PLOD3 – BCARD syndrome

BCARD syndrome (BCARD syndrome) is a rare autosomal recessive connective tissue disorder characterized by bone fragility, joint contractures, congenital cataract, risk of arterial aneurysm with potential rupture, and sensorineural hearing loss. To date, 11 independent probands have been reported with biallelic PLOD3 (PLOD3) variants across six publications (PMID:40289369). PLOD3 encodes lysyl hydroxylase 3, which modifies collagen lysines through hydroxylation and glycosylation to stabilize extracellular matrix. PLOD3 loss-of-function disrupts collagen crosslinking, leading to multisystem connective tissue pathology. The expanding clinical spectrum now includes genitourinary reflux, cerebral cortical malformations, and focal epilepsy in addition to core BCARD manifestations.

Inheritance is strictly autosomal recessive, with all probands harboring either homozygous or compound heterozygous PLOD3 variants. Although detailed segregation analyses are limited, disease co-occurrence in multiple sibships implies familial segregation consistent with recessive inheritance. No reports describe asymptomatic heterozygotes with biallelic status. Parental carrier testing has confirmed trans configuration of alleles in compound heterozygotes. The absence of dominant-negative effects and presence of truncating alleles further support a loss-of-function mechanism.

Variant spectrum in BCARD includes both missense and protein-truncating alleles. Two novel variants were identified in the latest case: a cryptic splice-site variant c.335A>G causing a 4 bp exon 3 truncation and frameshift (p.Asp112AlafsTer4), and a nonsense variant c.2158G>T (p.Glu720Ter) in the terminal exon (PMID:40289369). Previously reported variants also include missense substitutions disrupting enzymatic domains and frameshifts leading to premature stop codons. Although recurrent or founder alleles have not been described, the observed allelic heterogeneity underscores the critical nature of lysyl hydroxylase 3 activity in collagen integrity.

Functional assays of the c.335A>G allele demonstrated aberrant splicing with exon 3 deletion and predicted nonsense-mediated decay of PLOD3 transcripts (PMID:40289369). Expression profiling in mouse and human embryonic tissues shows PLOD3 expression in cochlear, ocular, vascular, skin, cartilage, and bone tissues, correlating with multisystem features of BCARD syndrome (PMID:31129566). These data confirm that PLOD3 is required in connective tissue-rich organs and support the pathogenicity of loss-of-function alleles.

Collectively, the genetic findings—biallelic loss-of-function variants in multiple unrelated probands—and functional concordance reinforce a strong gene–disease relationship for PLOD3 and BCARD syndrome. No conflicting data have been reported, and current evidence aligns with ClinGen’s criteria for a strong clinical validity classification. The loss-of-function mechanism is supported by both variant type and expression analyses.

Key take-home: Biallelic PLOD3 variants cause autosomal recessive BCARD syndrome, and recognition of genitourinary, cerebral, and ocular involvement can guide targeted genetic testing and early multidisciplinary management.

References

• Clinical genetics • 2025 • Expanding the Clinical Spectrum of BCARD Syndrome Caused by Novel Biallelic Variants in the PLOD3 Gene. PMID:40289369
• Journal of medical genetics • 2019 • Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications. PMID:31129566

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