phenotype , electrospray ionization , biology , intellectual disability , genetics , gene , mass spectrometry , endocrinology , glycoprotein , chemistry , chromatography
Pathogenic variants in ALG13 ( ALG13 UDP‐N‐acetylglucosaminyltransferase subunit ) cause an X‐linked congenital disorder of glycosylation (ALG13‐CDG) where individuals have variable clinical phenotypes that include developmental delay, intellectual disability, infantile spasms, and epileptic encephalopathy. Girls with a recurrent de novo c.3013C>T; p.(Asn107Ser) variant have normal transferrin glycosylation. Using a highly sensitive, semi‐quantitative flow injection‐electrospray ionization‐quadrupole time‐of‐flight mass spectrometry (ESI‐QTOF/MS) N‐glycan assay, we report subtle abnormalities in N‐glycans that normally account for <0.3% of the total plasma glycans that may increase up to 0.5% in females with the p.(Asn107Ser) variant. Among our 11 unrelated ALG13‐CDG individuals, one male had abnormal serum transferrin glycosylation. We describe seven previously unreported subjects including three novel variants in ALG13 and report a milder neurodevelopmental course. We also summarize the molecular, biochemical, and clinical data for the 53 previously reported ALG13‐CDG individuals. We provide evidence that ALG13 pathogenic variants may mildly alter N‐linked protein glycosylation in both female and male subjects, but the underlying mechanism remains unclear.