BEST1 – Retinitis Pigmentosa 50

Autosomal recessive retinitis pigmentosa 50 (RP50) is caused by biallelic mutations in BEST1, which encodes the bestrophin-1 chloride channel (BEST1; Retinitis Pigmentosa 50). A multi-center study reported six unrelated families (six probands) presenting in childhood to young adulthood with reduced visual acuity (0.1/10–3/10), macular and midperipheral vitelliform lesions, and absent electro-oculogram light rise ([PMID:31766397]). All probands harbored rare biallelic BEST1 variants, with heterozygous parents showing no full-blown phenotype, confirming autosomal recessive inheritance.

Clinical Validity (ClinGen: Strong)

• Six unrelated probands with recessive BEST1 variants segregating in AR families ([PMID:31766397]).
• Functional concordance with loss of chloride channel activity in patch-clamp assays ([PMID:18179881]).

Genetic Evidence (ClinGen: Strong)

• Inheritance: Autosomal recessive.
• Probands: 6 unrelated individuals with biallelic rare BEST1 variants (nonsense, missense) segregating with disease in each family ([PMID:31766397]).
• Segregation: All parents heterozygous and clinically unaffected; no additional affected relatives.
• Variant spectrum: LoF (nonsense) and missense across the first half of the protein; recurrent alleles include c.658C>T (p.Gln220Ter).

Functional Evidence (ClinGen: Strong)

• Mechanism: Loss of chloride channel function (haploinsufficiency/null phenotype).
• Patch-clamp studies in HEK293 cells show ARB-associated missense isoforms severely reduce Cl⁻ currents and do not exert dominant-negative effects on wild-type channels ([PMID:18179881]).

Integration & Conclusion

Biallelic BEST1 mutations cause a distinct autosomal recessive bestrophinopathy manifesting as RP50, characterized by central visual loss, vitelliform lesions, and absent EOG light rise. Genetic evidence from six families and robust functional assays support a strong clinical validity of this gene–disease association. Additional studies may refine genotype–phenotype correlations, but current data suffice for diagnostic testing and therapeutic development.

Key Take-home: BEST1 biallelic loss-of-function variants reliably underlie autosomal recessive RP50, enabling molecular diagnosis and informing potential gene therapy strategies.

References

• Genes • 2019 • Clinical and Genetic Findings of Autosomal Recessive Bestrophinopathy (ARB) PMID:31766397
• American Journal of Human Genetics • 2008 • Biallelic mutation of BEST1 causes a distinct retinopathy in humans. PMID:18179881

Evidence Based Scoring (AI generated)