COG6-CDG: Expanding the Phenotype with emphasis on glycosylation defects involved in the causation of Male Disorders of Sex Development.

01. Oktober, 2020

Hanna Mandel1, Nehama Cohen Kfir1,2, Ayalla Fedida1,2, Efrat Shuster Biton1, Marwan Odeh3, Limor Kalfon1, Shani Ben Harouch1, Vered Sheffer Fleischer4, Yoav Hoffman5, Yael Goldberg6, April Dinwiddie7, Elena Dumin8, Ayelet Eran9, Liat Apel-Sarid 10, Dov Tiosano11, Tzipora C Falik-Zaccai1,2.


COG6-congenital disorder of glycosylation (COG6-CDG) is caused by biallelic mutations in COG6. To-date, 12 variants causing COG6-CDG in less than 20 patients have been reported. Using whole exome sequencing we identified two siblings with a novel homozygous deletion of 26 bp in COG6, creating a splicing variant (c.518_540 + 3del) and a shift in the reading frame. The phenotype of COG6-CDG includes growth and developmental retardation, microcephaly, liver and gastrointestinal disease, hypohydrosis and recurrent infections. We report two patients with novel phenotypic features including bowel malrotation and ambiguous genitalia, directing attention to the role of glycoprotein metabolism in the causation of disorders of sex development (DSD). Searching the glycomic literature, we identified 14 CDGs including males with DSD, a feature not previously accentuated. This study broadens the genetic and phenotypic spectrum of COG6-CDG and calls for increasing awareness to the central role of glycosylation processes in development of human sex and genitalia.