Expanding the Clinical Spectrum of <scp>BCARD</scp> Syndrome Caused by Novel Biallelic Variants in the <scp> <i>PLOD3</i> </scp> Gene

BCARD syndrome is a rare autosomal recessive connective tissue disorder characterized by bone abnormalities, cataract, risk of arterial rupture due to vascular aneurisms or dissections, and sensorineural deafness. BCARD, linked to biallelic pathogenic variants in the PLOD3 gene, was characterized in 10 cases across six reports. Here we present an 11-year-old female patient whose phenotype, alongside the clinical features specific to BCARD syndrome, also exhibited vesico-ureteral reflux, intestinal anomaly, minor cardiac anomalies, focal epilepsy, and brain abnormalities, including polymicrogyria and heterotopia. Whole-exome sequencing revealed two novel nucleotide variants (c.335A>G and c.2158G>T) in the PLOD3 gene. The first variant functions as a cryptic splice site variant, and RNA analysis confirmed that it causes a 4 bp truncation of exon 3. This truncation induces a frameshift, resulting in the formation of a premature termination codon (p.(Asp112AlafsTer4)). The second variant, a nonsense mutation located in the final exon, leads to the truncation of a functionally critical protein domain. This case expands our understanding of BCARD syndrome variability, aiding in earlier detection of skeletal pathology, brain, ocular, vascular complications, and intestinal, ureteral, cardiac abnormalities.