Case of the Month- November

Whole Exome Sequencing Uncovers COG6-Associated CDG in Recurrent Adverse Pregnancies

A consanguineous couple presented to our centre with a challenging reproductive history and multiple unexplained adverse pregnancy outcomes. The wife, now 12.6 weeks pregnant, had experienced two early pregnancy losses. Their third pregnancy was marked by markedly reduced fetal movements, and detailed imaging at 33.5 weeks (ultrasound and fetal MRI) revealed:

Rocker-bottom feet
Clenched hands
Retrognathia
Over-distended bladder
Severe IUGR
Polyhydramnios

The baby was delivered at term with a low birth weight (1.9 kg), significant dysmorphism, and multiple joint contractures, and unfortunately passed away on day two of life. Autopsy findings suggested a fetal akinesia/arthrogryposis sequence.

Previous Genetic Workup

Chromosomal microarray analysis from the prior pregnancy was normal. Parental WES was performed, revealing VUS in NEB, ADCY6, and ERGIC1 in the husband, and a pathogenic G6PD variant in the wife—but no unifying diagnosis explaining the severe fetal anomalies.

Current Pregnancy: Diagnostic Breakthrough with WES

Given the family history and consanguinity, invasive prenatal sampling followed by Whole Exome Sequencing was performed early in the current pregnancy.

WES revealed a homozygous deletion in COG6, confirming COG6-associated Congenital Disorder of Glycosylation type III (CDG2L)—a rare autosomal recessive, multisystemic, and typically lethal condition.

Additional findings included:

Hemizygous G6PD pathogenic variant
Heterozygous VUS related to arthrogryposis (previously detected in the father)

This molecular diagnosis directly explains the anomalies observed in the previous pregnancy, including arthrogryposis, reduced fetal movement, polyhydramnios, and early neonatal death—features well documented in COG6-related CDG2L.

The Gut–Brain Connection

The couple was counselled regarding:

25% recurrence risk due to autosomal recessive inheritance
Additional incidental findings
Reproductive options, including PGT-M, early targeted prenatal diagnosis in future pregnancies, and supportive reproductive planning

This case underscores the power of Whole Exome Sequencing in uncovering the underlying cause of complex fetal phenotypes—particularly in consanguineous families, where rare autosomal recessive disorders are more likely. Early WES provided a definitive diagnosis, enabling accurate recurrence risk assessment and empowering the couple with informed reproductive choices.

WES continues to transform prenatal genetics by offering clarity in situations where conventional testing falls short—ultimately improving outcomes and guiding families with precision and confidence.