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Table of Contents
Year : 2021  |  Volume : 3  |  Issue : 1  |  Page : 10

Chromosomal microarray in isolated congenital and developmental cataract

1 Moorfields Eye Hospital; UCL Institute of Ophthalmology, University College London, London, United Kingdom
2 Pediatric Ophthalmology and Ocular Genetics, Wills Eye Hospital, Philadelphia, Pennsylvania, USA
3 Department of Ophthalmology, Queen Sirikit National Institute of Child Health, Bangkok, Thailand
4 Department of Ophthalmology and Visual Sciences, College of Medicine and Philippine General Hospital, University of the Philippines Manila, Manila; Pediatric Ophthalmology and Strabismus and Ocular Genetics, Asian Eye Institute, Makati City, Philippines
5 Department of Ophthalmology, Faculty of Medicine, Ramathibodi Hospital, Bangkok, Thailand
6 Department of Ophthalmology, Kaohsiung Medical University Hospital; Department of Ophthalmology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
7 Molecular Pathology Laboratory, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
8 Facultad De Medicina Clínica Alemana, Universidad Del Desarrollo, Santiago, Chile
9 Department of Vitreoretinal Services, Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, Tamil Nadu, India
10 Department of Pathology and Laboratory Medicine, St. Christopher's Hospital for Children, Philadelphia, Pennsylvania, USA
11 Department of Pathology, Anatomy and Cell Biology at Thomas Jefferson University, Philadelphia, Pennsylvania, USA
12 Pediatric Ophthalmology and Ocular Genetics, Wills Eye Hospital, Philadelphia, Pennsylvania; Pediatric Ophthalmology and Ocular Genetics, Flaum Eye Institute; Rochester, New York, USA

Date of Submission05-Nov-2020
Date of Acceptance13-Jan-2021
Date of Web Publication07-Apr-2021

Correspondence Address:
Dr. Alex V Levin
Pediatric Ophthalmology and Ocular Genetics, Flaum Eye Institute, Rochester, NY 14642, New York
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/pajo.pajo_63_20

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Introduction: The etiologies of congenital and developmental cataracts are diverse. Most are not syndromic and have no identifiable cause, thus creating a diagnostic dilemma. We investigated the utility of chromosomal microarray in identifying the etiology of isolated childhood cataracts.
Methods: Patients with congenital or developmental cataracts without other associated abnormalities received a single-nucleotide polymorphism (SNP) microarray. copy number variations (CNV) and regions of homozygosity (ROH) were compared with previous literature reports and analyzed for candidate genes to assess pathogenicity.
Results: We enrolled 37 patients. The mean age of the patient population was 10.98 years old. Nineteen patients (51.4%) had bilateral cataract. Positive family history was found in 11 patients (29.7%). Eighteen patients (48.7%) had a variant on microarray: 10 (27%) with CNV, 5 (13.5%) with ROH, and 3 patients (8.1%) with both CNV and homozygosity. In five patients (13.5%), we found a potentially causative cataract gene within an ROH.
Discussion: There is a high rate of notable findings among the CNV and ROH detected. Three patients were homozygous in a region known to have a cataract gene suggesting a possible autosomal recessive disease. In those with CNV, segregation would help to affirm the pathogenicity of these regions and may lead to the identification of new genes.
Conclusion: SNP microarray had a surprisingly high rate of notable findings in patients with isolated cataract and may reveal the opportunities for genetic counseling, lead to discovering new cataract genes and identify additional affected genes that could lead to other clinical abnormalities.

Keywords: Congenital cataract, chromosomal microarray, copy number variation, genetics, developmental cataract

How to cite this article:
De Guimarães TA, Capasso JE, Bello NR, Wangtiraumnuay N, Lingao MD, Wuthisiri W, Lai YH, Johnson ES, Zanolli M, Khetan V, Bajaj R, Wang ZX, Peiper SC, Levin AV. Chromosomal microarray in isolated congenital and developmental cataract. Pan Am J Ophthalmol 2021;3:10

How to cite this URL:
De Guimarães TA, Capasso JE, Bello NR, Wangtiraumnuay N, Lingao MD, Wuthisiri W, Lai YH, Johnson ES, Zanolli M, Khetan V, Bajaj R, Wang ZX, Peiper SC, Levin AV. Chromosomal microarray in isolated congenital and developmental cataract. Pan Am J Ophthalmol [serial online] 2021 [cited 2021 Nov 27];3:10. Available from: https://www.thepajo.org/text.asp?2021/3/1/10/313166

  Introduction Top

Congenital and developmental cataracts are classified as an avoidable cause of blindness and have an estimated prevalence of 4.24 per 10,000 people.[1] Congenital and developmental cataract can occur independently (isolated cataract) or with eye or other abnormalities (syndromic cataract). Delay in the surgical treatment and detection is inversely proportional to the final visual outcome.[2],[3]

Genetic cataracts may occur through autosomal dominant (AD), autosomal recessive (AR), or X-linked recessive inheritance patterns.[4],[5],[6],[7] Of these, AD is most common.[5],[7] These cataracts demonstrate both clinical and genetic heterogeneity.[4],[8] Reserachers have mapped various loci and identified more than 40 genes.[9],[10] Large gene array sequencing panels can identify causative gene mutations in affected patients.[11] Other researchers have also detected potential disease-causing mutations by this method or by using single-nucleotide polymorphism (SNP) microarray followed by the polymerase chain reaction amplification and direct nucleotide sequencing of candidate genes.[12],[13],[14],[15]

Many cataract genes are waiting to be discovered. Chromosomal microarray is a technique that allows for the identification of dosage variations, such as deletions and duplications, across the genome. The affected regions can then be explored for relevant genes contributing to cataract formation. Microarray may also detect the regions of homozygosity (ROH) that raise the likelihood of AR disease. It is broadly used due to high resolution (compared to karyotype) and consistent results with particular applicability when the multiple body system abnormalities are present. In 2010, the American College of Medical Genetics and Genomics published the practice guidelines recommending chromosomal microarray as the first-tier diagnostic test for individuals with congenital anomalies.[16] It has been used in the investigation of primary open-angle glaucoma.[17],[18] CNV may occur de novo, making it a solid approach to identify the cases without a family history. The purpose of our study was to explore the potential role of microarray in otherwise idiopathic pediatric cataracts.

  Methods Top

This study adhered to the guidelines of the declaration of Helsinki and was approved by the Institutional Review Board of Wills Eye Hospital. We enrolled the patients diagnosed with congenital or developmental cataract, aphakic, pseudophakic, or phakic, who were seen in the Pediatric Ophthalmology or Ocular Genetics clinics at Wills Eye Hospital between June 2012 and April 2016 by the senior investigator Alex V. Levin (AVL).

All patients underwent ophthalmic examination as part of their routine care by the same examiner. Cataract phenotype was assessed through dilated slit examination or in those patients with aphakia/pseudophakia, using prior records of the lens before surgery. Only one member from each family was recruited. If both parent and child were affected, we offered that the blood draw initially be done on the parent. If a child was undergoing anesthesia as part of their necessary ophthalmic care, blood was drawn at that time. We excluded patients who had other ocular anomalies, traumatic cataract, ectopia lentis, systemic syndromes, metabolic disorders, or any reason that would make it unsafe for a subject to provide a blood sample. We included patients who had ocular abnormalities due to or highly associated with cataract, such as persistent fetal vasculature (PFV) or microphthalmia.

SNP microarray was performed. The first 11 patient samples were sent to one of two clinical laboratories (Lab Corp, North Carolina or Quest Diagnostics, Virginia). These tests were both done using Affymetrix CytoScan HD, and data were analyzed using Chromosome Analysis Suite (Affymetrix). Due to issues that arose regarding cost/insurance coverage, all subsequent analyses were conducted by the Molecular Pathology and Cytogenetics Laboratories of Thomas Jefferson University (Philadelphia, PA, USA) at no charge to the patients using the Agilent microarray scanner, and data analysis was carried out using DEVA software with the CGH microarray workflow. When rare or novel copy number variations (CNV) or intermediate or long (>3,000 kb) ROH were identified, those regions were searched using Chromosome Analysis Suite (Affymetrix). To further interpret the findings and assess relevancy to the cataract, the regions with CNV were also searched for known or candidate cataract genes using the OMIM database (https://www.ncbi.nlm.nih.gov/omim) and Cat-Map (https://cat-map.wustl.edu/), an online chromosome map and reference database for cataract in humans and mice.[9],[10] When possible, candidate genes were Sanger sequenced to identify the possible mutations. Segregation analysis, using available first-degree relatives, was done on specimens with either a known, clinically relevant pathogenic CNV or a region of CNV or homozygosity containing a candidate gene.

  Results Top

We enrolled 37 patients with congenital or developmental cataract. The mean age of the patient population was 10.98 years. Twenty-three (62.16%) patients were <10-year-old, 10 patients (27.03%) were 10-“18 years old, 2 patients (5.41%) were in their thirties, and 2 patients (5.41%) were in their forties. Nineteen patients (51.35%) had bilateral cataract. Positive family history was found in 11 patients (29.73%). Of the 9 patients who had first-degree relatives with childhood cataract, all had bilateral cataract and 8 showed pedigrees consistent with AD inheritance. The remaining one patient only had a sister with congenital cataract. Two patients who had more distant relatives with congenital or development cataract had unilateral cataract [Table 1]. [Figure 1] demonstrates the relationship between family history and microarray findings.
Table 1: Baseline characteristics of the sample

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Figure 1: Microarray results in 37 patients

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Six patients also had microphthalmia without PFV, 4 others had PFV without microphthalmia, and 1 patient had contralateral ptosis. Four patients had an underlying disease that was likely unrelated to the cataract, as these disorders did not segregate with the cataract in the family. The underlying disorders were as follows: Gastroesophageal reflux with asthma, speech delay, spontaneous closed atrial septal defect, and history of prematurity complicated by cardiac arrest due to apnea of prematurity.

We could identify the type of cataract in 23 patients [62.16%, [Table 1]]. The others 14 patients (37.84%), had aphakia or pseudophakia with insufficient documentation of preoperative cataract morphology. All four patients with PFV and two patients with posterior lenticonus had unilateral cataract [Table 1].

Karyotype was done in 19 patients (51.35%), all of which were normal 46, XX or 46, XY except for one specimen, which had a possible small interstitial deletion on 3p. Microarray result reported a ROH at 3p21.31 without deletion.

SNP microarray identified a total of 550 CNV containing 897 genes and 100 ROH containing 12,347 genes. Analysis using Chromosome Analysis Suite (Affymetrix) and comparison to OMIM and Cat-Map database yielded a conclusion of abnormal microarray in 18 patients (48.65%): 10 patients (27.03%) with CNV, 5 patients (13.51%) with ROH, and 3 patients with both CNV and homozygosity [Figure 1]. One patient (GM8) had dup7p14.1 within which there is no genes known to be related to a phenotype which includes cataract. In five other patients (13.51%), we found a potential cataract gene within an ROH: SIL1 in MT15-564, which is a resident endoplasmic reticulum glycoprotein that interacts with the ATPase domain of BIP; CHMP4B and NCOA6 in MT16-124, the former reported segregating in a Caucasian family with cataract and the latter proposed to be involved in mice with posterior lenticonus cataract;[19],[20] EPG5 in MT16-23, which encodes a protein with a key role in the autophagy pathway;[21] GPX1 in MT14-787, a gene which exhibits activity in antioxidant mechanisms of the lens;[22] and TMEM55A in GM10, a gene involved in the inositol pathway and previously noted to be involved in cataractogenesis [Table 2].[23]
Table 2: Single-nucleotide polymorphism microarray abnormalities with candidate genes

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The microarray results led us to consider further investigations in three cases. MT16-24 had a 373 kbp dup11q24.1 that includes the SCN3B and GRAMD1B genes, which are associated with familial atrial fibrillation and susceptibility for chronic lymphocytic leukemia, respectively.[24],[25] To our knowledge, there are no reports in the literature of duplications being associated with disease. However, given the significance of the systemic association, we recommended electrocardiogram and complete blood count. MT15-608 had a 279 kbp dup22q13.32, which includes the PPARA and TRMU genes. These have been associated with susceptibility to hyperapobetalipoproteinemia and transient infantile liver failure, respectively.[26],[27],[28] To our knowledge, duplications in PPARA or TMRU have never been associated with diseases. Furthermore, the patient is older and not a match for the phenotype which would have been obvious at the patient's age. Therefore, no further testing was recommended. Sequencing was done in a research lab for TMEM55A in GM10. We did not find any sequence variations in the mother, but we found a 2-bp variant at 723-“724 of the ORF of TMEM55A in the father. Unfortunately, we did not have sufficient DNA from the child's sample for further analysis and the family declined additional sampling. Segregation was not performed in any patient due to limited funding.

  Discussion Top

Mutation in many genes has been previously reported to cause various types of cataract, the most common being genes encoding crystalline proteins such as CRYAA, CRYBB2, CRYGC, and CRYAB.[10] Others encode for different lens proteins such as membrane proteins (connexins-“ GJA3, GJA8; major intrinsic protein-“ MIP; lens intrinsic membrane protein 2-“ LIM2), transcription factors (PAX6, PITX3, and FOXE3), and cytoskeletal proteins (vimentin-“ VIM, beaded filament structural protein 2-“ BFSP2).[5],[29] Gillespie et al. reported that next generation DNA sequencing technologies could determine the genetic cause of congenital cataract in approximately 75% of cases.[11] Such panels may not be able to identify CNVs, can result in difficulties in distinguishing mutations from polymorphisms, can be costly or not covered by insurance, and may be difficult to interpret in terms of genotype-phenotype correlations. Chromosomal microarray is a technique which identifies CNV or ROH as a possible inroad to establishing the molecular basis of disease. Although CNV is more often associated with disease in more than one organ system, as more than one gene may be within the deleted or duplicated region, we investigated how microarray might be helpful in identifying causative genes in patients with isolated congenital or developmental cataract.

Almost half (48.65%) of our patients had abnormalities detected on microarray. CNV can represent benign polymorphic variants not associated with disease.[30] We found rare CNV in 13 patients (35.14%) in which there was no known cataract gene but may perhaps have the genes of unknown phenotype and function. Segregation would help to assess the possible pathogenicity of these regions and may still lead to discovery of new cataract genes.

Some genes within the CNV of our other patients were previously reported to be associated with disease other than cataract. Mutations in NKAIN2 were previously reported to cause encephalopathy, spastic tetraparesis, hypogonadism, developmental delay, and recurrent infection, which does not match the clinical presentation of our patient. Mutations in PPARA can cause hyperapobetalipoproteinemia, and TRMU mutations are known to be associated with liver failure, however, to our knowledge, has never been reported associated with duplications, as seen in our patients. Mutations in GRAMD1B have been reported in genome-wide association studies as risk alleles for leukemia, and SCN3B missense mutations have been associated with atrial fibrillation and Brugada syndrome, although other types of mutations have not been fully investigated. The gene ZNF202 is located within 11q23, which has been deleted in breast, lung, ovarian, cervical, and melanoma tumors. Further sequencing of the other allele in our patients would therefore not be informative, as germline variants in this gene have not been associated with increased risk for these cancers.

We found eight patients (21.62%) who harbored significant ROH, of which 5 harbored known cataract genes [Table 2]. One patient with bilateral posterior lenticonus and negative family history, had ROH in a region which includes SIL1, in which biallelic mutations cause AR Marinesco-Sjogren syndrome, characterized by congenital cataract, cerebellar ataxia, progressive myopathy, and mental retardation.[31] The patient also had this gene sequenced on a clinical custom cataract gene panel using exome analysis, and no mutation was identified in this gene. Another patient had bilateral cataract with negative family history and ROH containing CHMP4B, a gene for AD posterior subcapsular cataract and NCOA6, in which dominant negative gene mutations were reported to cause multiple anomalies with posterior lenticonus in mice.[32],[33] We do not know the morphology of the cataract in our patient as they presented to us aphakic from prior surgery elsewhere. One patient with bilateral fetal nuclear cataract and an AD pedigree, has ROH containing EPG5, which when mutated caused AR Vici syndrome, characterized by agenesis of the corpus callosum, cataracts, cardiomyopathy, combined immunodeficiency, psychomotor delay, and hypopigmentation.[22],[34] However, this does not seem to match with the patient's pedigree or phenotype. A patient with unilateral cataract with negative family history, was found to have an ROH containing GPX1, in which biallelic mutations cause AR hemolytic anemia due to glutathione peroxidase deficiency and cataract in mice as well as COL7A1, the AR and AD gene for epidermolysis bullosa.[22],[35] A final patient has unilateral cortical cataract with a history of cataract in a distant relative, and ROH which contains TMEM55A, encoding the catalyzed protein for degradation of phosphatidylinositol 4,5-bisphosphate, a pathway implicated in cataract biogenesis.[23] In each of these patients, sequencing of these candidate genes may confirm the cause of their cataract and may identify the important needs for further systemic evaluation and ongoing screening or indicate novel phenotypes with isolated cataracts.

Our study has limitations. Due to limited funding, we were not able to sequence the candidate genes or do segregation analysis to confirm the pathogenicity of the CNVs. These would be the requisite next steps to explore the implications of our results.

In our study, SNP microarray had a surprisingly high rate of abnormal findings in patients despite having isolated cataract and may reveal opportunities for genetic counseling, lead to the discovery of new cataract genes, and identify additional affected genes that could lead to other clinical abnormalities. Although multigene sequencing panels may have utility, they would often fail to detect deletions or duplicated genes and will only sequence genes previously reported to cause cataract. For example, on one commercially available panel (https://www.ncbi.nlm.nih.gov/gtr/tests/521132), only 4 of the 6 candidate genes suggested by ROH analysis in our patients, are covered. We therefore suggest that SNP microarray might have a role in detecting candidate genes for subsequent direct sequencing.

Financial support and sponsorship

Funded in part by The Foerderer Fund (AVL), The Robison D. Harley, MD Endowed Chair in Pediatric Ophthalmology and Ocular Genetics (AVL), The Dean's Office to the Wills Vision Research Center at Jefferson and the Division of Genomic Pathology (AVL), and an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology at the University of Rochester (AVL).

Conflicts of interest

There are no conflicts of interest.

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  [Figure 1]

  [Table 1], [Table 2]


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