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Familial exudative vitreoretinopathy in a 4 generations family of South-East Asian Descendent with FZD4 mutation (c.1501_1502del)

Familial exudative vitreoretinopathy in a 4 generations family of South-East Asian Descendent... Background: Familial Exudative Vitreoretinopathy (FEVR) is a hereditary disorder characterized by peripheral avascu- lar retina with neovascularization. Although FEVR has been thoroughly described in multiple literature publications from different countries, there are currently limited articles describing the phenotypes of FEVR among South-East Asian Descendent. This paper describes the clinical phenotype of the FZD4 gene with c.1501_1502 deletion in a 4-generation case series of a South East Asian family. Methods: We reviewed a 4-generation case series of a South-East Asian descendent family consisting of 27 family members with 10 members diagnosed with FEVR. We observed the clinical phenotype of these series of patients, including some of the family members who underwent whole-exome sequencing, PCR amplification and DNA sequencing techniques to identify the mutated gene. Results: Frameshift mutation (c.1501_1502del) were found in FZD4 gene in this series of patients with the age ranging from 1 month old to 69 years old. There was a 100% (4/4) of our paediatric patients being diagnosed within 21 days of life. It was also found that 75% of patients (6/8) less than 40 years old exhibited disease asymmetry of 2 stages or more and 80% (8/10) had a history of vitreoretinal surgery or diode laser photocoagulation, with a further 50% of the adult patients identified as legally blind; the mean age of blindness was 18-years-old. Conclusions: Phenotypic manifestation of FZD4 gene with c.1501_1502del mutation can be identified within the neonatal period. They have relatively greater clinical asymmetry of 2 stages or more compared to other mutations. Without treatment, most of them will have bilateral severe visual impairment around the adolescent age group. Keywords: Familial exudative vitreoretinopathy, FEVR, FZD4 genes premature birth and oxygen therapy [1].  FEVR is char- Background acterized by the peripheral avascular retina and subse- Familial exudative vitreoretinopathy (FEVR) was first quently lead to complication due to retina ischemia [2]. described by Criswick and Schepens in 1969 as con- These includes peripheral neovascularization, vitre - genital, bilateral vitreoretinopathy with no history of ous haemorrhage, retinal traction with temporal drag- ging, macular dragging, falciform retinal fold and retinal *Correspondence: yong_zheng92@hotmail.com detachment [2, 3]. FEVR can be inherited in different modes which Ophthalmology Department, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia include autosomal dominant, autosomal recessive and Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom- mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wai et al. International Journal of Retina and Vitreous (2022) 8:30 Page 2 of 6 X-linked recessive [4–6]. Autosomal dominant FEVR is other family members and all the clinical data were docu- the most common, it involves a mutation in frizzled class mented and analysed. Some of the family members were receptor 4 (FZD4), low-density lipoprotein receptor pro- previously treated in our centre, whereby retrospective tein 5 (LRP5) or tetraspanin 12 (TSPAN12) [7–9]. data extraction was done from the clinical notes. FZD4 genes are located in chromosome 11q14.2 and encode a 7-transmembrane protein of 537 amino acids Whole exome sequencing (WES) [10]. FZD4 genes encode Wnt receptor which plays an Whole exome sequencing was performed on genomic important role in retinal angiogenesis [9]. To date, there DNA using Agilent v6CREv2 targeted sequence cap- are more than 50 mutations in FZD4 genes linked with ture method to enrich the exome. Direct sequencing of FEVR reported [11]. Deletion of c.1501_1502 is one of the amplified captured regions was performed using the reported mutations in FZD4 genes. In regards to 2 × 100  bp reads on Illumina next-generation sequenc- FZD4 genes related FEVR disease, most of the published ing (NGS) systems. Alignments to the human reference articles originate from Caucasian, South Asian (Indian) genome (hg 19) are performed and annotated variants East Asian (Chinese and Japanese) [9, 11–13]. To our are identified in the targeted region. Primary data analy - best knowledge, there is currently no published litera- sis was performed using Illumina DRAGON Bio-IT Plat- ture describing the phenotypic manifestations of FZD4 form v.2.03. Secondary and tertiary data analysis was c.1501_1502 deletion among South-East Asian descents. performed using PerkinElmer’s internal ODIN v.1.01 software for single nucleotide variants and Biodiscov- Methods ery’s NxClinical v.4.3 or Illumina DRAGEN Bio-IT Plat- Written informed consent was taken from the patients form v.2.03 for copy number variation and absence of or their guardians before clinical data and blood samples heterozygosity. were collected. This research adhered to the tenets of the Declaration of Helsinki and was registered under the Results Malaysian National Medical Research Registry (NMRR We identified 10 FEVR patients (20 eyes) within 1 fam - ID-21-02310-O5A). This study was conducted in Hospi - ily of South-East Asian descendent. Data were retro- tal Kuala Lumpur from April 2021 until December 2021. spectively extracted and analysed. Of the 10 patients, 7 The diagnosis of FEVR was based on the presence of (70%) were male, their age ranged from 1-month-old to typical clinical features: peripheral retinal avascular areas 69 years old. The family pedigree is displayed in Fig. 1. or proliferative changes, dragged disc or macula, retinal detachment with exudation or falciform retinal folds and no history of prematurity or oxygen supplementation. Genotype: Frameshift mutation (c.1501_1502del) in FZD4 We identified one Malaysian patient as a proband with gene autosomal dominant FEVR and investigated the molecu- Proband is Patient No. 10, WES was done to identify the lar basis of the disorder with Whole Exome Sequencing genetic mutation. Results revealed deletion of two nucle- (WES). Once the pathogenic gene was identified, some otides at position c.1501_1502 of the FZD4 gene causing family members who have the phenotype of FEVR went a frameshift in the protein reading frame. PCR amplifica - for polymerase chain reaction (PCR) and DNA sequenc- tion and DNA sequencing techniques were performed on ing techniques for the determination of the targeted Patient No. 9 to detect the c.1501_1502delCT mutation mutation. We conducted clinical examination on the in the FZD4 gene. Results were positive. Fig. 1 A family pedigree from South-East Asian descent consists of 4 generations, 27 family members with 10 of them diagnosed with FEVR W ai et al. International Journal of Retina and Vitreous (2022) 8:30 Page 3 of 6 Phenotype: extremely asymmetric clinical severity Visual acuity ranged from logMAR 0.2 to no percep- The clinical severity of FEVR was graded using Revised tion of light. We could not take the visual acuity for the FEVR Clinical Staging System 2014 [14]. The grading 1-month-old patient. Only 3 out of 9 patients (33.3%) ranged from stage 1 to 5B (Table 1). Among 10 patients, have visual acuity of logMAR 1.0 or better in either eye. only 4 (40%) have similar staging in both eyes. Clini- All 3 of them had laser therapy or vitreoretinal surgery cal asymmetry become more apparent among younger performed on their better eye. patients, 6 out of 8 patients (75%) that are younger than Among paediatric patients, all 4 patients (No. 5, 6, 40-years-old have asymmetry FEVR clinical grade. All 7 & 10) were diagnosed in our centre before 21 days of of the patients (100%) that have clinical asymmetry, life (Table 2). None of them was born prematurely. All of have differences of at least 2 stages between their eyes them had asymmetric retinal folds during our first exam - (Fig. 2). ination (Fig.  3). The better eye ranged from stage 1 to Table 1 Revised FEVR clinical staging system 2014 and number of eyes Stage Description No. of eyes 1 Avascular periphery or anomalous intraretinal vascularization 1A Without exudate or leakage 1 1B With exudate or leakage 0 2 Avascular retinal periphery with extraretinal vascularization 2A Without exudate or leakage 2 2B With exudate or leakage 1 3 Extramacular retinal detachment 3A Without exudate or leakage 2 3B With exudate or leakage 1 4 Macula-involving retinal detachment, subtotal 4A Without exudate or leakage 3 4B With exudate or leakage 0 5 Total retinal detachment 5A Open funnel 0 5B Closed funnel 10 Fig. 2 FEVR interocular disease asymmetry vs. age Wai et al. International Journal of Retina and Vitreous (2022) 8:30 Page 4 of 6 Table 2 FEVR among paediatric age group members No. Current age Age of diagnosis Better eye (stage), Worse eye (stage), Procedure Progression after Interocular disease (months) (days-old) VA (LogMAR) VA (LogMAR) procedure asymmetry (stage) 5 1 11 LE 2A* RE 4A* BE LIO Nil 2 6 4 14 LE 1A, 1.74 RE 3B, 2.04 BE LIO Nil 2 7 60 10 RE 4A, 1.14 LE 4A, 2.04 BE LIO Progress 0 10 108 21 LE 3A, 0.60 RE 5B, PL LE LIO Nil 2 RE VR op VA Visual acuity in LogMAR, PL Perception of light, RE Right eye, LE Left eye, BE Both eye, LIO Diode Laser Indirect Ophthalmoscopy, VR op Vitreo-retinal operation, Nil No progression after procedure *Unable to check the visual acuity as patient was too young Fig. 3 Fundus photo of patient no. 6 shows asymmetric clinical severity. A  Right eye shows extramacular full-thickness retina fold with haemorrhage. No obvious exudation was seen. Stage 3A FEVR. B  Left eye posterior pole appears flat, arrow shows the border of vascularized retinal with minimal exudates, no laser marks over avascular retina area. Stage 1B FEVR 4A, the worse eye ranged from 3B to 5B. Diode laser was FEVR remained stable despite absent of vitreoretinal sur- given to all 4 of them and monitored closely to look for gery. The remaining 2 adult patients (33.3%) did not seek any progression. Despite laser photocoagulation, patient any medical treatment. The disease remained static after no. 7 still progressed to Stage 4A with retinal fold touch- adolescence. ing posterior capsule of the crystalline lens. To date, patients 5, 6 & 10 have been clinically stable, but they are Discussion too young to conclude that the disease is static. Familial exudative vitreoretinopathy (FEVR, OMIM: The mean age for adult family members is 43.1 years 133,780) caused by FZD4 gene with c.1501_1502 dele- old. (Table  3) 50% (No. 1, 2, 8) of the adult family mem- tion was only briefly described by Toomes et al. [7]. This bers are legally blind. All 3 of them are the eldest among mutation has been previously reported in individuals all 10 patients. They gave a history of bilateral eye blind - with FEVR (PMID: 12172548). There is a paucity of the ness when they were teenagers (ages ranged from 15 to detailed phenotypic description on c.1501_1502 deletion. 21 years old). The mean age of their blindness was 18 To our best knowledge, to date, there has been no article years old. describing the genotypic-phenotypic correlation of this All 6 adult patients complained of unilateral blurring mutation among South-East Asian descents. of vision at a very young age (ranged 3 to 10 years old). Subsequently, the better eye will deteriorate and 3 (50%) Early detection of them underwent vitreoretinal surgery on their better FZD4 gene with c.1501_1502 deletion showed signs eye. 1 patient (16.6%) underwent lens extraction over the of FEVR as early as 10 days of life. Our study managed better eye and suffered from secondary glaucoma, his to diagnose all the 4th generation children during their W ai et al. International Journal of Retina and Vitreous (2022) 8:30 Page 5 of 6 Table 3 FEVR among adult family members No. Current age Better eye (Stage), VA Worse eye (Stage), Procedure Progression of Interocular disease (years) (LogMAR) VA (LogMAR) disease after asymmetry (stage) procedure 1 69 RE 5B, NPL* LE 5B, NPL LE VR op Progress 0 2 34 RE 5B, PL LE 5B, NPL Nil - 0 3 31 LE 2A, 0.22 RE 5B, NPL RE VR op Nil 3 4 29 LE 2B, 1.30 RE 5B, NPL LE lens aspiration & IOL Nil, Worsening VA 3 Implantation due to secondary glaucoma 8 64 RE 5B, NPL* LE 5B, NPL Nil - 0 9 32 LE 3A, 0.90 RE 5B, PL RE VR op Nil 2 VA Visual acuity in LogMAR, PL Perception of light, NPL No perception of light, RE, Right eye, LE Left eye, BE Both eye, VR op Vitreo-retinal operation, IOL Intraocular lens, Nil None (No procedure done or No progression of disease) *Both eyes have similar severity neonatal period (mean age of diagnosis is 14 days of higher than FEVR patients with TSPAN12, KIF11 or life) due to positive FEVR family history, compared to a NDP mutation [17]. large study that has a mean age of diagnosis of 6 years Our results showed greater asymmetry in younger old.[15] This shows that FEVR caused by FZD4 gene patients with 75% of patients (6/8) who aged younger c.1501_1502delCT mutation can be diagnosed at a very than 40-years-old exhibited disease asymmetry. All 6 young age within the neonatal period. Screening should of them (100%) have a difference of 2 stages or more. be done as early as 10 days old for neonates who have a Ranchod et  al. reported 71% of FEVR patients have 2 family history of FEVR, especially for those who had a eyes within 1 stage of each other [3]. We hypothesize definitive genetic diagnosis of c.1501_1502 deletion. that the FZD4 gene c.1501_1502 deletion can produce greater clinical asymmetry compared to other genotype mutations. Disease progression and age group Genotype-phenotype association will be the future Disease progression was expected to occur before age of of diagnostic medicine. FEVR can be caused by varies 20 years old [16]. Among the 10 patients in our series, 2 genotype mutations, and detailed description of the of them (No. 1 & 7) exhibited disease progression despite phenotype manifestation, correlating with the genotype treatment. Progression occurred at the age of 3-years- mutations for each mutation will help both physicians old (No. 7) and 17-years-old (No. 1). Disease severity and patients to understand and manage the disease bet remained static for the other 6 patients who received ter, with a more realistic visual prognostic expectations, treatment. Only 2 patients did not receive any form of instead of generalising the disease into a broad spec- treatment (No. 2 & 8), and both of them translated the trum of phenotypic manifestations. natural history of progression in FEVR and became legally blind around adolescent age. Some studies described FEVR as a lifelong disease Conclusions where progression can occur at any age after varying To our best knowledge, this is the first case series periods of apparent quiescent [13, 16]. However, these describing the phenotypic expression of FZD4 gene studies lacked genotypic information. Patients with dele- with c.1501_1502 deletion in South-East Asian tion of c.1501_1502 in FZD4 gene might have a relatively descents, spanning a 4-generation case series. Our lesser risk of progression after the adolescent period. study highlights that FEVR signs due to c.1501_1502del can appear very early in life (neonatal period) and thus fundus screening is very important among new- Disease asymmetry borns with a family history of FEVR. A deletion in Interocular clinical asymmetry among FEVR has been c.1501_1502 could manifest greater clinical asymmetry largely reported by multiple articles [3, 9, 13, 17]. Gen- of 2 stages or more compared to other mutation. Fur- erally, 57% of FEVR patients have asymmetry staging, ther studies are needed for detail phenotype descrip- in which 71% presented with the 2 eyes within 1 stage tion in other FEVR genetic mutations. of each other [15]. FEVR with FDZ4 gene mutation shows 47.4% of asymmetric disease severity which is Wai et al. International Journal of Retina and Vitreous (2022) 8:30 Page 6 of 6 Abbreviations vitreoretinopathy locus on chromosome 11q. Am J Hum Genet. FEVR: Familial Exudative Vitreoretinopathy; FZD4: Frizzled Class Receptor 4; 2004;74(4):721–30. PCR: Polymerase chain reaction; DNA: deoxyribonucleic acid; LRP5: Low- 8. Nikopoulos K, Gilissen C, Hoischen A, van Nouhuys CE, Boonstra FN, Blok- density lipoprotein receptor protein 5; TSPAN12: Tetraspanin 12; WES: Whole land EAW, et al. Next-generation sequencing of a 40 Mb linkage interval exome sequencing; VA: Visual acuity; RE: Right eye; LE: Left eye; BE: Both eye; reveals TSPAN12 mutations in patients with familial exudative vitreoretin- PL: Perception of light; NPL: Non perception of light; VR op: Vitreo-retinal opathy. Am J Hum Genet. 2010;86(2):240–7. operation; IOL: Intraocular lens; KIF11: Kinesin Family Member 11; NDP: Norrin 9. Kaykas A, Yang-Snyder J, Héroux M, Shah KV, Bouvier M, Moon RT. Mutant Cystine Knot Growth Factor. Frizzled 4 associated with vitreoretinopathy traps wild-type Frizzled in the endoplasmic reticulum by oligomerization. Nat Cell Biol. 2004;6(1):52–8. Acknowledgements 10. Warden SM, Andreoli CM, Mukai S. The Wnt signaling pathway in familial The authors would like to thank the Director-General of Ministry of Health exudative vitreoretinopathy and Norrie disease. Semin Ophthalmol. Malaysia for his kind permission to publish this article. 2007;22(4):211–7. 11. Tang M, Ding X, Li J, Hu A, Yuan M, Yang Y, et al. Novel mutations in FZD4 Author contributions and phenotype–genotype correlation in chinese patients with familial YZW gathered the necessary information about the patient. YZW and YYC exudative vitreoretinopathy. Mol Vis. 2016;22:917–32. wrote the manuscript under supervision of NH and JR. LTL did a thorough 12. Omoto S, Hayashi T, Kitahara K, Takeuchi T, Ueoka Y. Autosomal dominant revision of the work. NH and JR are the main consultants that managed the familial exudative vitreoretinopathy in two Japanese families with FZD4 patients. All authors read and approved the final manuscript. mutations (H69Y and C181R). Ophthalmic Genet. 2004;25(2):81–90. 13. Shukla D, Singh J, Sudheer G, Soman M, John RK, Ramasamy K, et al. Funding Familial exudative vitreoretinopathy (FEVR). Clinical profile and manage - There is no financial support received for this study. ment. Indian J Ophthalmol. 2003;51(4):323–8. 14. Kashani AH, Learned D, Nudleman E, Drenser KA, Capone A, Trese MT. Availability of data and materials High prevalence of peripheral retinal vascular anomalies in family mem- All data and materials gathered during this study are included in this study. bers of patients with familial exudative vitreoretinopathy. Ophthalmol- ogy. 2014;121(1):262–8. 15. Ranchod TM, Ho LY, Drenser KA, Capone A, Trese MT. Clinical pres- Declarations entation of familial exudative vitreoretinopathy. Ophthalmology. 2011;118(10):2070–5. Ethics approval and consent to participate 16. Benson WE. Familial exudative vitreoretinopathy. Trans Am Ophthalmol This case series is registered under Malaysian National Medical Research Reg- Soc. 1995;93:473–521. istry (NMRR ID-21-02310-O5A) which follows the tenets of the Declaration of 17. Wang Z, Chen C, Sun L, Zhang A, Liu C, Huang L, et al. Symmetry of Helsinki. Written consent was taken from the patients for participation . folds in FEVR: a genotype-phenotype correlation study. Exp Eye Res. 2019;186:107720. Consent for publication Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in pub- Competing interests lished maps and institutional affiliations. The authors declare that they have no competing interests. Author details Ophthalmology Department, Hospital Kuala Lumpur, Kuala Lumpur, Malay- 2 3 sia. Ampang Hospital, Ampang Jaya, Malaysia. Ophthalmology Depar t- ment, Faculty of Medicine and Health Sciences, Universiti Malaysia Sarawak (UNIMAS), Kota Samarahan, Malaysia. Paediatric Ophthalmology Department, Hospital Tunku Azizah, Kuala Lumpur, Malaysia. Received: 23 March 2022 Accepted: 4 May 2022 References 1. Criswick VG, Schepens CL. Familial exudative vitreoretinopathy. Am J Ophthalmol. 1969;68(4):578–94. 2. Gow J, Oliver GL. Familial exudative vitreoretinopathy. An expanded view. Arch Ophthalmol (Chicago, Ill 1960). 1971;86(2):150–5. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : 3. Ranchod TM, Ho LY, Drenser KA, Capone AJ, Trese MT. Clinical pres- entation of familial exudative vitreoretinopathy. Ophthalmology. fast, convenient online submission 2011;118(10):2070–5. 4. Feldman EL, Norris JL, Cleasby GW. Autosomal dominant exudative vit- thorough peer review by experienced researchers in your field reoretinopathy. Arch Ophthalmol. 1983;101(10):1532–5. https:// doi. org/ rapid publication on acceptance 10. 1001/ archo pht. 1983. 01040 02053 4004. support for research data, including large and complex data types 5. de Crecchio G, Simonelli F, Nunziata G, Mazzeo S, Greco GM, Rinaldi E, et al. Autosomal recessive familial exudative vitreoretinopathy: evidence • gold Open Access which fosters wider collaboration and increased citations for genetic heterogeneity. Clin Genet. 1998;54(4):315–20. maximum visibility for your research: over 100M website views per year 6. Plager DA, Orgel IK, Ellis FD, Hartzer M, Trese MT, Shastry BS. X-Linked recessive familial exudative vitreoretinopathy. Am J Ophthalmol. At BMC, research is always in progress. 1992;114(2):145–8. 7. Toomes C, Bottomley HM, Jackson RM, Towns KV, Scott S, Mackey DA, Learn more biomedcentral.com/submissions et al. Mutations in LRP5 or FZD4 underlie the common familial exudative http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Journal of Retina and Vitreous Springer Journals

Familial exudative vitreoretinopathy in a 4 generations family of South-East Asian Descendent with FZD4 mutation (c.1501_1502del)

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Abstract

Background: Familial Exudative Vitreoretinopathy (FEVR) is a hereditary disorder characterized by peripheral avascu- lar retina with neovascularization. Although FEVR has been thoroughly described in multiple literature publications from different countries, there are currently limited articles describing the phenotypes of FEVR among South-East Asian Descendent. This paper describes the clinical phenotype of the FZD4 gene with c.1501_1502 deletion in a 4-generation case series of a South East Asian family. Methods: We reviewed a 4-generation case series of a South-East Asian descendent family consisting of 27 family members with 10 members diagnosed with FEVR. We observed the clinical phenotype of these series of patients, including some of the family members who underwent whole-exome sequencing, PCR amplification and DNA sequencing techniques to identify the mutated gene. Results: Frameshift mutation (c.1501_1502del) were found in FZD4 gene in this series of patients with the age ranging from 1 month old to 69 years old. There was a 100% (4/4) of our paediatric patients being diagnosed within 21 days of life. It was also found that 75% of patients (6/8) less than 40 years old exhibited disease asymmetry of 2 stages or more and 80% (8/10) had a history of vitreoretinal surgery or diode laser photocoagulation, with a further 50% of the adult patients identified as legally blind; the mean age of blindness was 18-years-old. Conclusions: Phenotypic manifestation of FZD4 gene with c.1501_1502del mutation can be identified within the neonatal period. They have relatively greater clinical asymmetry of 2 stages or more compared to other mutations. Without treatment, most of them will have bilateral severe visual impairment around the adolescent age group. Keywords: Familial exudative vitreoretinopathy, FEVR, FZD4 genes premature birth and oxygen therapy [1].  FEVR is char- Background acterized by the peripheral avascular retina and subse- Familial exudative vitreoretinopathy (FEVR) was first quently lead to complication due to retina ischemia [2]. described by Criswick and Schepens in 1969 as con- These includes peripheral neovascularization, vitre - genital, bilateral vitreoretinopathy with no history of ous haemorrhage, retinal traction with temporal drag- ging, macular dragging, falciform retinal fold and retinal *Correspondence: yong_zheng92@hotmail.com detachment [2, 3]. FEVR can be inherited in different modes which Ophthalmology Department, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia include autosomal dominant, autosomal recessive and Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom- mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wai et al. International Journal of Retina and Vitreous (2022) 8:30 Page 2 of 6 X-linked recessive [4–6]. Autosomal dominant FEVR is other family members and all the clinical data were docu- the most common, it involves a mutation in frizzled class mented and analysed. Some of the family members were receptor 4 (FZD4), low-density lipoprotein receptor pro- previously treated in our centre, whereby retrospective tein 5 (LRP5) or tetraspanin 12 (TSPAN12) [7–9]. data extraction was done from the clinical notes. FZD4 genes are located in chromosome 11q14.2 and encode a 7-transmembrane protein of 537 amino acids Whole exome sequencing (WES) [10]. FZD4 genes encode Wnt receptor which plays an Whole exome sequencing was performed on genomic important role in retinal angiogenesis [9]. To date, there DNA using Agilent v6CREv2 targeted sequence cap- are more than 50 mutations in FZD4 genes linked with ture method to enrich the exome. Direct sequencing of FEVR reported [11]. Deletion of c.1501_1502 is one of the amplified captured regions was performed using the reported mutations in FZD4 genes. In regards to 2 × 100  bp reads on Illumina next-generation sequenc- FZD4 genes related FEVR disease, most of the published ing (NGS) systems. Alignments to the human reference articles originate from Caucasian, South Asian (Indian) genome (hg 19) are performed and annotated variants East Asian (Chinese and Japanese) [9, 11–13]. To our are identified in the targeted region. Primary data analy - best knowledge, there is currently no published litera- sis was performed using Illumina DRAGON Bio-IT Plat- ture describing the phenotypic manifestations of FZD4 form v.2.03. Secondary and tertiary data analysis was c.1501_1502 deletion among South-East Asian descents. performed using PerkinElmer’s internal ODIN v.1.01 software for single nucleotide variants and Biodiscov- Methods ery’s NxClinical v.4.3 or Illumina DRAGEN Bio-IT Plat- Written informed consent was taken from the patients form v.2.03 for copy number variation and absence of or their guardians before clinical data and blood samples heterozygosity. were collected. This research adhered to the tenets of the Declaration of Helsinki and was registered under the Results Malaysian National Medical Research Registry (NMRR We identified 10 FEVR patients (20 eyes) within 1 fam - ID-21-02310-O5A). This study was conducted in Hospi - ily of South-East Asian descendent. Data were retro- tal Kuala Lumpur from April 2021 until December 2021. spectively extracted and analysed. Of the 10 patients, 7 The diagnosis of FEVR was based on the presence of (70%) were male, their age ranged from 1-month-old to typical clinical features: peripheral retinal avascular areas 69 years old. The family pedigree is displayed in Fig. 1. or proliferative changes, dragged disc or macula, retinal detachment with exudation or falciform retinal folds and no history of prematurity or oxygen supplementation. Genotype: Frameshift mutation (c.1501_1502del) in FZD4 We identified one Malaysian patient as a proband with gene autosomal dominant FEVR and investigated the molecu- Proband is Patient No. 10, WES was done to identify the lar basis of the disorder with Whole Exome Sequencing genetic mutation. Results revealed deletion of two nucle- (WES). Once the pathogenic gene was identified, some otides at position c.1501_1502 of the FZD4 gene causing family members who have the phenotype of FEVR went a frameshift in the protein reading frame. PCR amplifica - for polymerase chain reaction (PCR) and DNA sequenc- tion and DNA sequencing techniques were performed on ing techniques for the determination of the targeted Patient No. 9 to detect the c.1501_1502delCT mutation mutation. We conducted clinical examination on the in the FZD4 gene. Results were positive. Fig. 1 A family pedigree from South-East Asian descent consists of 4 generations, 27 family members with 10 of them diagnosed with FEVR W ai et al. International Journal of Retina and Vitreous (2022) 8:30 Page 3 of 6 Phenotype: extremely asymmetric clinical severity Visual acuity ranged from logMAR 0.2 to no percep- The clinical severity of FEVR was graded using Revised tion of light. We could not take the visual acuity for the FEVR Clinical Staging System 2014 [14]. The grading 1-month-old patient. Only 3 out of 9 patients (33.3%) ranged from stage 1 to 5B (Table 1). Among 10 patients, have visual acuity of logMAR 1.0 or better in either eye. only 4 (40%) have similar staging in both eyes. Clini- All 3 of them had laser therapy or vitreoretinal surgery cal asymmetry become more apparent among younger performed on their better eye. patients, 6 out of 8 patients (75%) that are younger than Among paediatric patients, all 4 patients (No. 5, 6, 40-years-old have asymmetry FEVR clinical grade. All 7 & 10) were diagnosed in our centre before 21 days of of the patients (100%) that have clinical asymmetry, life (Table 2). None of them was born prematurely. All of have differences of at least 2 stages between their eyes them had asymmetric retinal folds during our first exam - (Fig. 2). ination (Fig.  3). The better eye ranged from stage 1 to Table 1 Revised FEVR clinical staging system 2014 and number of eyes Stage Description No. of eyes 1 Avascular periphery or anomalous intraretinal vascularization 1A Without exudate or leakage 1 1B With exudate or leakage 0 2 Avascular retinal periphery with extraretinal vascularization 2A Without exudate or leakage 2 2B With exudate or leakage 1 3 Extramacular retinal detachment 3A Without exudate or leakage 2 3B With exudate or leakage 1 4 Macula-involving retinal detachment, subtotal 4A Without exudate or leakage 3 4B With exudate or leakage 0 5 Total retinal detachment 5A Open funnel 0 5B Closed funnel 10 Fig. 2 FEVR interocular disease asymmetry vs. age Wai et al. International Journal of Retina and Vitreous (2022) 8:30 Page 4 of 6 Table 2 FEVR among paediatric age group members No. Current age Age of diagnosis Better eye (stage), Worse eye (stage), Procedure Progression after Interocular disease (months) (days-old) VA (LogMAR) VA (LogMAR) procedure asymmetry (stage) 5 1 11 LE 2A* RE 4A* BE LIO Nil 2 6 4 14 LE 1A, 1.74 RE 3B, 2.04 BE LIO Nil 2 7 60 10 RE 4A, 1.14 LE 4A, 2.04 BE LIO Progress 0 10 108 21 LE 3A, 0.60 RE 5B, PL LE LIO Nil 2 RE VR op VA Visual acuity in LogMAR, PL Perception of light, RE Right eye, LE Left eye, BE Both eye, LIO Diode Laser Indirect Ophthalmoscopy, VR op Vitreo-retinal operation, Nil No progression after procedure *Unable to check the visual acuity as patient was too young Fig. 3 Fundus photo of patient no. 6 shows asymmetric clinical severity. A  Right eye shows extramacular full-thickness retina fold with haemorrhage. No obvious exudation was seen. Stage 3A FEVR. B  Left eye posterior pole appears flat, arrow shows the border of vascularized retinal with minimal exudates, no laser marks over avascular retina area. Stage 1B FEVR 4A, the worse eye ranged from 3B to 5B. Diode laser was FEVR remained stable despite absent of vitreoretinal sur- given to all 4 of them and monitored closely to look for gery. The remaining 2 adult patients (33.3%) did not seek any progression. Despite laser photocoagulation, patient any medical treatment. The disease remained static after no. 7 still progressed to Stage 4A with retinal fold touch- adolescence. ing posterior capsule of the crystalline lens. To date, patients 5, 6 & 10 have been clinically stable, but they are Discussion too young to conclude that the disease is static. Familial exudative vitreoretinopathy (FEVR, OMIM: The mean age for adult family members is 43.1 years 133,780) caused by FZD4 gene with c.1501_1502 dele- old. (Table  3) 50% (No. 1, 2, 8) of the adult family mem- tion was only briefly described by Toomes et al. [7]. This bers are legally blind. All 3 of them are the eldest among mutation has been previously reported in individuals all 10 patients. They gave a history of bilateral eye blind - with FEVR (PMID: 12172548). There is a paucity of the ness when they were teenagers (ages ranged from 15 to detailed phenotypic description on c.1501_1502 deletion. 21 years old). The mean age of their blindness was 18 To our best knowledge, to date, there has been no article years old. describing the genotypic-phenotypic correlation of this All 6 adult patients complained of unilateral blurring mutation among South-East Asian descents. of vision at a very young age (ranged 3 to 10 years old). Subsequently, the better eye will deteriorate and 3 (50%) Early detection of them underwent vitreoretinal surgery on their better FZD4 gene with c.1501_1502 deletion showed signs eye. 1 patient (16.6%) underwent lens extraction over the of FEVR as early as 10 days of life. Our study managed better eye and suffered from secondary glaucoma, his to diagnose all the 4th generation children during their W ai et al. International Journal of Retina and Vitreous (2022) 8:30 Page 5 of 6 Table 3 FEVR among adult family members No. Current age Better eye (Stage), VA Worse eye (Stage), Procedure Progression of Interocular disease (years) (LogMAR) VA (LogMAR) disease after asymmetry (stage) procedure 1 69 RE 5B, NPL* LE 5B, NPL LE VR op Progress 0 2 34 RE 5B, PL LE 5B, NPL Nil - 0 3 31 LE 2A, 0.22 RE 5B, NPL RE VR op Nil 3 4 29 LE 2B, 1.30 RE 5B, NPL LE lens aspiration & IOL Nil, Worsening VA 3 Implantation due to secondary glaucoma 8 64 RE 5B, NPL* LE 5B, NPL Nil - 0 9 32 LE 3A, 0.90 RE 5B, PL RE VR op Nil 2 VA Visual acuity in LogMAR, PL Perception of light, NPL No perception of light, RE, Right eye, LE Left eye, BE Both eye, VR op Vitreo-retinal operation, IOL Intraocular lens, Nil None (No procedure done or No progression of disease) *Both eyes have similar severity neonatal period (mean age of diagnosis is 14 days of higher than FEVR patients with TSPAN12, KIF11 or life) due to positive FEVR family history, compared to a NDP mutation [17]. large study that has a mean age of diagnosis of 6 years Our results showed greater asymmetry in younger old.[15] This shows that FEVR caused by FZD4 gene patients with 75% of patients (6/8) who aged younger c.1501_1502delCT mutation can be diagnosed at a very than 40-years-old exhibited disease asymmetry. All 6 young age within the neonatal period. Screening should of them (100%) have a difference of 2 stages or more. be done as early as 10 days old for neonates who have a Ranchod et  al. reported 71% of FEVR patients have 2 family history of FEVR, especially for those who had a eyes within 1 stage of each other [3]. We hypothesize definitive genetic diagnosis of c.1501_1502 deletion. that the FZD4 gene c.1501_1502 deletion can produce greater clinical asymmetry compared to other genotype mutations. Disease progression and age group Genotype-phenotype association will be the future Disease progression was expected to occur before age of of diagnostic medicine. FEVR can be caused by varies 20 years old [16]. Among the 10 patients in our series, 2 genotype mutations, and detailed description of the of them (No. 1 & 7) exhibited disease progression despite phenotype manifestation, correlating with the genotype treatment. Progression occurred at the age of 3-years- mutations for each mutation will help both physicians old (No. 7) and 17-years-old (No. 1). Disease severity and patients to understand and manage the disease bet remained static for the other 6 patients who received ter, with a more realistic visual prognostic expectations, treatment. Only 2 patients did not receive any form of instead of generalising the disease into a broad spec- treatment (No. 2 & 8), and both of them translated the trum of phenotypic manifestations. natural history of progression in FEVR and became legally blind around adolescent age. Some studies described FEVR as a lifelong disease Conclusions where progression can occur at any age after varying To our best knowledge, this is the first case series periods of apparent quiescent [13, 16]. However, these describing the phenotypic expression of FZD4 gene studies lacked genotypic information. Patients with dele- with c.1501_1502 deletion in South-East Asian tion of c.1501_1502 in FZD4 gene might have a relatively descents, spanning a 4-generation case series. Our lesser risk of progression after the adolescent period. study highlights that FEVR signs due to c.1501_1502del can appear very early in life (neonatal period) and thus fundus screening is very important among new- Disease asymmetry borns with a family history of FEVR. A deletion in Interocular clinical asymmetry among FEVR has been c.1501_1502 could manifest greater clinical asymmetry largely reported by multiple articles [3, 9, 13, 17]. Gen- of 2 stages or more compared to other mutation. Fur- erally, 57% of FEVR patients have asymmetry staging, ther studies are needed for detail phenotype descrip- in which 71% presented with the 2 eyes within 1 stage tion in other FEVR genetic mutations. of each other [15]. FEVR with FDZ4 gene mutation shows 47.4% of asymmetric disease severity which is Wai et al. International Journal of Retina and Vitreous (2022) 8:30 Page 6 of 6 Abbreviations vitreoretinopathy locus on chromosome 11q. Am J Hum Genet. FEVR: Familial Exudative Vitreoretinopathy; FZD4: Frizzled Class Receptor 4; 2004;74(4):721–30. PCR: Polymerase chain reaction; DNA: deoxyribonucleic acid; LRP5: Low- 8. Nikopoulos K, Gilissen C, Hoischen A, van Nouhuys CE, Boonstra FN, Blok- density lipoprotein receptor protein 5; TSPAN12: Tetraspanin 12; WES: Whole land EAW, et al. Next-generation sequencing of a 40 Mb linkage interval exome sequencing; VA: Visual acuity; RE: Right eye; LE: Left eye; BE: Both eye; reveals TSPAN12 mutations in patients with familial exudative vitreoretin- PL: Perception of light; NPL: Non perception of light; VR op: Vitreo-retinal opathy. Am J Hum Genet. 2010;86(2):240–7. operation; IOL: Intraocular lens; KIF11: Kinesin Family Member 11; NDP: Norrin 9. Kaykas A, Yang-Snyder J, Héroux M, Shah KV, Bouvier M, Moon RT. Mutant Cystine Knot Growth Factor. Frizzled 4 associated with vitreoretinopathy traps wild-type Frizzled in the endoplasmic reticulum by oligomerization. Nat Cell Biol. 2004;6(1):52–8. Acknowledgements 10. Warden SM, Andreoli CM, Mukai S. The Wnt signaling pathway in familial The authors would like to thank the Director-General of Ministry of Health exudative vitreoretinopathy and Norrie disease. Semin Ophthalmol. Malaysia for his kind permission to publish this article. 2007;22(4):211–7. 11. Tang M, Ding X, Li J, Hu A, Yuan M, Yang Y, et al. Novel mutations in FZD4 Author contributions and phenotype–genotype correlation in chinese patients with familial YZW gathered the necessary information about the patient. YZW and YYC exudative vitreoretinopathy. Mol Vis. 2016;22:917–32. wrote the manuscript under supervision of NH and JR. LTL did a thorough 12. Omoto S, Hayashi T, Kitahara K, Takeuchi T, Ueoka Y. Autosomal dominant revision of the work. NH and JR are the main consultants that managed the familial exudative vitreoretinopathy in two Japanese families with FZD4 patients. All authors read and approved the final manuscript. mutations (H69Y and C181R). Ophthalmic Genet. 2004;25(2):81–90. 13. Shukla D, Singh J, Sudheer G, Soman M, John RK, Ramasamy K, et al. Funding Familial exudative vitreoretinopathy (FEVR). Clinical profile and manage - There is no financial support received for this study. ment. Indian J Ophthalmol. 2003;51(4):323–8. 14. Kashani AH, Learned D, Nudleman E, Drenser KA, Capone A, Trese MT. Availability of data and materials High prevalence of peripheral retinal vascular anomalies in family mem- All data and materials gathered during this study are included in this study. bers of patients with familial exudative vitreoretinopathy. Ophthalmol- ogy. 2014;121(1):262–8. 15. Ranchod TM, Ho LY, Drenser KA, Capone A, Trese MT. Clinical pres- Declarations entation of familial exudative vitreoretinopathy. Ophthalmology. 2011;118(10):2070–5. Ethics approval and consent to participate 16. Benson WE. Familial exudative vitreoretinopathy. Trans Am Ophthalmol This case series is registered under Malaysian National Medical Research Reg- Soc. 1995;93:473–521. istry (NMRR ID-21-02310-O5A) which follows the tenets of the Declaration of 17. Wang Z, Chen C, Sun L, Zhang A, Liu C, Huang L, et al. Symmetry of Helsinki. Written consent was taken from the patients for participation . folds in FEVR: a genotype-phenotype correlation study. Exp Eye Res. 2019;186:107720. Consent for publication Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in pub- Competing interests lished maps and institutional affiliations. The authors declare that they have no competing interests. Author details Ophthalmology Department, Hospital Kuala Lumpur, Kuala Lumpur, Malay- 2 3 sia. Ampang Hospital, Ampang Jaya, Malaysia. Ophthalmology Depar t- ment, Faculty of Medicine and Health Sciences, Universiti Malaysia Sarawak (UNIMAS), Kota Samarahan, Malaysia. Paediatric Ophthalmology Department, Hospital Tunku Azizah, Kuala Lumpur, Malaysia. Received: 23 March 2022 Accepted: 4 May 2022 References 1. Criswick VG, Schepens CL. Familial exudative vitreoretinopathy. Am J Ophthalmol. 1969;68(4):578–94. 2. Gow J, Oliver GL. Familial exudative vitreoretinopathy. An expanded view. Arch Ophthalmol (Chicago, Ill 1960). 1971;86(2):150–5. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : 3. Ranchod TM, Ho LY, Drenser KA, Capone AJ, Trese MT. Clinical pres- entation of familial exudative vitreoretinopathy. Ophthalmology. fast, convenient online submission 2011;118(10):2070–5. 4. 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Toomes C, Bottomley HM, Jackson RM, Towns KV, Scott S, Mackey DA, Learn more biomedcentral.com/submissions et al. Mutations in LRP5 or FZD4 underlie the common familial exudative

Journal

International Journal of Retina and Vitreous – Springer Journals

Published: May 16, 2022

Keywords: Familial exudative vitreoretinopathy; FEVR; FZD4 genes

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