Dataset Information

Clinical and Genetic Features of Familial Exudative Vitreoretinopathy With Only-Unilateral Abnormalities in a Chinese Cohort.

ABSTRACT:

Importance

Familial exudative vitreoretinopathy (FEVR) with only-unilateral abnormalities may masquerade as other vitreoretinal disorders. Clinicians should be vigilant of patients with unilateral FEVR, recognizing that the relatively normal vision of the fellow eye could compromise a patient's attention to the decreasing vision of the affected eye.

Objective

To describe the clinical findings and genetic spectrum of patients with FEVR and only-unilateral abnormalities.

Design, setting, and participants

A medical records review included all patients (N = 621) with a diagnosis of FEVR between January 1, 2010, and October 31, 2017, from Xinhua Hospital in Shanghai, China. Patients were excluded if retinal abnormalities were noted in both eyes or if a diagnosis of FEVR could not be confirmed by genetic testing. Inclusion criteria included clinical diagnosis of FEVR with only-unilateral features on widefield angiography and confirmed mutations in 5 FEVR targeted genes (LRP5, FZD4, ZNF408, NDP, and TSPAN12).

Exposures

Clinical data were collected from patient medical records. Widefield angiography and targeted gene sequencing were performed in all patients of this cohort.

Main outcomes and measures

Clinical findings and genetic spectrum.

Results

Of the 621 patients with a clinical diagnosis of FEVR, 20 with unilateral FEVR (3.22%; 95% CI, 1.83%-4.61%; 18 males [90%] and a mean [SD] age at presentation of 2.6 [2.7] years) were identified. All patients were Han Chinese. The most common clinical presentations were total retinal detachment (12 [60%]) and retinal fold (6 [30%]). Mutations in the LRP5 gene were the most prevalent (11 [55%]), followed by the genes FZD4 (4 [20%]), ZNF408 (2 [10%]), TSPAN12 (2 [10%]), and NDP (1 [5%]).

Conclusions and relevance

The findings of this study suggest that the identification of unilateral peripheral retinal abnormalities should include a consideration of FEVR, perhaps more often seen with mutations in the LRP5 gene; variable phenotypic penetrance of the retinal abnormalities can lead to seemingly unilateral disease.

SUBMITTER: Tian T

PROVIDER: S-EPMC6555475 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Familial exudative vitreoretinopathy (FEVR) is a rare hereditary retinal disorder characterized by the premature arrest of vascularization in the peripheral retina. The aim of the present study was to characterize the clinical presentations of a Chinese family affected by bilateral severe FEVR, and to identify the underlying genetic variations. One family that presented with bilateral FEVR was recruited for this study. Comprehensive ophthalmic examinations, including best‑corrected visual acuity, slit‑lamp examination, fundus photography, fundus fluorescein angiography imaging and electroretinogram were performed. Genomic DNA was extracted from leukocytes of the peripheral blood collected from the affected and unaffected family members, as well as 200 unrelated control subjects from the same population. Next‑generation sequencing of the candidate genes associated with ocular diseases was performed, and the identified mutations were validated by conventional polymerase chain reaction‑based sequencing. The functional effects of the mutations were analyzed by polymorphism phenotyping (PolyPhen) and sorting intolerant from tolerant (SIFT). One heterozygous ATP binding cassette subfamily A member 4 (ABCA4) c.5693G>A (p.R1898H) mutation in exon 40 and one heterozygous LDL receptor related protein 5 (LRP5) c.260T>G (p.I87S) mutation in exon 2 were identified in this family. To the best of our knowledge, the ABCA4 c.5693G>A (p.R1898H) mutation has not been reported in FEVR, and the LRP5 c.260T>G (p.I87S) mutation is a novel mutation. PolyPhen and SIFT predicted that the amino acid substitution R1898H in protein ABCA4 is benign, whereas the amino acid substitution I87S in protein LRP5 is damaging. A single nucleotide polymorphism c.266A>G (p.Q89R, rs41494349) was identified in exon 2 of LRP5. These findings expand the mutation spectrums of ABCA4 and LRP5, and will be valuable for genetic counseling and development of therapeutic interventions for patients with FEVR.

Project description:BACKGROUND:Familial exudative vitreoretinopathy (FEVR) is a severe clinically and genetically heterogeneous retinal disorder characterized with failure of vascular development of the peripheral retina. The symptoms of FEVR vary widely among patients in the same family, and even between the two eyes of a given patient. The purpose of this study was to investigate the molecular mechanisms by which the start codon mutation of the TSPAN12 causes difference in clinical manifestations between individuals in the same family. METHODS:Next-generation sequencing (NGS)-based target capture sequencing was performed in proband with a diagnosis of FEVR and their normal visual acuity family members. Cosegregation analysis of the candidate causative variant was performed in additional family members by using Sanger sequencing. Complete fundus examination, fundus fluorescein angiography (FFA), and family history collection were performed in all family members. Potential candidate causative variants were verified with reference to guidelines and standards from the American College of Medical Genetics and Genomics. RESULTS:We identified a novel heterozygous missense mutation (c.1A>G, p.M1V) localized in the start codon of the TSPAN12 and was detected as a potentially disease-causing variant for the proband. Retrospective analysis of clinical data, fundus examination, and FFA showed that the mutant carrier presented peripheral retinal vascular anomalies in early stages, and visual acuity did not show significant effects. However, the proband who carried this mutation and his cousin showed typical high-stage FEVR fundus changes coupled with a sharp decline in vision. CONCLUSIONS:We report a novel start codon mutation (c.1A>G, p.M1V) in the TSPAN12 that causes clinically heterogeneous manifestations. Our results expand the mutation spectrums of TSPAN12, and will be valuable for disease diagnosis, prognosis, genetic counseling, and enriching our understanding of the role of the tetraspanin-12 protein in the pathogenesis of FEVR.