LCA5 – Severe early-childhood-onset retinal dystrophy

Leber congenital amaurosis (LCA) and severe early-childhood-onset retinal dystrophy are autosomal recessive disorders characterized by profound visual impairment in infancy and early childhood. The LCA5 gene encodes lebercilin, a ciliary protein critical for photoreceptor function. Biallelic pathogenic variants in LCA5 lead to retinal degeneration presenting as early-onset retinal dystrophy.

Clinical sequencing in a Chilean cohort of 67 patients from 60 families demonstrated a 95.5% molecular diagnostic rate, with 17 genes implicated including LCA5. In this cohort, recurrent homozygous variants such as p.Glu415Ter were observed, reflecting inbreeding and a limited mutation spectrum (PMID:38892339).

A large-scale screening of 1,008 unrelated individuals (797 LCA, 211 arRP) identified 18 probands harboring 19 distinct LCA5 variants, 17 of which were novel. Most mutations were protein-truncating, consistent with loss-of-function, and segregated in homozygous or compound heterozygous states. A representative allele is c.624_625del (p.Glu208fs) (PMID:23946133).

Segregation analysis across 60 families confirmed autosomal recessive inheritance with multiple affected siblings carrying concordant truncating alleles, supporting high penetrance and consistency with a recessive mechanism.

Functional assessment using optical coherence tomography and fundus autofluorescence revealed loss of the photoreceptor inner/outer segment junction in truncating variant carriers. In silico modelling predicted deleterious effects on lebercilin stability, concordant with the severe retinal phenotype (PMID:23946133).

Conflicting evidence arises from a Korean study in which a missense variant, c.1642C>T (p.Pro548Ser), was found in controls and shown to be benign by mRNA analysis and in silico prediction, suggesting that not all LCA5 variants impair function (PMID:19172513).

Integration of genetic and functional data supports a Strong association between LCA5 and severe early-childhood-onset retinal dystrophy with evidence of biallelic loss-of-function variants in >18 probands, segregation in 60 families, and concordant retinal structural defects. Key take-home: LCA5 sequencing is clinically actionable for diagnosis, counseling, and eligibility for emerging gene therapy trials.

References

• Clinical and molecular architecture of syndromic and non-syndromic LCA/EOSRD in Chilean families • 2024 • PMID:38892339
• Screening of a large cohort of leber congenital amaurosis and retinitis pigmentosa patients identifies novel LCA5 mutations and new genotype-phenotype correlations • 2013 • PMID:23946133
• LCA5, a rare genetic cause of leber congenital amaurosis in Koreans • 2009 • PMID:19172513

Evidence Based Scoring (AI generated)