Abstract
OBJECTIVE: To characterize the clinical features of a fetus with postaxial polydactyly caused by a de novo PRKACB gene variant and to perform a genetic analysis. METHODS: A pregnant woman who presented to Zhejiang Provincial People's Hospital on 4 December 2024 was enrolled in this study. Fetal clinical data were collected, and genomic DNA was extracted from the fetus and both parents. Clinical whole-exome sequencing (WES) was performed on the trio (fetus and both parents). Candidate variants were identified and validated by Sanger sequencing, followed by bioinformatics analysis. This study was approved by the Medical Ethics Committee of Zhejiang Provincial People's Hospital (approval number: QT2025076). RESULTS: Prenatal ultrasonography revealed bilateral postaxial polydactyly and several fetal biometric measurements that were inconsistent with gestational age. The clinical diagnoses were intrauterine growth restriction and polydactyly. WES identified a de novo heterozygous variant (c.802 G>A; p.Asp268Asn) in exon 8 of the fetal PRKACB gene (NM_182948.4). According to the ACMG variant-classification guidelines, this variant was interpreted as likely pathogenic (PS2_Moderate, PM1, PM2_Supporting and PP3). AlphaFold-based structural prediction indicated that the PRKACB p.Asp268Asn substitution resulted in the loss of two hydrogen bonds, thereby altering the protein's three-dimensional conformation and affecting structural stability. CONCLUSION: The PRKACB gene c.802 G>A (p.Asp268Asn) variant is a potential genetic cause of bilateral postaxial polydactyly in the fetus. Identification of this variant expands the known mutational spectrum of PRKACB gene and provides an important reference for genetic counselling and prenatal diagnosis.