COG6‐CDG: Expanding the phenotype with emphasis on glycosylation defects involved in the causation of male disorders of sex development

Abstract

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

Disorder of sex development associated with a novel homozygous nonsense mutation in COG6 expands the phenotypic spectrum of COG6‐CDG

“…This can be related to the fact that the c.782 T > A p.(Leu261*) variant is a nonsense variant, which likely prevents any functional COG6 protein production. In addition to these phenotypic features, our patient exhibited a DSD, which has been rarely described in COG6‐CDG (Mandel et al, 2020). Interestingly, his brother, showing a similar phenotype with hypotonia, cerebral malformation and early death, exhibited also cryptorchidism, which could be an expression of a sexual differentiation disorder.…”

“…Sequencing analysis of the COG6‐cDNA revealed a homozygous variant (c. 1646G > T), leading to amino acid exchange p.Gly549Val in the COG6 protein (Lubbehusen et al, 2010). At the best of our knowledge, since Lubbehusen and colleagues described the first COG6‐CDG patient in 2010, only 23 patients with COG6‐gene mutation have been described so far worldwide (Alsubhi et al, 2017; Althonaian et al, 2018; Huybrechts et al, 2012; Komlosi et al, 2020; Li et al, 2019; Lubbehusen et al, 2010; Mandel et al, 2020; Rymen et al, 2015; Shaheen et al, 2013). The clinical phenotype related to mutation of COG6 gene (MIM *606977) is named COG6‐CDG (OMIM #614576), except in the case of the deep intronic splice site mutation (c.1167‐24A > G), which results in Shaheen syndrome (OMIM #615328), a milder phenotype than severe COG6‐CDG (Alsubhi et al, 2017; Althonaian et al, 2018; Shaheen et al, 2013).…”

“…To better understand the genotype–phenotype correlation, our patient was compared with 16 previously described patients with COG6‐CDG (OMIM #614576) (Alsubhi et al, 2017; Althonaian et al, 2018; Huybrechts et al, 2012; Komlosi et al, 2020; Li et al, 2019; Lubbehusen et al, 2010; Mandel et al, 2020; Rymen et al, 2015; Shaheen et al, 2013) (Table 1), excluding patients with Shaheen syndrome (OMIM #615328) (Alsubhi et al, 2017; Althonaian et al, 2018; Shaheen et al, 2013). To date, only 13 pathogenetic variants have been reported in the COG6 gene (HGMD professional udate 2020.3, https://portal.biobase-international.com/hgmd/pro/start.php), including five missense variants, two nonsense variants, four splicing variants, one insertion, and one deletion.…”

“…If there is a genotype–phenotype correlation for COG6‐related disorders, it is elusive to our understanding due to the limited number of patients known so far (Li et al, 2019; Rymen et al, 2015). However, a phenotypic variation has been observed in COG6‐CDG and the most severe phenotype with early lethality has been found more frequently in association with loss‐of‐function variants (Mandel et al, 2020; Rymen et al, 2015). This observation finds confirmation in the natural history of COG6‐CDG experienced by our patient.…”

“…Usually these patients present with multi‐systemic disease and involvement of central nervous system (Arora et al, 2019). Among the defects of the COG complex, COG6‐CDG is a very rare disease which counts less than 25 patients reported worldwide (Althonaian, Abdulrahman Alsultan, Morava, & Alfadhel, 2018; Alsubhi et al, 2017; Huybrechts et al, 2012; Komlosi et al, 2020; Li et al, 2019; Lubbehusen et al, 2010; Mandel et al, 2020; Rymen et al, 2015). The most common clinical features of COG6‐CDG are growth retardation, microcephaly, developmental disability, liver or gastrointestinal disease, hepatosplenomegaly, recurrent infections, hypohidrosis/hyperthermia and hyperkeratosis (Li et al, 2019; Rymen et al, 2015).…”