EditorialGenetics in Ophthalmology

Lev Prasov ,1,2 Stephen T. Armenti,2 Virginia Miraldi Utz,3 Julia E. Richards,2,4

and Robert B. Hufnagel1

1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, 10 Center Drive,Bethesda, MD 20892, USA2Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, University of Michigan, 1000Wall St., Ann Arbor,MI 48105, USA3Department of Ophthalmology, Abrahamson Eye Institute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave.,No. 4008, Cincinnati, OH 45229, USA4Department of Epidemiology, University of Michigan, 1415 Washington Heights, Ann Arbor, MI 48109, USA

Correspondence should be addressed to Lev Prasov; lprasov@umich.edu

Received 28 May 2018; Accepted 28 May 2018; Published 29 August 2018

Copyright © 2018 Lev Prasov et al. "is is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

"e clinical and molecular diagnostic evaluation of patientswith heritable ocular disorders has evolved immensely sincethe first retinal dystrophy genes were cloned and sequencedin 1988 [1]. In addition, the modalities for studying thepathogenesis and future therapeutics for genetic eye dis-orders are constantly advancing. "rough thoughtful con-sideration and detailed examination, imaging,electrophysiology, and family history, ophthalmologists andgeneticists can select cytogenetic testing that confirms theclinical diagnosis in more than 50% of patients with retinaldystophies [2]. However, our understanding of disorderswith complex inheritance as well as some Mendelian eyeconditions is still in need of further investigation. For theseunsolved traits, whole-exome and whole-genome sequenc-ing provides a route for further investigation to identifya causative gene. "is special issue of the Journal of Oph-thalmology highlights the range of clinical and genetictesting modalities both for common and rare disorders, aswell as complex and Mendelian traits.

Classic familial studies are highlighted in several studiespresented in this issue. Wang and colleagues present a 4-generation family with a novel loss-of-function frameshiftmutation in PAX6. "e seven affected family membershighlight significant intrafamilial ocular phenotypic vari-ability. "e authors propose mechanisms for phenotypicvariability including interaction with and expression of other

transcriptional factors involved in embryonic development,as well as variations in transcription and other epigeneticfactors involved in PAX6 expression. Falfoul et al. describedtwo branches of a consanguineous Tunisian family har-boring two ABCA4 alleles, where different allelic combi-nations all led to cone-rod degeneration. "ey describea novel complex structural ABCA4 variant that has not beenpreviously reported. In the paper by Smaragda et al., nearly60 Greek patients with Stargardt disease were genotyped forABCA4 single-nucleotide and copy-number variant alleles,and almost 90% were detected to have pathogenic alleles.Surprisingly, the two most prevalent alleles were alleles withmild phenotypic expression. Beyond characterizing variant-level prevalence in specific populations, these studies mayprovide insight into predicting disease burden and pro-gression in individuals based on their geographical origin.

Genetic and phenotypic heterogeneity are two importantideas that are continually discussed in this volume. A reviewpaper by Carricondo et al. presents the clinical features ofnanophthalmos and discusses the genetic factors implicated inthis disease. Both autosomal dominant inheritance and au-tosomal recessive inheritance of nanophthalmos have beenreported, and a fair amount of genetic heterogeneity is sug-gested by the finding so far of five nanophthalmos genes andtwo nanophthalmos loci. Phenotypic heterogeneity is reflectedin the fact that four of the five known nanophthalmos genes

HindawiJournal of OphthalmologyVolume 2018, Article ID 4608946, 3 pageshttps://doi.org/10.1155/2018/4608946

(MFRP, PRSS56, CRB1, and BEST1/VMD1) can cause phe-notypes other than nanophthalmos, although that level ofheterogeneity has not yet been reported for nanophthalmosgene TMEM98. Sisk and colleagues present three patients whoshare a common phenotype of peripheral cone dystrophy(PCD), a condition in which the fovea and central visual acuityare preserved, but parafoveal photoreceptors undergoatrophy-accompanied macular vascular attenuation. "e au-thors have redefined the clinical features to also includea nonprogressive course, normal choroidal thickness in areasof atrophy, and large affected regions giving a “bifocal”atrophic experience in 2 of 3 patients."e authors propose thatgenotypic heterogeneity and/or environmental influences maycontribute to a common phenotype, as whole-exome se-quencing failed to identify a common gene.

Association and gene expression studies have signifi-cantly advanced our understanding of complex traits. In thepaper by Mingzen et al., the association of genes in the high-density lipopoprotein metabolic pathway with polypoidalchoroidal vasculopathy (PCV) is explored. "e authorsfound that 7 polymorphisms in genes in this pathway in-crease susceptibility to PCV, suggesting that the mis-regulation of this lipoprotein metabolismmay be involved inthe pathogenesis of this condition. Banevicius and colleaguesevaluated the risk for optic neuritis in patients suspected tohave impaired arachadonic acid (AA) metabolism and in-creased "17 cell regulation. "e authors show that single-nucleotide polymorphisms (SNPs) in CYPF2, a cytochromeP450 enzyme suspected to impair AA metabolism, weremore frequent in men with optic neuritis (ON) and multiplesclerosis (MS) and that serum inflammatory cytokines (IL-17a) are elevated in patients with ON and MS. "ese resultssuggest that these factors may be associated with pre-disposition to ON and MS. In the paper by Stafiej et al., theauthors explore the levels of TGF-beta2 and VEGF-a ex-pression in epiretinal membranes (ERM) and internallimiting membranes (ILM) from vitrectomy specimens."ey identify that TGF-beta2 and VEGF-a, factors associ-ated with angiogenesis and wound healing, are upregulatedin ERM as compared to ILM in all vitrectomy groups. Lumiand colleagues evaluate the frequency of SNPs in patientswith and without proliferative vitreoretinopathy (PVR) tofurther validate whether polymorphisms in specific growthfactors or cytokines may help stratify patients at risk forsubsequent PVR after vitrectomy. Here, the authors suggestthat although the variability in the distribution of SNPsacross European subpopulations is significant, there arespecific SNPs that occur with higher frequency in patientswith PVR after vitrectomy compared to healthy controls inboth interleukins and tumor necrosis factor genes. Drs.Lahola-Chomiak and Walter review the molecular geneticsof pigment dispersion syndrome and pigmentary glaucoma,highlighting the clear genetic components of these disordersbut the absence of clear single-gene mutations. Animalstudies have demonstrated a role of melanosome function inthe disease mechanism, but the precise pathogenic role ofthese genes in humans remains to be determined.

Epigenetic mechanisms also play a substantial role ingene regulation and the pathogenesis of ocular disease. In

the paper by Chansangpetch et al., the authors explore theDNA methylation status of trabeculectomy specimens fromprimary open-angle glaucoma, primary angle-closureglaucoma, and secondary glaucoma patients, as comparedto control specimens. "ey identified differences in themethylation status of Alu elements among glaucomaspecimens as compared to controls, suggesting that meth-ylation patterns may be associated with glaucomapathogenesis.

"e mixture of clinical ophthalmology and ophthalmicgenetics found in these papers reflects the dawning role ofprecision medicine in ophthalmology. Diagnosis andmedical management in a successful ophthalmic geneticspractice requires expertise found in ophthalmology, medicalgenetics, genetic counseling, clinical molecular genetics, andoften pediatrics. "e team must apply rapidly changingmolecular advances in the recent literature to patient care.Because so few individuals are trained and board-certified inall or most of these specialties, a multidisciplinary clinic isa viable alternative to have a single destination for familieswith inherited ocular disease. Another benefit to the com-bined clinic model is added power to interpret next-generation sequencing results and added education be-tween specialties. As clinical molecular genetic testing op-tions expand, we expect to see an increase in patients withdisorders that cannot be diagnosed by gene panels orchromosomal technologies alone. As the range of moleculardiagnoses delineate the list of clinical diagnoses into gene-specific diseases, involving medical and molecular geneti-cists for interpretation and second opinion of variants ofuncertain or unknown significance may be crucial. It willhelp families and providers guide reproductive planning,medical and surgical interventions, and testing and sur-veillance of other family members where appropriate.

Optimally, the scope of testing will include knowndisease genes related to phenotypes. However, as the cost ofwhole-exome and whole-genome sequencing becomes moreaffordable, these technologies will be more frequentlyadopted. While analyzing with the intention to determinethe primary cause of a condition, these methods will alsoyield additional information about variants of known orunknown significance (VOUS) without relation to thephenotype or desired diagnosis. So far, the American Collegeof Medical Genetics has released a recommendation tocounsel about unrelated results found in 59 genes that aremedically actionable [3]. Perhaps more importantly, seeingthe patient in a multidisciplinary clinic prior to orderingexome sequencing will aid in fully comprehending thefamily’s intention and desire either to learn these unrelatedrisks or to blind themselves from knowledge of conditionsfor which no treatment exists.

In summary, this issue highlights the importance ofgenetics in every clinical specialty in ophthalmology. In thisera of rapid genomics advancements, we face the challengeof interpreting and explaining complex testing options andresults to patients. "us, a collaborative, multidisciplinaryapproach is needed to provide comprehensive and informedcare to patients. With recent advances in testing modalities,it will become increasingly important and complicated to

2 Journal of Ophthalmology

obtain, distill, and present results of large datasets to ourpatients. Genetic testing has become more prevalent foridentifying disease risk and for prognosis and is increasinglybecoming used for understanding disease mechanism anddeveloping new treatments. "is in turn is creating im-portant new opportunities that will call for every specialty inophthalmology to join in this multidisciplinaryclinical/genomic perspective on diagnostic and treatmentchoices. As our knowledge and experience expands, the roleof genetics in ophthalmology will continue to grow in theyears to come.

Lev PrasovStephen T. ArmentiVirginia Miraldi Utz

Julia E. RichardsRobert B. Hufnagel

References

[1] G. A. Mitchell, L. C. Brody, J. Looney et al., “An initiator codonmutation in ornithine-delta-aminotransferase causing gyrateatrophy of the choroid and retina,” Journal of Clinical In-vestigation, vol. 81, no. 2, pp. 630–633, 1988.

[2] J. M. Ellingford, S. Barton, S. Bhaskar et al., “Molecular findingsfrom 537 individuals with inherited retinal disease,” Journal ofMedical Genetics, vol. 53, no. 11, pp. 761–767, 2016.

[3] S. S. Kalia, K. Adelman, S. J. Bale et al., “Recommendations forreporting of secondary findings in clinical exome and genomesequencing, 2016 update (ACMG SF v2.0): a policy statementof the American College of Medical Genetics and Genomics,”Genetics in Medicine, vol. 19, no. 2, pp. 249–255, 2017.

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