Novel compound heterozygous DOCK6 variants expand the mutational spectrum in prenatal diagnosis of Adams-Oliver syndrome 2.

BACKGROUND

Adams-Oliver syndrome (AOS) is a rare developmental disorder, and the DOCK6 gene is an identified AOS gene. This report highlights the prenatal diagnosis of AOS-2 by ultrasonography and genetic testing.

METHODS

A growth-restricted fetus with bilateral ventriculomegaly, paraventricular calcifications, and ventricular septal defect underwent trio-whole-exome sequencing (trio-WES). Functional validation of the splice-altering variant was performed via minigene assays and protein structural modeling.

RESULTS

Trio-WES revealed compound heterozygous DOCK6 variants: a paternal frameshift (c.3190_3191del; p. Leu1064Valfs60) and a maternal splice-site variant (c.3241-1G > T). Minigene assays demonstrated that c.3241-1G > T caused intron 26 retention (486 bp), introducing a premature termination codon (p. Val1081Glufs37). Structural modeling confirmed the loss of critical DHR2 domains in both truncated proteins.

CONCLUSIONS

This study expands the mutational spectrum of DOCK6 and underscores the importance of combining prenatal imaging with functional genomics for early diagnosis of AOS2.