Dataset Information

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 SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.

SUBMITTER: Ng BG

PROVIDER: S-EPMC6661012 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Publications

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

Ng Bobby G BG Sosicka Paulina P Agadi Satish S Almannai Mohammed M Bacino Carlos A CA Barone Rita R Botto Lorenzo D LD Burton Jennifer E JE Carlston Colleen C Chung Brian Hon-Yin BH Cohen Julie S JS Coman David D Dipple Katrina M KM Dorrani Naghmeh N Dobyns William B WB Elias Abdallah F AF Epstein Leon L Gahl William A WA Garozzo Domenico D Hammer Trine Bjørg TB Haven Jaclyn J Héron Delphine D Herzog Matthew M Hoganson George E GE Hunter Jesse M JM Jain Mahim M Juusola Jane J Lakhani Shenela S Lee Hane H Lee Joy J Lewis Katherine K Longo Nicola N Lourenço Charles Marques CM Mak Christopher C Y CCY McKnight Dianalee D Mendelsohn Bryce A BA Mignot Cyril C Mirzaa Ghayda G Mitchell Wendy W Muhle Hiltrud H Nelson Stanley F SF Olczak Mariusz M Palmer Christina G S CGS Partikian Arthur A Patterson Marc C MC Pierson Tyler M TM Quinonez Shane C SC Regan Brigid M BM Ross M Elizabeth ME Guillen Sacoto Maria J MJ Scaglia Fernando F Scheffer Ingrid E IE Segal Devorah D Singhal Nilika Shah NS Striano Pasquale P Sturiale Luisa L Symonds Joseph D JD Tang Sha S Vilain Eric E Willis Mary M Wolfe Lynne A LA Yang Hui H Yano Shoji S Powis Zöe Z Suchy Sharon F SF Rosenfeld Jill A JA Edmondson Andrew C AC Grunewald Stephanie S Freeze Hudson H HH

Human mutation 20190424 7

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 SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of ...[more]

PMID: 30817854

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Project description:Background: NANS-CDG is a recently described congenital disorder of glycosylation caused by biallelic genetic variants in NANS, encoding an essential enzyme in de novo sialic acid synthesis. Sialic acid at the end of glycoconjugates plays a key role in biological processes such as brain and skeletal development. Here, we present an observational cohort study to delineate the genetic, biochemical, and clinical phenotype and assess possible correlations. Methods: Medical and laboratory records were reviewed with retrospective extraction and analysis of genetic, biochemical, and clinical data (2016-2020). Results: Nine NANS-CDG patients (nine families, six countries) referred to the Radboudumc CDG Center of Expertise were included. Phenotyping confirmed the hallmark features including intellectual developmental disorder (IDD) (n = 9/9; 100%), facial dysmorphisms (n = 9/9; 100%), neurologic impairment (n = 9/9; 100%), short stature (n = 8/9; 89%), skeletal dysplasia (n = 8/9; 89%), and short limbs (n = 8/9; 89%). Newly identified features include ophthalmological abnormalities (n = 6/9; 67%), an abnormal septum pellucidum (n = 6/9; 67%), (progressive) cerebral atrophy and ventricular dilatation (n = 5/9; 56%), gastrointestinal dysfunction (n = 5/9; 56%), thrombocytopenia (n = 5/9; 56%), and hypo-low-density lipoprotein cholesterol (n = 4/9; 44%). Biochemically, elevated urinary excretion of N-acetylmannosamine (ManNAc) is pathognomonic, the concentrations of which show a significant correlation with clinical severity. Genotypically, eight novel NANS variants were identified. Three severely affected patients harbored identical compound heterozygous pathogenic variants, one of whom was initiated on experimental prenatal and postnatal treatment with oral sialic acid. This patient showed markedly better psychomotor development than the other two genotypically identical males. Conclusions: ManNAc screening should be considered in all patients with IDD, short stature with short limbs, facial dysmorphisms, neurologic impairment, and an abnormal septum pellucidum +/- congenital and neurodegenerative lesions on brain imaging, to establish a precise diagnosis and contribute to prognostication. Personalized management includes accurate genetic counseling and access to proper supports and tailored care for gastrointestinal symptoms, thrombocytopenia, and epilepsy, as well as rehabilitation services for cognitive and physical impairments. Motivated by the short-term positive effects of experimental treatment with oral sialic, we have initiated this intervention with protocolized follow-up of neurologic, systemic, and growth outcomes in four patients. Research is ongoing to unravel pathophysiology and identify novel therapeutic targets.

Dataset Information

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

Publications

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

Similar Datasets

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