Best Vitelliform Macular Dystrophy (BVMD) and Bestrophinopathies via the BEST1 Gene

Visual acuity in humans and other higher primates is mediated by the central (or macular) region of the retina called the fovea, which has the highest density of cone photoreceptor cells (Sun et al. Proc Natl Acad Sci USA 99(6):4008-4013, 2002). Age related-Macular degeneration (AMD) is the most common cause of irreversible vision loss that usually affects older adults due to progressive changes in the retina and/or the underlying retinal pigment epithelium (RPE). Both genetic and environmental factors influence AMD, but juvenile-onset macular degeneration (MD) or Best vitelliform macular dystrophy (BVMD/Best disease, OMIM 153700) is exclusively a genetic disorder (Hartzell et al. Physiology 20:292-302, 2005). Autosomal dominant (AD) BVMD is one of the most common retinal degeneration disorders, with an estimated prevalence of 1.5 per 100 000 individuals in Denmark (Bitner, H. et al. Am J Ophthalmol 154(2):403-412, 2012). BVMD is clinically characterized by large deposits of lipofuscin-like material in the RPE, which forms the characteristic macular lesions resembling the egg yolk ('vitelliform'), a normal electoretinogram (ERG) and an unusual electrooculogram (EOG) light rise and risk of angle-closure glaucoma (Low et al. Mol Vis 17:2272-2282, 2011). The BEST1 gene (Gene/Locus OMIM 607854; previously known as VMD2) has been linked to BVMD. Over 250 causative mutations have been identified in this gene and are associated with clinically distinct ocular phenotypes that are collectively referred as bestrophinopathies (Piñeiro-Gallego et al. Mol Vis 17:1607-1617, 2011). The other clinical phenotypes associated with BEST1 mutations are AD Vitreo-retino-choroidopathy (ADVIRC, OMIM 193220) (Kaufman et al. Arch Ophthalmol 100(2):272-278, 1982), Vitelliform macular dystrophy, adult-onset (AVMD, OMIM 608161)(Do and Ferrucci. Optometry 77(4):156-166, 2006), Autosomal recessive (AR) Bestrophinopathy (ARB, OMIM 611809) (Burgess et al. Am J Hum Genet 82(1):19-31, 2008) and AD/AR Retinitis pigmentosa-50 (RP50, OMIM 613194) (Davidson et al. Am J Hum Genet 85(5):581-592, 2009).

While BEST1 mutations typically cause AD inheritance, AR inheritance has also been reported (Bitner, H. et al. Invest Ophthalmol Vis Sci 52(8):5332-5338, 2011). BEST1, located on the long arm (q13) of chromosome 11, encodes Bestrophin, a transmembrane protein that is located in the basolateral portion of the RPE and is responsible for the basolateral Cl- conductance that regulates voltage-dependent Ca2+ channels and generates the light peak. Dysfunction of this transport due to mutations in BEST1 might result in significant accumulation of lipofuscin, ion imbalance in the space around the photoreceptor outer segments and characteristically reduced light peak, which is a pathological hallmark of Best disease. BEST1 is predominantly expressed in RPE and is comprised of 11 exons coding 585 amino acids (aa). Causative mutations in BEST1 are distributed throughout the first 312 aa, and it has been reported that aa 293–311 are especially highly conserved and have functional importance. Mutations in 16 of these 18 aa are linked to Best disease (Hartzell et al. 2005; White et al Hum Mutat 15(4):301-308, 2000). BVMD, AVMD and AMD share some phenotypic features, though AVMD and AMD differ from BVMD by later onset. Along with BEST1 (responsible for 25% of AVMD cases), PRPH2 (periperin/RDS) mutations are linked to AVMD (~36% of cases), indicating genetic heterogeneity of the disorder (Zhuk and Edwards. Mol Vis 12:811-815, 2006). BEST1 pre-mRNA splicing mutations that lead to in-frame deletions are reported in ADVIRC (Yardley et al Invest Ophthalmol Vis Sci 45(10):3683-3689, 2004), whereas missense mutations were associated with AD/AR Retinitis Pigmentosa (Davidson et al. 2009) . The vast majority of identified BEST1 mutations (90/93) in patients with classical Best disease are missense mutations or small in-frame deletions (MacDonald, I.M. and Lee, T., GeneReviews, 2009 ; Bitner, H. et al. Am J Ophthalmol 154(2):403-412, 2012). There are a few reports of de novo mutations in BVMD patients whose parents were phenotypically and genetically unaffected (Apushkin et al. Arch Ophthalmol 124(6):887-889, 2006; Palomba et al. Am J Ophthalmol 129(2):260-262, 2000)

Krämer et al detected 23 unique BEST1 mutations in 34 of 41 BVMD affected patients. Out of 25 probands who had positive family history, 96% (24/25) had BEST1 mutations, whereas with unknown family history the detection rate was significantly reduced to 69% (11/16) (Krämer et al. Eur J Hum Genet 8(4):286-292, 2000). Marchant et al also reports high detection rate for BEST1 mutations in BVMD patients (at least one mutation in each patient) (Marchant et al. J Med Genet 44(3):e70).

Thus far, no gross insertions/deletions have been identified in BEST1 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the BEST1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).