Variable expressivity of BEST1-associated autosomal dominant vitreoretinochoroidopathy (ADVIRC) in a three-generation pedigree

Objective Autosomal dominant vitreoretinochoroidopathy (ADVIRC) is associated with pathogenic variants in BEST1, which typically causes visual impairment in the late stage of disease. We present a pedigree with variable expressivity and the youngest case in the literature with visual impairment in early childhood. Methods and analysis This is a retrospective, observational, case series describing multigenerational members of one family affected with ADVIRC. Patients underwent examination, ultra-widefield fundus photography and angiography, optical coherence tomography, full-field electroretinography (ffERG) and full-field perimetry. Results Three affected members of the pedigree, one from each successive generation, were found to harbour a mutation, c.715G>A:p.Val239Met, in BEST1. The proband characterised in this report is, to our knowledge, the youngest documented case of ADVIRC in early childhood. Yet, this patient has the most severe retinal dysfunction compared with the father and paternal grandmother, whom exhibit classic characteristics of ADVIRC. Longitudinal data from the paternal grandmother showed that there was a rapid decline in ffERG responses (photopic decline worse than scotopic) from the fourth to fifth decade of life, which correlated with severe concentric constriction of visual fields. Conclusion This multigenerational case series provides new insights into the ADVIRC disease spectrum and rate of progression. While ADVIRC typically causes a slowly progressive disease, we show that variable phenotypic expressivity is possible among affected members of the same family with the same mutation in BEST1. Thus, ADVIRC must also be considered in the differential diagnosis of paediatric patients with severe retinal dystrophy in early childhood.

[1]  C. Brandl,et al.  Mutation-Dependent Pathomechanisms Determine the Phenotype in the Bestrophinopathies , 2020, International journal of molecular sciences.

[2]  S. Tsang,et al.  Investigation and Restoration of BEST1 Activity in Patient-derived RPEs with Dominant Mutations , 2019, Scientific Reports.

[3]  V. Mahajan,et al.  Early Onset Neovascular Inflammatory Vitreoretinopathy Due to a De Novo CAPN5 Mutation: Report of a Case , 2019, Ocular immunology and inflammation.

[4]  J. Pulido,et al.  A novel missense mutation in BEST1 associated with an autosomal-dominant vitreoretinochoroidopathy (ADVIRC) phenotype , 2018, Ophthalmic genetics.

[5]  K. Packo,et al.  Ocular Histopathology and Immunohistochemical Analysis in the Oldest Known Individual with Autosomal Dominant Vitreoretinochoroidopathy. , 2017, Ophthalmology. Retina.

[6]  J. Roider,et al.  Long-term changes in autosomal dominant vitreoretinochoroidopathy (ADVIRC) , 2018, Graefe's Archive for Clinical and Experimental Ophthalmology.

[7]  J. Pulido,et al.  Bestrophin 1 and retinal disease , 2017, Progress in Retinal and Eye Research.

[8]  L. da Cruz,et al.  Mislocalisation of BEST1 in iPSC-derived retinal pigment epithelial cells from a family with autosomal dominant vitreoretinochoroidopathy (ADVIRC) , 2016, Scientific Reports.

[9]  Dorothy A. Thompson,et al.  Unilateral BEST1-Associated Retinopathy , 2016, American journal of ophthalmology.

[10]  H. Stöhr,et al.  Long-Term Macular Changes in the First Proband of Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC) Due to a Newly Identified Mutation in BEST1 , 2016, Ophthalmic genetics.

[11]  M. Goldberg,et al.  Progressive Cone Dysfunction and Geographic Atrophy of the Macula in Late Stage Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC) , 2014, Ophthalmic genetics.

[12]  S. Tsang,et al.  BEST1: the Best Target for Gene and Cell Therapies. , 2015, Molecular therapy : the journal of the American Society of Gene Therapy.

[13]  Michael Bach,et al.  ISCEV Standard for full-field clinical electroretinography (2015 update) , 2014, Documenta Ophthalmologica.

[14]  F. Torricelli,et al.  BEST1 sequence variants in Italian patients with vitelliform macular dystrophy , 2012, Molecular vision.

[15]  V. Sheffield,et al.  Calpain-5 Mutations Cause Autoimmune Uveitis, Retinal Neovascularization, and Photoreceptor Degeneration , 2012, PLoS genetics.

[16]  M. Margaglione,et al.  Functional and clinical data of Best vitelliform macular dystrophy patients with mutations in the BEST1 gene , 2009, Molecular vision.

[17]  B. J. Klevering,et al.  The spectrum of ocular phenotypes caused by mutations in the BEST1 gene , 2009, Progress in Retinal and Eye Research.

[18]  P. Campochiaro,et al.  BEST1 expression in the retinal pigment epithelium is modulated by OTX family members. , 2009, Human molecular genetics.

[19]  G. Holder,et al.  ADVIRC is caused by distinct mutations in BEST1 that alter pre-mRNA splicing , 2008, Journal of Medical Genetics.

[20]  E. Stone,et al.  Differential macular and peripheral expression of bestrophin in human eyes and its implication for best disease. , 2007, Investigative ophthalmology & visual science.

[21]  P. Campochiaro,et al.  VMD2 Promoter Requires Two Proximal E-box Sites for Its Activity in Vivo and Is Regulated by the MITF-TFE Family* , 2007, Journal of Biological Chemistry.

[22]  K. Oh,et al.  Central cone dysfunction in autosomal dominant vitreoretino choroidopathy (ADVIRC). , 2006, American journal of ophthalmology.

[23]  D. Baralle,et al.  Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC). , 2004, Investigative ophthalmology & visual science.

[24]  P. Campochiaro,et al.  Analysis of the VMD2 Promoter and Implication of E-box Binding Factors in Its Regulation* , 2004, Journal of Biological Chemistry.

[25]  A. Hutchinson,et al.  Phenotype and genotype correlations in two best families. , 2003, Ophthalmology.

[26]  S. Bhattacharya,et al.  A clinical and molecular genetic study of a rare dominantly inherited syndrome (MRCS) comprising of microcornea, rod-cone dystrophy, cataract, and posterior staphyloma , 2003, The British journal of ophthalmology.

[27]  W. Spileers,et al.  Clinical and electrophysiological findings in autosomal dominant vitreoretinochoroidopathy: report of a new pedigree , 2001, Graefe's Archive for Clinical and Experimental Ophthalmology.

[28]  H. Stöhr,et al.  Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease). , 1998, Human molecular genetics.

[29]  M. Metzker,et al.  Identification of the gene responsible for Best macular dystrophy , 1998, Nature Genetics.

[30]  D. Walker,et al.  Molecular evidence for non-penetrance in Best's disease. , 1994, Journal of medical genetics.

[31]  J. Folk,et al.  Autosomal dominant neovascular inflammatory vitreoretinopathy. , 1990, Ophthalmology.

[32]  G. Fishman,et al.  Autosomal dominant vitreoretinochoroidopathy (ADVIRC). , 1984, The British journal of ophthalmology.

[33]  G. Fishman,et al.  Autosomal dominant vitreoretinochoroidopathy. , 1982, Archives of ophthalmology.

[34]  R. Weleber The effect of age on human cone and rod ganzfeld electroretinograms. , 1981, Investigative ophthalmology & visual science.