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Joana Catanho1; Inês Carvalho1; Marta Amorim1

1 - Serviço de Genética Médica, Centro Hospitalar e Universitário de Lisboa Central, Lisboa, Portugal 

- Simpósio Internacional da Sociedade Portuguesa de Doenças Metabólicas 2022 (Poster) 

Background: Congenital disorders of glycosylation (CDG) constitutes a group of rare metabolic diseases. Two types of CDG related to N-glycan biosynthesis are known and CDG-type II defects represents abnormalities in the protein-bound oligosaccharides reactions. MAN1B1-CDG (MIM#614202) is an autosomal recessive disorder, caused by variants in MAN1B1 gene that encodes for MAN1B1, a mannosyl-oligosaccharide alpha-1,2-mannosidase enzyme, involved in maturation and secretory pathway of N-glycans. It contributes to the disposal of misfolded glycoproteins through the endoplasmic reticulum-associated degradation pathway. MAN1B1-CDG is characterized by variable intellectual/developmental delay (IDD), facial dysmorphism (prominent eyebrows with lateral thinning, downward-slanting palpebral fissures, bulbous tip of the nose, large ears, thin upper lip), truncal obesity, hypotonia. Behavioral problems (overeating, verbal, physical aggression) have been described. 
Case Report: We report an 18-year-old (yo) girl, first seen in our Clinic at 12 yo, due to Intellectual Disability. She is the first child of a healthy, nonconsanguineous couple, with no relevant family history. Pregnancy occurred without complications. She was born at 37 weeks of gestation, with birthweight and length at 50th centile, head circumference at 97th centile. She had a personal history of psychomotor delay (walked at 3 yo) and learning difficulties. At examination, she presented mild dysmorphic features (epicanthus, bulbous nose), obesity, joint hyperlaxity, mood and behavioral disorders. Brain MRI and microarray analysis were normal. Next-generation Sequencing (NGS) Panel for Syndromic Intellectual Disability (1174 genes) revealed a homozygous likely pathogenic variant c.172G>T p.(Glu58*) in MAN1B1 gene. This variant was previously reported in a portuguese patient with CDG-type II. Parental segregation is ongoing, but genetic study and literature review supports MAN1B1-CDG type II diagnosis.
Conclusion: MAN1B1-CDG  is a  rare potentially undiagnosed form of CDG, with up to 40 affected individuals described so far, presenting IDD as the common feature in reported cases. We bring to attention the importance of NGS as a powerful method to use in IDD diagnosis. Targeted gene panels generated for developmental delay should include genes associated with CDG,  enhancing the diagnostic yield of this metabolic disease, with implications for management and recurrence risk counseling to the family.

Palavras Chave: Congenital disorders of glycosylation; Intellectual disability;  MAN1B1 ; MAN1B1-CDG; NGS panels