COG6 Novel Variant: From Prenatal Diagnosis to Successful Preimplantation Genetic Testing

COG6-congenital disorder of glycosylation type IIL (CDG2L) is a rare multisystemic autosomal recessive disorder caused by variants in the COG6 gene, a core component of the conserved oligomeric Golgi (COG) complex. To date, approximately 50 affected individuals with only 20 variants have been reported worldwide. We investigated a pregnant mother with a history of CDG2L in three affected neonates (two females and one male), who died within the 1 ^st month of life due to severe multisystem manifestations of the disease. The first affected girl presented with microcephaly and congenital heart defects. The second affected girl manifested microcephaly, clubfoot, and congenital heart defects. The third affected boy presented with microcephaly, clubfoot, imperforated anus, hydronephrosis, congenital heart defects, and seizures. Whole-exome sequencing of the most recent affected male neonate (12 days old) identified a novel homozygous missense variant (c.1074G>C) in the COG6 gene. During the subsequent pregnancy, Sanger sequencing was done at 12 weeks of gestation using chorionic villus sampling (CVS), which detected the same homozygous variant in the fetus. Functional analysis using reverse transcription-polymerase chain reaction from the CVS showed that this variant causes abnormal splicing, resulting in skipping of exon 11. The parents received appropriate genetic counseling for future reproductive planning. Following prenatal diagnosis of the affected fetus, the pregnancy was terminated. Preimplantation genetic testing was later performed, which resulted in the birth of a healthy male child. This report expands the variant spectrum of COG6 and underscores the importance of functional RNA analysis for accurate variant interpretation. To our knowledge, this is the first study to report a deleterious missense variant in the COG6 gene causing aberrant splicing and lethal CDG2L.