Screening of BEST1 Gene in a Chinese Cohort With Best Vitelliform Macular Dystrophy or Autosomal Recessive Bestrophinopathy

Abstract

PURPOSE. Mutations in the BEST1 gene can cause Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB). The aim of the current study was to establish the BEST1 mutation spectrum in Chinese patients with BVMD and ARB and to describe the phenotypic characteristics of patients carrying BEST1 mutations. METHODS.A total of 37 probands with a clinical diagnosis of BVMD (17 patients) or ARB (20 patients) were recruited for genetic analysis; of these, only 5 probands had a family history. All probands underwent detailed ophthalmic examinations. All coding exons and exon-intron boundaries of the BEST1 gene were screened by PCR-based DNA sequencing. In silico programs were used to analyze the pathogenicity of all the variants. Genomic DNA rearrangements of the BEST1 gene were identified by real-time quantitative PCR (RQ-PCR).RESULTS. For patients with BVMD, single heterozygous BEST1 mutations were identified in 13 patients and compound heterozygous mutations were found in 3 patients. For patients with ARB, biallelic mutations were found in 13 probands and single mutant alleles in six patients. Overall, 36 disease-causing variants (20 novel mutations) of the BEST1 gene were identified, including 28 (77.8%) missense, 3 (8.3%) nonsense, 4 (11.1%) splicing effect, and 1 (2.8%) frameshift small duplication mutations.CONCLUSIONS. The mutation spectrum of the BEST1 gene in Chinese patients differed from those of Caucasian patients. Mutations that cause ARB differ from those that cause BVMD. BEST1 screening is important for precise diagnosis of BVMD or ARB.

Novel BEST1 gene mutations associated with two different forms of macular dystrophy in Tunisian families

“…In parallel, one additional new mutation in BEST1 was identified in family 2 affected with BVMD. Although most mutations associated with BVMD are missense mutations that do not compromise protein synthesis (Table S2), we identified a nonsense mutation, p.S517X that perfectly segregates within the family. Usually BVMD is transmitted in an autosomal dominant fashion, but as we show in this family it may also be inherited as an autosomal recessive disease due to homozygosity as previously reported …”

“…Schematic localization of different variants responsible for BVMD or autosomal recessive bestrophinopathy with the two new mutations L31M and S517X included. L31M is located in the first transmembrane domain and S517X is located in the C‐terminal cytoplasmic domain (modified from References)…”

“…Moreover, these different forms of macular dystrophies encompass a wide range of clinical, psychophysical, ecophysiological (electroretinography [ERG], electrooculography [EOG]) and histological findings. BVMD is clinically characterized by morphologic variability: the deposition of yellowish, lipofuscin‐like or vitelliform lesions usually evolves through previtelliform, vitelliform with “egg‐yolk,” pseudohypopyon, vitelliruptive with scrambled egg and atrophic stages . Although ARB is considered as a null phenotype of bestrophin‐1 in humans, it displays serous retinal detachment with extramacular vitelliform lesions and it is likely that this form affects the eye development more than BVMD .…”

“…Although the mechanisms underlying these diseases and the spectrum of phenotypes associated with the large number of different mutations are largely unknown, some genotype‐phenotype correlations have been suggested in the BEST1 gene to better understand the pathophysiology. In fact, mutations causing ARB are different from that causing BVMD . Genetically and especially in BVMD, the most of BEST1 mutations are missense .…”

“…In fact, mutations causing ARB are different from that causing BVMD . Genetically and especially in BVMD, the most of BEST1 mutations are missense . Whereas in ARB, mutations vary from missense to truncating or intronic single nucleotide changes which appear generally in a compound heterozygous state …”