Novel Compound Heterozygous Variants in the COG5 Gene Causing Fetal Hydrops and Skeletal Dysplasia.

introductionCongenital Disorders of Glycosylation (CDG) are a complex and highly heterogeneous group of rare metabolic disorders characterized by defects in enzymes and transporter proteins crucial for glycosylation pathways, including N-linked, O-linked, and glycolipid glycosylation. To date, over 160 distinct subtypes have been identified. CDG are characterized by significant clinical heterogeneity, which presents substantial challenges for diagnosis, especially in the prenatal setting. While prenatal ultrasound serves as a crucial tool for screening potential cases, the intricate nature of CDG often necessitates the use of advanced techniques such as whole-exome sequencing (WES) to obtain more precise molecular genetic evidence.

methodsTo investigate the genetic causes of suspected CDG in a Chinese fetus, WES was performed. Subsequently, the detected variants and their origins were validated by Sanger sequencing and classified according to the guidelines of the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP).

resultsA non-consanguineous couple had previously experienced fetal hydrops with skeletal dysplasia during midpregnancy. In their subsequent pregnancy, second-trimester ultrasonography again revealed fetal hydrops, a previously unreported complication. Fetal WES revealed two novel heterozygous variants in the COG5 gene (NM_006348.5), namely c.1972del(p.Val658Serfs*23) and c.2168_2168+4delinsCATAAAA. Sanger sequencing confirmed that the c.1972del(p.Val658Serfs*23) variant was paternally inherited, while the c.2168_2168+4delinsCATAAAA variant was maternal inherited. Both variants were classified as likely pathogenic according to the ACMG/AMP guidelines.

conclusionsThis study further expands the phenotypic and mutational spectrum of the COG5 gene, enhancing our understanding of COG5-CDG. Clinically, intellectual disability, developmental delay, brain abnormalities, skeletal deformities, microcephaly, short stature, vision abnormalities, and hepatic lesions are crucial diagnostic criteria for COG5-CDG. Other variable phenotypes of COG5-CDG can provide supporting information for prenatal diagnosis. The combined application of prenatal ultrasound and WES enables a more comprehensive and precise diagnosis of COG5-CDG, which will facilitate the implementation of early intervention and treatment.