PRDM5 – Brittle Cornea Syndrome Type 2

Brittle cornea syndrome type 2 (BCS2) is a rare autosomal recessive connective tissue disorder caused by biallelic loss-of-function variants in PRDM5. It manifests with marked corneal thinning leading to keratoglobus and increased risk of rupture. Patients frequently exhibit blue sclerae, joint hypermobility, and sensorineural hearing loss. Ocular complications may include high myopia and spontaneous corneal perforation. Developmental glaucoma and corneal deformations are emerging features. Early molecular diagnosis is critical for guiding management.

Autosomal recessive inheritance in BCS2 is supported by reports of five affected individuals from four unrelated families. Recent case reporting identified a singleton with congenital glaucoma, keratoglobus, decreased corneal thickness, joint hypermobility, and hearing impairment carrying a novel homozygous nonsense variant c.400G>T (p.Glu134Ter) in PRDM5 (PMID:39278530). In a separate consanguineous pedigree, two affected cousins harboring a multi-exon 9–14 deletion demonstrated cosegregation of the deletion with disease (PMID:26395458). Additional unrelated probands with PRDM5 variants p.Arg590Ter and p.Arg83Cys further establish allelic heterogeneity (PMID:26395458). To date, five probands across four families have been reported (PMID:26395458, PMID:39278530). These segregation data, although limited, provide strong genetic evidence.

Variant spectrum in BCS2 encompasses a predominance of predicted loss-of-function alleles including nonsense (e.g., p.Glu134Ter, p.Arg232Ter), frameshift (e.g., p.Leu279ValfsTer5, p.Cys325fs), splice-site (c.945+1G>T, c.1030+2T>C), and multi-exon deletions (exons 9–14) (PMID:26395458). Two rare missense changes affecting key zinc-finger residues (p.Arg83His, p.Arg83Cys) have also been described. No clear founder effect has been observed, and these variants are absent or extremely rare in population databases. The preponderance of null alleles implicates haploinsufficiency as the primary pathogenic mechanism. Allele frequencies remain below detection in gnomAD. Phenotypic consistency across genotypes further supports pathogenicity.

In vitro and histological studies demonstrate that PRDM5 acts as an epigenetic regulator via H3K9 di-methylation at target promoters of extracellular matrix (ECM) genes. Patient-derived fibroblasts and retinal tissues show reduced interaction between PRDM5 and the NuRD complex member CHD4 and heterochromatin interactor HP1BP3, leading to dysregulated H3K9me2 marks and upregulation of COL13A1, COL15A1, NTN1, and CDH5 (PMID:26395458). Abnormal retinal vascular morphology and impaired ECM stability reflect the clinical ocular fragility observed in BCS2. Co-immunoprecipitation, ChIP-seq, ChIP-qPCR, and western blotting converge to confirm defective PRDM5-mediated repression. These functional data provide moderate to strong mechanistic support for PRDM5 loss-of-function. No rescue studies have been reported to date.

No studies have reported conflicting or alternative gene associations for BCS2, and PRDM5 remains the sole gene conclusively linked to this phenotype. While one study suggested a variant in SEC24D in BCS1, this association does not implicate PRDM5 in other phenotypes. There is no evidence of PRDM5 variants causing autosomal dominant or unrelated ocular syndromes. Functional findings are consistent across independent cohorts. Thus, there is no disputing evidence for PRDM5 in BCS2. Further surveillance for conflicting data is warranted but currently not indicated.

In summary, biallelic PRDM5 loss-of-function variants consistently underlie brittle cornea syndrome type 2, with strong genetic and functional validation. The identification of congenital glaucoma and keratoglobus expands the known ocular phenotype, emphasizing the need for comprehensive ocular assessment. Genetic testing for PRDM5 should be incorporated into diagnostic panels for early detection of at-risk individuals. Knowledge of specific PRDM5 variants informs prognosis and guides surgical planning for corneal stabilization. Ongoing functional studies are refining the epigenetic basis of ECM dysregulation in BCS2. Key Take-home: PRDM5-mediated epigenetic control is essential for corneal integrity, and its disruption necessitates early molecular diagnosis for optimal management.

References

• Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus • 2024 • Congenital glaucoma in brittle cornea syndrome type 2 with a novel mutation in PRDM5. PMID:39278530
• Human molecular genetics • 2015 • A role for repressive complexes and H3K9 di-methylation in PRDM5-associated brittle cornea syndrome. PMID:26395458

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