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Hum Mutat. 2020 Mar;41(3):655-667. doi: 10.1002/humu.23952. Epub 2019 Dec 3.

CSGALNACT1-congenital disorder of glycosylation: A mild skeletal dysplasia with advanced bone age.

Author information

1
Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
2
Department of Women's and Children's Health, Clinical Genetics Group, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
3
Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
4
Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
5
Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina.
6
Institute of Bioinformatics, Johannes Kepler University, Linz, Austria.
7
Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina.
8
Department of Medical Genetics, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
9
Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.
10
Department of Pathology, Duke University Medical Center, Durham, North Carolina.
11
Advanced Center for Translational and Genetic Medicine (ACT-GeM), Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
12
Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
13
Department of Pediatrics, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.

Abstract

Congenital disorders of glycosylation (CDGs) comprise a large number of inherited metabolic defects that affect the biosynthesis and attachment of glycans. CDGs manifest as a broad spectrum of disease, most often including neurodevelopmental and skeletal abnormalities and skin laxity. Two patients with biallelic CSGALNACT1 variants and a mild skeletal dysplasia have been described previously. We investigated two unrelated patients presenting with short stature with advanced bone age, facial dysmorphism, and mild language delay, in whom trio-exome sequencing identified novel biallelic CSGALNACT1 variants: compound heterozygosity for c.1294G>T (p.Asp432Tyr) and the deletion of exon 4 that includes the start codon in one patient, and homozygosity for c.791A>G (p.Asn264Ser) in the other patient. CSGALNACT1 encodes CSGalNAcT-1, a key enzyme in the biosynthesis of sulfated glycosaminoglycans chondroitin and dermatan sulfate. Biochemical studies demonstrated significantly reduced CSGalNAcT-1 activity of the novel missense variants, as reported previously for the p.Pro384Arg variant. Altered levels of chondroitin, dermatan, and heparan sulfate moieties were observed in patients' fibroblasts compared to controls. Our data indicate that biallelic loss-of-function mutations in CSGALNACT1 disturb glycosaminoglycan synthesis and cause a mild skeletal dysplasia with advanced bone age, CSGALNACT1-CDG.

KEYWORDS:

CSGALNACT1-CDG; CSGalNAcT-1; advanced bone age; cartilage and brain development; glycosaminoglycan; joint laxity; macrocephaly; proteoglycan; short stature

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