RFT1 – RFT1-congenital disorder of glycosylation

RFT1-congenital disorder of glycosylation is an autosomal recessive N-glycosylation defect caused by biallelic variants in RFT1. Since the first report in 2008, at least 14 affected individuals from seven unrelated families have been described, with clinical presentations ranging from neonatal lethality to adult onset intellectual disability ([PMID:18313027]; [PMID:29923091]).

Genetic evidence supports autosomal recessive inheritance, with patients harboring two missense variants distributed across luminal loops and transmembrane domains. A representative pathogenic allele is c.199C>T (p.Arg67Cys) ([PMID:18313027]). Segregation of disease alleles in sibships has been documented in adult siblings ([PMID:23111317]) and in a lethal neonatal family with multiple affected offspring ([PMID:30071302]).

The phenotypic spectrum includes profound intellectual disability (HP:0002187), epilepsy (HP:0001250), ataxia (HP:0001251), intrauterine growth retardation (HP:0001511), facial dysmorphism (HP:0000271), high arched palate (HP:0000218) and bilateral cryptorchidism (HP:0008689); hearing impairment and thrombotic events are variably present ([PMID:23111317]; [PMID:29923091]; [PMID:30071302]).

Functional assays demonstrate that RFT1 deficiency disrupts DolPP-GlcNAc₂Man₅ translocation across the ER membrane. Yeast complementation of Deltarft1 cells and rescue of glycosylation in patient fibroblasts after lentiviral RFT1 expression confirm the pathogenicity of missense variants such as p.Arg67Cys and p.Lys152Glu ([PMID:18313027]; [PMID:19701946]).

Integration of genetic and functional data over more than a decade establishes a definitive gene–disease relationship. Clinical genetic testing for RFT1-CDG enhances diagnostic accuracy, informs prognosis, and enables genetic counseling for families at risk.

Key take-home: Biallelic RFT1 missense variants cause a definitive autosomal recessive congenital disorder of glycosylation with a spectrum from neonatal lethality to adult intellectual disability.

References

• American journal of human genetics • 2008 • Human RFT1 deficiency leads to a disorder of N-linked glycosylation. PMID:18313027
• Human mutation • 2009 • RFT1 deficiency in three novel CDG patients. PMID:19701946
• Molecular genetics and metabolism • 2012 • RFT1-CDG in adult siblings with novel mutations. PMID:23111317
• JIMD reports • 2019 • RFT1-CDG: Absence of Epilepsy and Deafness in Two Patients with Novel Pathogenic Variants. PMID:29923091
• European journal of medical genetics • 2019 • A family with floppy neonates with severe respiratory insufficiency: A lethal phenotype of RFT1-CDG due to a novel mutation. PMID:30071302

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