Next generation sequencing identifies novel disease-associated BEST1 mutations in Bestrophinopathy patients

Thong T Nguyen,B Poornachandra,Sameer Phalke,Rajani Battu,Somasekar Seshagiri,Andrew S Peterson,Ruchir A Mehta,Anshuman Verma,Arkasubhra Ghosh,Vedam L Ramprasad

doi:10.1038/s41598-018-27951-8

Thong T Nguyen, B Poornachandra + Show 8 more

Open Access

https://doi.org/10.1038/s41598-018-27951-8

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Journal: Scientific Reports	Publication Date: Jul 5, 2018
Citations: 12	License type: open-access

Affiliation: Narayana Nethralaya, SciGenom Labs (India)

Abstract

Bestinopathies are a spectrum of retinal disorders associated with mutations in BEST1 including autosomal recessive bestrophinopathy (ARB) and autosomal dominant Best vitelliform macular dystrophy (BVMD). We applied whole-exome sequencing on four unrelated Indian families comprising eight affected and twelve unaffected individuals. We identified five mutations in BEST1, including p.Tyr131Cys in family A, p.Arg150Pro in family B, p.Arg47His and p.Val216Ile in family C and p.Thr91Ile in family D. Among these, p.Tyr131Cys, p.Arg150Pro and p.Val216Ile have not been previously reported. Further, the inheritance pattern of BEST1 mutations in the families confirmed the diagnosis of ARB in probands in families A, B and C, while the inheritance of heterozygous BEST1 mutation in family D (p.Thr91Ile) was suggestive of BVMD. Interestingly, the ARB families A and B carry homozygous mutations while family C was a compound heterozygote with a mutation in an alternate BEST1 transcript isoform, highlighting a role for alternate BEST1 transcripts in bestrophinopathy. In the BVMD family D, the heterozygous BEST1 mutation found in the proband was also found in the asymptomatic parent, suggesting an incomplete penetrance and/or the presence of additional genetic modifiers. Our report expands the list of pathogenic BEST1 genotypes and the associated clinical diagnosis.

Highlights

Mutations in BEST1 gene have been described in a variety of ocular disease phenotypes including autosomal recessive bestrophinopathy (ARB, MIM 611809)[1,2], Best vitelliform macular dystrophy (MIM 153700)[3,4], autosomal dominant vitreoretinochoroidopathy (MIM 193220)[5,6], autosomal dominant microcornea, rod-cone dystrophy, early-onset cataract posterior staphyloma syndrome and retinitis pigmentosa (MIM 613194)[7,8]
The BEST1 gene has been associated with a wide range of ocular phenotypes
Clinical presentation of the autosomal recessive form of bestrophinopathy is distinct from the autosomal dominant form, both these conditions are known to arise from BEST1 (VMD2) gene alterations

Summary

Introduction

Mutations in BEST1 gene have been described in a variety of ocular disease phenotypes including autosomal recessive bestrophinopathy (ARB, MIM 611809)[1,2], Best vitelliform macular dystrophy (MIM 153700)[3,4], autosomal dominant vitreoretinochoroidopathy (MIM 193220)[5,6], autosomal dominant microcornea, rod-cone dystrophy, early-onset cataract posterior staphyloma syndrome and retinitis pigmentosa (MIM 613194)[7,8]. The BEST1 (bestrophin-1) protein is expressed in the basolateral plasma membrane of the retinal pigment epithelium (RPE) where it regulates multiple functions essential for normal vision[7,9]. It primarily functions as a calcium-activated chloride channel[7,9,10]. We analyzed four Indian families with clinically diagnosed bestrophinopathy using whole exome sequencing and identified novel BEST1 mutations

Methods

Results

Conclusion