@article {771, title = {Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease.}, journal = {J Clin Invest}, volume = {130}, year = {2020}, month = {2020 01 02}, pages = {507-522}, abstract = {

X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4-CD8-B220-TCRαβ+ T cells (αβDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4+ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) receptor. EBV-associated B cell malignancies occurred frequently in EBV-infected patients. We studied patients with XMEN and patients with autoimmune lymphoproliferative syndrome (ALPS) by deep immunophenotyping (32 immune markers) using time-of-flight mass cytometry (CyTOF). Our analysis revealed that the abundance of 2 populations of naive B cells (CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4++CD10+CD38+ and CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4+CD10-CD38-) could differentially classify XMEN, ALPS, and healthy individuals. We also performed glycoproteomics analysis on T lymphocytes and show that XMEN disease is a congenital disorder of glycosylation that affects a restricted subset of glycoproteins. Transfection of MAGT1 mRNA enabled us to rescue proteins with defective glycosylation. Together, these data provide new clinical and pathophysiological foundations with important ramifications for the diagnosis and treatment of XMEN disease.

}, keywords = {Antigens, CD, Autoimmune Lymphoproliferative Syndrome, Cation Transport Proteins, CD4-CD8 Ratio, Female, Glycosylation, Humans, Magnesium Deficiency, Male, X-Linked Combined Immunodeficiency Diseases}, issn = {1558-8238}, doi = {10.1172/JCI131116}, author = {Ravell, Juan C and Matsuda-Lennikov, Mami and Chauvin, Samuel D and Zou, Juan and Biancalana, Matthew and Deeb, Sally J and Price, Susan and Su, Helen C and Notarangelo, Giulia and Jiang, Ping and Morawski, Aaron and Kanellopoulou, Chrysi and Binder, Kyle and Mukherjee, Ratnadeep and Anibal, James T and Sellers, Brian and Zheng, Lixin and He, Tingyan and George, Alex B and Pittaluga, Stefania and Powers, Astin and Kleiner, David E and Kapuria, Devika and Ghany, Marc and Hunsberger, Sally and Cohen, Jeffrey I and Uzel, Gulbu and Bergerson, Jenna and Wolfe, Lynne and Toro, Camilo and Gahl, William and Folio, Les R and Matthews, Helen and Angelus, Pam and Chinn, Ivan K and Orange, Jordan S and Trujillo-Vargas, Claudia M and Franco, Jose Luis and Orrego-Arango, Julio and Guti{\'e}rrez-Hincapi{\'e}, Sebastian and Patel, Niraj Chandrakant and Raymond, Kimiyo and Patiroglu, Turkan and Unal, Ekrem and Karakukcu, Musa and Day, Alexandre Gr and Mehta, Pankaj and Masutani, Evan and De Ravin, Suk S and Malech, Harry L and Altan-Bonnet, Gr{\'e}goire and Rao, V Koneti and Mann, Matthias and Lenardo, Michael J} } @article {749, title = {A missense mutation in the catalytic domain of O-GlcNAc transferase links perturbations in protein O-GlcNAcylation to X-linked intellectual disability.}, journal = {FEBS Lett}, volume = {594}, year = {2020}, month = {2020 02}, pages = {717-727}, abstract = {

X-linked intellectual disabilities (XLID) are common developmental disorders. The enzyme O-GlcNAc transferase encoded by OGT, a recently discovered XLID gene, attaches O-GlcNAc to nuclear and cytoplasmic proteins. As few missense mutations have been described, it is unclear what the aetiology of the patient phenotypes is. Here, we report the discovery of a missense mutation in the catalytic domain of OGT in an XLID patient. X-ray crystallography reveals that this variant leads to structural rearrangements in the catalytic domain. The mutation reduces in~vitro OGT activity on substrate peptides/protein. Mouse embryonic stem cells carrying the mutation reveal reduced O-GlcNAcase (OGA) and global O-GlcNAc levels. These data suggest a direct link between changes in the O-GlcNAcome and intellectual disability observed in patients carrying OGT mutations.

}, keywords = {Animals, Catalytic Domain, Cell Line, Glycosylation, Humans, Intellectual Disability, Mice, Models, Molecular, Mutation, Missense, N-Acetylglucosaminyltransferases}, issn = {1873-3468}, doi = {10.1002/1873-3468.13640}, author = {Pravata, Veronica M and Gundogdu, Mehmet and Bartual, Sergio G and Ferenbach, Andrew T and Stavridis, Marios and {\~O}unap, Katrin and Pajusalu, Sander and {\v Z}ordania, Riina and Wojcik, Monica H and van Aalten, Daan M F} } @article {928, title = {Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 04 01}, pages = {1114-1126}, abstract = {

Congenital disorders of glycosylation are a growing group of rare genetic disorders caused by deficient protein and lipid glycosylation. Here, we report the clinical, biochemical, and molecular features of seven patients from four families with GALNT2-congenital disorder of glycosylation (GALNT2-CDG), an O-linked glycosylation disorder. GALNT2 encodes the Golgi-localized polypeptide N-acetyl-d-galactosamine-transferase 2 isoenzyme. GALNT2 is widely expressed in most cell types and directs initiation of mucin-type protein O-glycosylation. All patients showed loss of O-glycosylation of apolipoprotein C-III, a non-redundant substrate for GALNT2. Patients with GALNT2-CDG generally exhibit a syndrome characterized by global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities. In behavioural studies, GALNT2-CDG mice demonstrated cerebellar motor deficits, decreased sociability, and impaired sensory integration and processing. The multisystem nature of phenotypes in patients and rodent models of GALNT2-CDG suggest that there are multiple non-redundant protein substrates of GALNT2 in various tissues, including brain, which are critical to normal growth and development.

}, keywords = {Adolescent, Animals, Apolipoprotein C-III, Child, Child, Preschool, Developmental Disabilities, Female, Glycosylation, Humans, Loss of Function Mutation, Male, Mice, N-Acetylgalactosaminyltransferases, Pedigree, Rats, Young Adult}, issn = {1460-2156}, doi = {10.1093/brain/awaa063}, author = {Zilmer, Monica and Edmondson, Andrew C and Khetarpal, Sumeet A and Alesi, Viola and Zaki, MAH S and Rostasy, Kevin and Madsen, Camilla G and Lepri, Francesca R and Sinibaldi, Lorenzo and Cusmai, Raffaella and Novelli, Antonio and Issa, Mahmoud Y and Fenger, Christina D and Abou Jamra, Rami and Reutter, Heiko and Briuglia, Silvana and Agolini, Emanuele and Hansen, Lars and Pet{\"a}j{\"a}-Repo, Ulla E and Hintze, John and Raymond, Kimiyo M and Liedtke, Kristen and Stanley, Valentina and Musaev, Damir and Gleeson, Joseph G and Vitali, Cecilia and O{\textquoteright}Brien, W Timothy and Gardella, Elena and Rubboli, Guido and Rader, Daniel J and Schjoldager, Katrine T and M{\o}ller, Rikke S} } @article {978, title = {POGLUT1 biallelic mutations cause myopathy with reduced satellite cells, α-dystroglycan hypoglycosylation and a distinctive radiological pattern.}, journal = {Acta Neuropathol}, volume = {139}, year = {2020}, month = {2020 03}, pages = {565-582}, abstract = {

Protein O-glucosyltransferase 1 (POGLUT1) activity is critical for the Notch signaling pathway, being one of the main enzymes responsible for the glycosylation of the extracellular domain of Notch receptors. A biallelic mutation in the POGLUT1 gene has been reported in one family as the cause of an adult-onset limb-girdle muscular dystrophy (LGMD R21; OMIM$\#$ 617232). As the result of a collaborative international effort, we have identified the first cohort of 15 patients with LGMD R21, from nine unrelated families coming from different countries, providing a reliable phenotype-genotype and mechanistic insight. Patients carrying novel mutations in POGLUT1 all displayed a clinical picture of limb-girdle muscle weakness. However, the age at onset was broadened from adult to congenital and infantile onset. Moreover, we now report that the unique muscle imaging pattern of "inside-to-outside" fatty degeneration observed in the original cases is indeed a defining feature of POGLUT1 muscular dystrophy. Experiments on muscle biopsies from patients revealed a remarkable and consistent decrease in the level of the NOTCH1 intracellular domain, reduction of the pool of satellite cells (SC), and evidence of α-dystroglycan hypoglycosylation. In vitro biochemical and cell-based assays suggested a pathogenic role of the novel POGLUT1 mutations, leading to reduced enzymatic activity and/or protein stability. The association between the POGLUT1 variants and the muscular phenotype was established by in vivo experiments analyzing the indirect flight muscle development in transgenic Drosophila, showing that the human POGLUT1 mutations reduced its myogenic activity. In line with the well-known role of the Notch pathway in the homeostasis of SC and muscle regeneration, SC-derived myoblasts from patients{\textquoteright} muscle samples showed decreased proliferation and facilitated differentiation. Together, these observations suggest that alterations in SC biology caused by reduced Notch1 signaling result in muscular dystrophy in LGMD R21 patients, likely with additional contribution from α-dystroglycan hypoglycosylation. This study settles the muscular clinical phenotype linked to POGLUT1 mutations and establishes the pathogenic mechanism underlying this muscle disorder. The description of a specific imaging pattern of fatty degeneration and muscle pathology with a decrease of α-dystroglycan glycosylation provides excellent tools which will help diagnose and follow up LGMD R21 patients.

}, keywords = {Animals, Animals, Genetically Modified, Drosophila melanogaster, Dystroglycans, Female, Genetic Association Studies, Glucosyltransferases, Glycosylation, Humans, Male, Muscle, Skeletal, Muscular Dystrophies, Limb-Girdle, Mutation, Pedigree, Satellite Cells, Skeletal Muscle}, issn = {1432-0533}, doi = {10.1007/s00401-019-02117-6}, author = {Servi{\'a}n-Morilla, E and Cabrera-Serrano, M and Johnson, K and Pandey, A and Ito, A and Rivas, E and Chamova, T and Muelas, N and Mongini, T and Nafissi, S and Claeys, K G and Grewal, R P and Takeuchi, M and Hao, H and B{\"o}nnemann, C and Lopes Abath Neto, O and Medne, L and Brandsema, J and T{\"o}pf, A and Taneva, A and Vilchez, J J and Tournev, I and Haltiwanger, R S and Takeuchi, H and Jafar-Nejad, H and Straub, V and Paradas, Carmen} } @article {487, title = {Detection of variants in dystroglycanopathy-associated genes through the application of targeted whole-exome sequencing analysis to a large cohort of patients with unexplained limb-girdle muscle weakness.}, journal = {Skelet Muscle}, volume = {8}, year = {2018}, month = {2018 07 30}, pages = {23}, abstract = {

BACKGROUND: Dystroglycanopathies are a clinically and genetically heterogeneous group of disorders that are typically characterised by limb-girdle muscle weakness. Mutations in 18 different genes have been associated with dystroglycanopathies, the encoded proteins of which typically modulate the binding of α-dystroglycan to extracellular matrix ligands by altering its glycosylation. This results in a disruption of the structural integrity of the myocyte, ultimately leading to muscle degeneration.

METHODS: Deep phenotypic information was gathered using the PhenoTips online software for 1001 patients with unexplained limb-girdle muscle weakness from 43 different centres across 21 European and Middle Eastern countries. Whole-exome sequencing with at least 250~ng DNA was completed using an Illumina exome capture and a 38~Mb baited target. Genes known to be associated with dystroglycanopathies were analysed for disease-causing variants.

RESULTS: Suspected pathogenic variants were detected in DPM3, ISPD, POMT1 and FKTN in one patient each, in POMK in two patients, in GMPPB in three patients, in FKRP in eight patients and in POMT2 in ten patients. This indicated a frequency of 2.7\% for the disease group within the cohort of 1001 patients with unexplained limb-girdle muscle weakness. The phenotypes of the 27 patients were highly variable, yet with a fundamental presentation of proximal muscle weakness and elevated serum creatine kinase.

CONCLUSIONS: Overall, we have identified 27 patients with suspected pathogenic variants in dystroglycanopathy-associated genes. We present evidence for the genetic and phenotypic diversity of the dystroglycanopathies as a disease group, while also highlighting the advantage of incorporating next-generation sequencing into the diagnostic pathway of rare diseases.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Dystroglycans, Female, Genetic Predisposition to Disease, Genetic Variation, Glycosylation, Heterozygote, Homozygote, Humans, Male, Middle Aged, Muscle Proteins, Muscular Dystrophies, Limb-Girdle, Mutation, Phenotype, Whole Exome Sequencing, Young Adult}, issn = {2044-5040}, doi = {10.1186/s13395-018-0170-1}, author = {Johnson, Katherine and Bertoli, Marta and Phillips, Lauren and Topf, Ana and Van den Bergh, Peter and Vissing, John and Witting, Nanna and Nafissi, Shahriar and Jamal-Omidi, Shirin and {\L}usakowska, Anna and Kostera-Pruszczyk, Anna and Potulska-Chromik, Anna and Deconinck, Nicolas and Wallgren-Pettersson, Carina and Strang-Karlsson, Sonja and Colomer, Jaume and Claeys, Kristl G and De Ridder, Willem and Baets, Jonathan and von der Hagen, Maja and Fern{\'a}ndez-Torr{\'o}n, Roberto and Zulaica Ijurco, Miren and Espinal Valencia, Juan Bautista and Hahn, Andreas and Durmus, Hacer and Willis, Tracey and Xu, Liwen and Valkanas, Elise and Mullen, Thomas E and Lek, Monkol and MacArthur, Daniel G and Straub, Volker} } @article {77, title = {ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients.}, journal = {Hum Mutat}, volume = {37}, year = {2016}, month = {2016 07}, pages = {653-60}, abstract = {

Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over 100 genes leading to impaired protein or lipid glycosylation. ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date 13 mutations in 18 patients from 14 families have been described with varying degrees of clinical severity. We identified and characterized 39 previously unreported cases of ALG1-CDG from 32 families and add 26 new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2 , was seen in all 27 patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.

}, keywords = {Biomarkers, Congenital Disorders of Glycosylation, Female, Genes, Lethal, Glycosylation, Humans, Male, Mannosyltransferases, Mutation, Polysaccharides, Sequence Analysis, DNA, Survival Analysis}, issn = {1098-1004}, doi = {10.1002/humu.22983}, author = {Ng, Bobby G and Shiryaev, Sergey A and Rymen, Daisy and Eklund, Erik A and Raymond, Kimiyo and Kircher, Martin and Abdenur, Jose E and Alehan, Fusun and Midro, Alina T and Bamshad, Michael J and Barone, Rita and Berry, Gerard T and Brumbaugh, Jane E and Buckingham, Kati J and Clarkson, Katie and Cole, F Sessions and O{\textquoteright}Connor, Shawn and Cooper, Gregory M and Van Coster, Rudy and Demmer, Laurie A and Diogo, Luisa and Fay, Alexander J and Ficicioglu, Can and Fiumara, Agata and Gahl, William A and Ganetzky, Rebecca and Goel, Himanshu and Harshman, Lyndsay A and He, Miao and Jaeken, Jaak and James, Philip M and Katz, Daniel and Keldermans, Liesbeth and Kibaek, Maria and Kornberg, Andrew J and Lachlan, Katherine and Lam, Christina and Yaplito-Lee, Joy and Nickerson, Deborah A and Peters, Heidi L and Race, Valerie and R{\'e}gal, Luc and Rush, Jeffrey S and Rutledge, S Lane and Shendure, Jay and Souche, Erika and Sparks, Susan E and Trapane, Pamela and Sanchez-Valle, Amarilis and Vilain, Eric and V{\o}llo, Arve and Waechter, Charles J and Wang, Raymond Y and Wolfe, Lynne A and Wong, Derek A and Wood, Tim and Yang, Amy C and Matthijs, Gert and Freeze, Hudson H} } @article {46, title = {Congenital nephrotic syndrome in an infant with ALG1-congenital disorder of glycosylation.}, journal = {Pediatr Int}, volume = {58}, year = {2016}, month = {2016 Aug}, pages = {785-8}, abstract = {

Congenital nephrotic syndrome (NS) in the newborn is most frequently related to mutations in genes specific for structural integrity of the glomerular basement membrane and associated filtration structures within the kidney, resulting in massive leakage of plasma proteins into the urine. Occurrence of congenital NS in a multi-system syndrome is less common. We describe the case of an infant with deteriorating neurological status, seizures, edema, and proteinuria who was found to have a mutation in gene ALG1 and a renal biopsy consistent with congenital NS. Furthermore, we briefly review rare existing case reports documenting congenital NS in patients with mutations in ALG1, and treatment strategies, including novel use of peritoneal dialysis.

}, keywords = {Abnormalities, Multiple, Congenital Disorders of Glycosylation, DNA, DNA Mutational Analysis, Glycosylation, Humans, Infant, Newborn, Male, Mannosyltransferases, Mutation, Nephrotic Syndrome, Peritoneal Dialysis}, issn = {1442-200X}, doi = {10.1111/ped.12988}, author = {Harshman, Lyndsay A and Ng, Bobby G and Freeze, Hudson H and Trapane, Pamela and Dolezal, Anna and Brophy, Patrick D and Brumbaugh, Jane E} } @article {31, title = {SRD5A3-CDG: Expanding the phenotype of a congenital disorder of glycosylation with emphasis on adult onset features.}, journal = {Am J Med Genet A}, volume = {170}, year = {2016}, month = {2016 Dec}, pages = {3165-3171}, abstract = {

Increasing numbers of congenital disorders of glycosylation (CDG) have been reported recently resulting in an expansion of the phenotypes associated with this group of disorders. SRD5A3 codes for polyprenol reductase which converts polyprenol to dolichol. This is a major pathway for dolichol biosynthesis for N-glycosylation, O-mannosylation, C-mannosylation, and GPI anchor synthesis. We present the features of five individuals (three children and two adults) with mutations in SRD5A3 focusing on the variable eye and skin involvement. We compare that to 13 affected individuals from the literature including five adults allowing us to delineate the features that may develop over time with this disorder including kyphosis, retinitis pigmentosa, and cataracts. {\textcopyright} 2016 Wiley Periodicals, Inc.

}, keywords = {3-Oxo-5-alpha-Steroid 4-Dehydrogenase, Adult, Child, Congenital Disorders of Glycosylation, Dolichols, Eye, Female, Glycosylation, Homozygote, Humans, Male, Membrane Proteins, Mutation, Phenotype, Skin, Tretinoin}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37875}, author = {Wheeler, Patricia G and Ng, Bobby G and Sanford, Laura and Sutton, V Reid and Bartholomew, Dennis W and Pastore, Matthew T and Bamshad, Michael J and Kircher, Martin and Buckingham, Kati J and Nickerson, Deborah A and Shendure, Jay and Freeze, Hudson H} } @article {283, title = {A new congenital disorder of glycosylation caused by a mutation in SSR4, the signal sequence receptor 4 protein of the TRAP complex.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Mar 15}, pages = {1602-5}, abstract = {

Nearly 50 congenital disorders of glycosylation (CDG) are known, but many patients biochemically diagnosed with CDG do not have mutations in known genes. Here, we describe a 16-year-old male who was born with microcephaly, developed intellectual disability, gastroesophageal reflux and a seizure disorder. We identified a de novo variant in the X-linked SSR4 gene which encodes a protein of the heterotetrameric translocon-associated protein (TRAP) complex. The c.316delT causes a p.F106Sfs*53 in SSR4 and also reduces expression of other TRAP complex proteins. The glycosylation marker Glyc-ER-GFP was used to confirm the underglycosylation in fibroblasts from the patient. Overexpression of the wild-type SSR4 allele partially restores glycosylation of the marker and of the other members of the TRAP complex. This is the first evidence that the TRAP complex, which binds to the oligosaccharyltransferase complex, is directly involved in N-glycosylation.

}, keywords = {Adolescent, Calcium-Binding Proteins, Cells, Cultured, Chromosomes, Human, X, Congenital Disorders of Glycosylation, Glycosylation, Humans, Male, Membrane Glycoproteins, Point Mutation, Receptors, Cytoplasmic and Nuclear, Receptors, Peptide}, issn = {1460-2083}, doi = {10.1093/hmg/ddt550}, author = {Losfeld, Marie Estelle and Ng, Bobby G and Kircher, Martin and Buckingham, Kati J and Turner, Emily H and Eroshkin, Alexey and Smith, Joshua D and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J and Freeze, Hudson H} } @article {265, title = {Solving glycosylation disorders: fundamental approaches reveal complicated pathways.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Feb 06}, pages = {161-75}, abstract = {

Over 100 human genetic disorders result from mutations in glycosylation-related genes. In 2013, a new glycosylation disorder was reported every 17 days. This trend will probably continue given that at least 2\% of the human genome encodes glycan-biosynthesis and -recognition proteins. Established biosynthetic pathways provide many candidate genes, but finding unanticipated mutated genes will offer new insights into glycosylation. Simple glycobiomarkers can be used in narrowing the candidates identified by exome and genome sequencing, and those can be validated by glycosylation analysis of serum or cells from affected individuals. Model organisms will expand the understanding of these mutations{\textquoteright} impact on glycosylation and pathology. Here, we highlight some recently discovered glycosylation disorders and the barriers, breakthroughs, and surprises they presented. We predict that some glycosylation disorders might occur with greater frequency than current estimates of their prevalence. Moreover, the prevalence of some disorders differs substantially between European and African Americans.

}, keywords = {Congenital Disorders of Glycosylation, Exome, Genome, Human, Glucose, Glycogen, Glycosylation, Homeostasis, Humans, Mannose, Mutation}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.10.024}, author = {Freeze, Hudson H and Chong, Jessica X and Bamshad, Michael J and Ng, Bobby G} } @article {305, title = {Mosaicism of the UDP-galactose transporter SLC35A2 causes a congenital disorder of glycosylation.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Apr 04}, pages = {632-6}, abstract = {

Biochemical analysis and whole-exome sequencing identified mutations in the Golgi-localized UDP-galactose transporter SLC35A2 that define an undiagnosed X-linked congenital disorder of glycosylation (CDG) in three unrelated families. Each mutation reduced UDP-galactose transport, leading to galactose-deficient glycoproteins. Two affected males were somatic mosaics, suggesting that a wild-type SLC35A2 allele may be required for survival. In infancy, the commonly used biomarker transferrin showed abnormal glycosylation, but its appearance became normal later in childhood, without any corresponding clinical improvement. This may indicate selection against cells carrying the mutant allele. To detect other individuals with such mutations, we suggest transferrin testing in infancy. Here, we report somatic mosaicism in CDG, and our work stresses the importance of combining both genetic and biochemical diagnoses.

}, keywords = {Biological Transport, Case-Control Studies, Child, Child, Preschool, Congenital Disorders of Glycosylation, Exome, Female, Glycosylation, Humans, Male, Monosaccharide Transport Proteins, Mosaicism, Mutation, Spectrometry, Mass, Electrospray Ionization, Transferrin, Uridine Diphosphate Galactose}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.03.012}, author = {Ng, Bobby G and Buckingham, Kati J and Raymond, Kimiyo and Kircher, Martin and Turner, Emily H and He, Miao and Smith, Joshua D and Eroshkin, Alexey and Szybowska, Marta and Losfeld, Marie E and Chong, Jessica X and Kozenko, Mariya and Li, Chumei and Patterson, Marc C and Gilbert, Rodney D and Nickerson, Deborah A and Shendure, Jay and Bamshad, Michael J and Freeze, Hudson H} }