Two heterozygous mutations identified in one Chinese patient with bilateral macular coloboma

Abstract

Congenital macular coloboma is characterized by defined punched out atrophic lesions of the macula. The present study aimed to investigate the genetic alterations of one Chinese sporadic patient with bilateral large macular coloboma. Complete ophthalmic examinations, including best-corrected visual acuity, slit-lamp examination, fundus examination, fundus photograph and fundus fluorescein angiography imaging, Pentacam, and optical coherence tomography were performed on the patient. Genomic DNA was extracted from leukocytes in a peripheral blood sample collected from the patient, the patient's unaffected family members and from 200 unrelated control subjects from the same population. Next-generation sequencing of the known genes involved in ocular disease was performed. The functional effects of the mutation were analyzed using Polymorphism Phenotyping (PolyPhen) and Sorting Intolerant From Tolerant (SIFT). One heterozygous bestrophin 1 (BEST1) mutation c.1037C>A (p.Pro346His, p.P346H) in exon 9 and one heterozygous regulating synaptic membrane exocytosis 1 (RIMS1) mutation c.3481A>G (p.Arg1161Gly, p.R1161G) in exon 23 were identified in the patient being investigated, but not in the unaffected family members or unrelated control subjects. Polyphen and SIFT predicted that the amino acid substitution p.P346H in the BEST1 protein is damaging. In addition, Polyphen predicted that the amino acid substitution p.R1161G in the RIM1 protein is damaging. The results of the current study have increased the mutation spectrums of BEST1 and RIMS1, and are valuable for improving the current genetic counseling process and developing novel therapeutic interventions for patients with macular coloboma.

Genetic variations in Bestrophin‑1 and associated clinical findings in two Chinese patients with juvenile‑onset and adult‑onset best vitelliform macular dystrophy

“…BEST1 gene mutations and polymorphisms have been reported in diverse ethnic groups ( 15 , 48 – 50 ). In this study, one recurrent mutation, c.903T>G (p.D301E) in exon 8, and one SNP, c.1608C>T (p.T536T), in exon 10 were reported.…”

Clinical and next-generation sequencing findings in a Chinese family exhibiting severe familial exudative vitreoretinopathy

“…The LRP5 mutation c.260T>G (p.I87S) in exon 2 identified in this family is a novel mutation. Compared with FZD4 , TSPN12 , NDP and ZNF408 , LRP5 is most frequently mutated in FEVR, likely due to its large coding region ( 22 , 43 – 45 ). LRP5 and its homologue LRP6 encode single-span transmembrane receptors, LRP5/LRP6 that interact with the seven-pass transmembrane receptor, FZD4 to bind Wnt, activating the canonical Wnt-β-catenin signaling pathway ( 46 , 47 ).…”

“…Subsequent to quality control, captured library sequencing was performed on the Illumina HiSeq2500 Analyzers (Illumina, Inc., San Diego, CA, USA) for 90 cycles per read to generate paired-end reads. Image analysis, error estimation and base calling were performed using the Illumina Pipeline software (version 1.3.4; Illumina, Inc.) to generate raw data ( 22 ).…”

“…A capture panel of inherited retinal-disease genes was previously designed and assessed in the present study. The capture panel comprised 708,919 bp that covered all exons together with the flanking exon and intron boundaries (±15 bp) of 175 genes, including 138 genes causing common inherited non-syndromic eye diseases and 54 genes causing syndromic eye diseases ( 22 , 23 ).…”

“…To predict the effect of missense variants, polymorphism phenotyping (PolyPhen) and sorting intolerant from tolerant (SIFT) were used to predict the potential impact of a single amino acid substitution on the protein structure and function using straight forward physical and comparative considerations ( 22 , 23 , 31 ). Variants were considered pathogenic when at least one of the two programs predicted deleterious effect of the amino acid substitution on the protein structure or function.…”