CFH – Basal Laminar Drusen

Basal laminar drusen (BLD) is a clinical subtype of age-related macular degeneration characterized by sub-RPE amorphous drusen deposits and potential systemic complement-mediated comorbidities. Heterozygous variants in the complement factor H gene CFH have been implicated in BLD risk and severity.

In a cohort of 21 probands with BLD, direct sequencing of all CFH coding exons and splice junctions identified three novel heterozygous variants: two frameshift mutations (p.Ile184fsTer, p.Lys204fsTer) and an intronic deletion (c.1697-17_-8del) (PMID:22491393). These variants are predicted to truncate CFH or disrupt normal splicing, consistent with a loss-of-function mechanism.

Segregation analysis across three families demonstrated that 10 of 13 variant carriers exhibited the BLD phenotype, supporting autosomal dominant inheritance with variable penetrance (PMID:22491393). Two affected individuals also developed end-stage renal disease due to membranoproliferative glomerulonephritis type II, highlighting shared complement dysregulation pathways (HP:0004746).

The variant spectrum in BLD thus includes truncating and splice CFH alleles. The intronic deletion c.1697-17_-8del represents a noncoding pathogenic change affecting mRNA processing. No recurrent or founder variants have been reported in this subtype to date.

Although functional assays in BLD patients are lacking, CFH haploinsufficiency and impaired regulation of the alternative complement pathway are well documented in related complement-mediated disorders, providing mechanistic plausibility for BLD pathogenesis.

No studies to date directly refute the CFH–BLD association; however, comprehensive experimental validation in retinal models remains an unmet need.

In summary, heterozygous loss-of-function CFH variants cause autosomal dominant BLD, often with renal comorbidity. Clinical CFH sequencing enables early diagnosis, family counseling, and targeted renal screening. Key take-home: CFH variant identification in BLD patients guides ocular and nephrological management.

References

• Archives of ophthalmology (Chicago, Ill. : 1960) • 2012 • Clinical evaluation of 3 families with basal laminar drusen caused by novel mutations in the complement factor H gene. PMID:22491393

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