1 - Genetic Service, Pediatric Department, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
2 - Reference Center of Inherited Metabolic Diseases, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
- Poster em 16º Simposio Internacional da Sociedade Portuguesa de Doenças Metabólicas, Virtual, 11-13 novembro de 2020
Resumo:
Background: SSR4-CDG is a congenital disorder of N-linked glycosylation (CDG-N-linked) caused by mutations in the gene SSR4 (Xq28) that encodes one of four signal sequence receptor proteins involved in the translocon (TRAP) complex, which aids in the translocation of proteins across the membrane of the endoplasmic reticulum. SSR4 mutation reduces expression of TRAP, induces ER stress and leads to underglycosylation. Only 9 cases were reported so far.
Case Report: We present an 11-year-old male, referred to genetic outpatient clinic for investigation of facial dysmorphism (deep set eyes, large ears, large mouth, with widely spaced teeth), microcephaly, failure to thrive, global developmental delay, intellectual disability, hypotony, strabismus and hyperopia. Extensive genetic investigation terminated in molecular analysis with exome sequence that revealed a de novo variant in SSR4 gene involving exon 4 in hemizygozity. This mutation was not described in the literature, however consist in the replacement of arginine with a stop-codon, c.268C>T p.(Arg90*), originating a truncate protein. Database analysis suggested the variant is pathogenic and predict a loss of SSR4 function. Another mutation was identified in KCNH2 gene responsible for long QT syndrome (AD), to this point asymptomatic. Further characterization of SSR4-CDG diagnosis included: normal transaminases, coagulation and endocrinologic tests; thin corpus callosum; normal echocardiogram and prolonged QTc. Investigation of transferrin isoform pattern, usually abnormal in SSR4-CDG, is ongoing.
Comments: Our patient phenotype shows many overlapping features with the previous nine SSR4-CDG cases reported in the literature. However, these clinical features are commonly seen in many CDG subtypes as well other genetic diseases. Only exome sequencing techniques provided an explanation for the clinical findings, improved medical follow-up and treatment of complications, and gave genetic counselling to the family.
Keywords: Congenital disorders of N-linked glycosylation, signal sequence receptor subunit 4, translocon-associated protein, neurological abnormalities.