Genetics of Eye Development and Disease

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (15 November 2023) | Viewed by 11591

Special Issue Editors

1. Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA
2. Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
Interests: ocular genetics; glaucoma syndromes; anterior segment dysgenesis; nanophthalmos; age-related macular degeneration
Ophthalmic Genetics and Visual Function Branch, National Institutes of Health, 10 Center Drive Rm 10D45, Bethesda, MD 20892, USA
Interests: ocular genetics; retinal dystrophy; maculopathy; syndromic retinal degeneration; neurodegenerative disorders

Special Issue Information

Dear Colleagues, 

Nearly a third of all syndromic disorders feature ocular defects.  Over the past 20 years, an explosion in genomic sequencing sparked by lower-cost high-throughput methods and the expansion of broad, clinical genetic testing have led to the discovery and definition of many new Mendelian disorders.  Nowadays, genotypes frequently guide the definition of disorders, and the spectrum of features and variable expressivity within and between families continues to expand.  Defining the variable genotypic and phenotypic characteristics of genetic disorders has thus become paramount for patient counselling on ocular and systemic disease risk.  Functional studies and animal models of disease variants provide a framework for the validation of these disease-associated variants.

The goals of this Special Issue are to describe novel genotype–phenotype associations in syndromic disorders featuring ocular defects, highlight the variable presentations of syndromic disorders, discuss mechanisms leading to phenotypic variability, and provide functional validation of disease associated variants.  In this Special Issue, we welcome original articles, family reports and case series, and reviews on the ocular features of multisystem disorders.  These include, but are not limited to, studies on genotype–phenotype correlations, intrafamilial variability of disorders, genetic heterogeneity in population cohorts, novel genetic or molecular mechanisms of disease, epidemiology of genetic disorders, functional analysis and animal models of disease variants.  We welcome reports on all genetic disorders with ocular and systemic features, including anterior segment dysgenesis disorders, syndromic retinal dystrophy, mitochondrial disorders, inborn errors of metabolism, congenital cataract syndromes, microphthalmia/anophthalmia/coloboma syndromes, syndromic optic neuropathies, chromosomal anomalies, imprinting disorders, and immunogenetic disorders. We look forward to your contributions.    

Dr. Lev Prasov
Dr. Laryssa Huryn
Guest Editors

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Keywords

  • ophthalmic genetics
  • ocular syndromes
  • anterior segment dysgenesis
  • syndromic retinal dystrophy
  • mitochondrial disorders
  • inborn errors of metabolism
  • congenital cataract syndromes
  • syndromic microphthalmia
  • optic neuropathies
  • chromosomal anomalies
  • immunogenetic disorders

Published Papers (7 papers)

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11 pages, 555 KiB  
Article
Epidemiology of PAX6 Gene Pathogenic Variants and Expected Prevalence of PAX6-Associated Congenital Aniridia across the Russian Federation: A Nationwide Study
by Tatyana A. Vasilyeva, Andrey V. Marakhonov, Anna A. Voskresenskaya, Vitaly V. Kadyshev, Natella V. Sukhanova, Marina E. Minzhenkova, Nadezhda V. Shilova, Alla A. Latyshova, Evgeny K. Ginter, Sergey I. Kutsev and Rena A. Zinchenko
Genes 2023, 14(11), 2041; https://doi.org/10.3390/genes14112041 - 04 Nov 2023
Cited by 1 | Viewed by 574
Abstract
This study investigates the distribution of PAX6-associated congenital aniridia (AN) and WAGR syndrome across Russian Federation (RF) districts while characterizing PAX6 gene variants. We contribute novel PAX6 pathogenic variants and 11p13 chromosome region rearrangements to international databases based on a cohort of [...] Read more.
This study investigates the distribution of PAX6-associated congenital aniridia (AN) and WAGR syndrome across Russian Federation (RF) districts while characterizing PAX6 gene variants. We contribute novel PAX6 pathogenic variants and 11p13 chromosome region rearrangements to international databases based on a cohort of 379 AN patients (295 families, 295 probands) in Russia. We detail 100 newly characterized families (129 patients) recruited from clinical practice and specialized screening studies. Our methodology involves multiplex ligase-dependent probe amplification (MLPA) analysis of the 11p13 chromosome, PAX6 gene Sanger sequencing, and karyotype analysis. We report novel findings on PAX6 gene variations, including 67 intragenic PAX6 variants and 33 chromosome deletions in the 100 newly characterized families. Our expanded sample of 295 AN families with 379 patients reveals a consistent global PAX6 variant spectrum, including CNVs (copy number variants) of the 11p13 chromosome (31%), complex rearrangements (1.4%), nonsense (25%), frameshift (18%), and splicing variants (15%). No genetic cause of AN is defined in 10 patients. The distribution of patients across the Russian Federation varies, likely due to sample completeness. This study offers the first AN epidemiological data for the RF, providing a comprehensive PAX6 variants spectrum. Based on earlier assessment of AN prevalence in the RF (1:98,943) we have revealed unexamined patients ranging from 55% to 87%, that emphases the need for increased awareness and comprehensive diagnostics in AN patient care in Russia. Full article
(This article belongs to the Special Issue Genetics of Eye Development and Disease)
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14 pages, 1750 KiB  
Article
A Novel 13q12 Microdeletion Associated with Familial Syndromic Corneal Opacification
by Jasmine Y. Serpen, William Presley, Adelyn Beil, Stephen T. Armenti, Kayla Johnson, Shahzad I. Mian, Jeffrey W. Innis and Lev Prasov
Genes 2023, 14(5), 1034; https://doi.org/10.3390/genes14051034 - 01 May 2023
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Abstract
Progressive corneal opacification can result from multiple etiologies, including corneal dystrophies or systemic and genetic diseases. We describe a novel syndrome featuring progressive epithelial and anterior stromal opacification in a brother and sister and their mildly affected father, with all three family members [...] Read more.
Progressive corneal opacification can result from multiple etiologies, including corneal dystrophies or systemic and genetic diseases. We describe a novel syndrome featuring progressive epithelial and anterior stromal opacification in a brother and sister and their mildly affected father, with all three family members having sensorineural hearing loss and two also with tracheomalacia/laryngomalacia. All carried a 1.2 Mb deletion at chromosome 13q12.11, with no other noteworthy co-segregating variants identified on clinical exome or chromosomal microarray. RNAseq analysis from an affected corneal epithelial sample from the proband’s brother revealed downregulation of XPO4, IFT88, ZDHHC20, LATS2, SAP18, and EEF1AKMT1 within the microdeletion interval, with no notable effect on the expression of nearby genes. Pathway analysis showed upregulation of collagen metabolism and extracellular matrix (ECM) formation/maintenance, with no significantly down-regulated pathways. Analysis of overlapping deletions/variants demonstrated that deleterious variants in XPO4 were found in patients with laryngomalacia and sensorineural hearing loss, with the latter phenotype also being a feature of variants in the partially overlapping DFNB1 locus, yet none of these had reported corneal phenotypes. Together, these data define a novel microdeletion-associated syndromic progressive corneal opacification and suggest that a combination of genes within the microdeletion may contribute to ECM dysregulation leading to pathogenesis. Full article
(This article belongs to the Special Issue Genetics of Eye Development and Disease)
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12 pages, 5188 KiB  
Article
Design and Outcomes of a Novel Multidisciplinary Ophthalmic Genetics Clinic
by Bela Parekh, Adelyn Beil, Bridget Blevins, Adam Jacobson, Pamela Williams, Jeffrey W. Innis, Amanda Barone Pritchard and Lev Prasov
Genes 2023, 14(3), 726; https://doi.org/10.3390/genes14030726 - 15 Mar 2023
Cited by 2 | Viewed by 1192
Abstract
The Multidisciplinary Ophthalmic Genetics Clinic (MOGC) at the University of Michigan Kellogg Eye Center aims to provide medical and ophthalmic genetics care to patients with inherited ocular conditions. We have developed a clinical and referral workflow where each patient undergoes coordinated evaluation by [...] Read more.
The Multidisciplinary Ophthalmic Genetics Clinic (MOGC) at the University of Michigan Kellogg Eye Center aims to provide medical and ophthalmic genetics care to patients with inherited ocular conditions. We have developed a clinical and referral workflow where each patient undergoes coordinated evaluation by our multidisciplinary team followed by discussions on diagnosis, prognosis, and genetic testing. Testing approaches are specific to each patient and can be targeted (single-gene, gene panel), broad (chromosomal microarray, whole-exome sequencing), or a combination. We hypothesize that this clinic model improves patient outcomes and quality of care. A retrospective chart review of patients in the MOGC from July 2020 to October 2022 revealed that the most common referral diagnoses were congenital cataracts, optic neuropathy, and microphthalmia, with 52% syndromic cases. Within this patient cohort, we saw a 76% uptake for genetic testing, among which 33% received a diagnostic test result. Our results support a tailored approach to genetic testing for specific conditions. Through case examples, we highlight the power and impact of our clinic. By integrating ophthalmic care with medical genetics and counseling, the MOGC has not only helped solve individual patient diagnostic challenges but has aided the greater population in novel genetic discoveries and research towards targeted therapeutics. Full article
(This article belongs to the Special Issue Genetics of Eye Development and Disease)
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12 pages, 651 KiB  
Article
Evaluation of Genetic Testing in a Cohort of Diverse Pediatric Patients in the United States with Congenital Cataracts
by Jennifer L. Rossen, Brenda L. Bohnsack, Kevin X. Zhang, Alexander Ing, Andy Drackley, Valerie Castelluccio and Hanta Ralay-Ranaivo
Genes 2023, 14(3), 608; https://doi.org/10.3390/genes14030608 - 28 Feb 2023
Cited by 1 | Viewed by 1234
Abstract
The aim of this study was to evaluate the diagnostic yield from prior genetic testing in a 20-year cohort of pediatric patients with congenital cataracts. A retrospective review of patients with congenital cataracts who underwent genetic testing was completed from 2003–2022. The diagnostic [...] Read more.
The aim of this study was to evaluate the diagnostic yield from prior genetic testing in a 20-year cohort of pediatric patients with congenital cataracts. A retrospective review of patients with congenital cataracts who underwent genetic testing was completed from 2003–2022. The diagnostic yield of the test was determined by variant classification and inheritance pattern. Variants from initial testing underwent reclassification in accordance with ACMG-AMP (American College of Medical Genetics and Genomics—American Association of Molecular Pathology) 2015 or 2020 ACMG CNV guidelines. A total of 95 variants were identified in 52 patients with congenital cataracts (42 bilateral, 10 unilateral); 42 % were White, 37% were Hispanic, 8% were Black, and 6% were Asian. The majority of patients (92%) did not have a family history of congenital cataracts but did have systemic illnesses (77%). Whole exome sequencing and targeted congenital cataract panels showed diagnostic yields of 46.2% and 37.5%, respectively. Microarray had the lowest yield at 11%. Compared to the initial classification, 16% (15 of 92 variants) had discrepant reclassifications. More testing is needed, and an increased focus is warranted in the field of ocular genetics on congenital cataracts, particularly in those with systemic illnesses and no family history, to advance our knowledge of this potentially blinding condition. Full article
(This article belongs to the Special Issue Genetics of Eye Development and Disease)
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10 pages, 1524 KiB  
Article
Diagnostic Yield of Genetic Testing for Ocular and Oculocutaneous Albinism in a Diverse United States Pediatric Population
by Kyle S. Chan, Brenda L. Bohnsack, Alexander Ing, Andy Drackley, Valerie Castelluccio, Kevin X. Zhang, Hanta Ralay-Ranaivo and Jennifer L. Rossen
Genes 2023, 14(1), 135; https://doi.org/10.3390/genes14010135 - 03 Jan 2023
Cited by 2 | Viewed by 2981
Abstract
The diagnostic yield of genetic testing for ocular/oculocutaneous albinism (OA/OCA) in a diverse pediatric population in the United States (U.S.) is unclear. Phenotypes of 53 patients who presented between 2006–2022 with OA/OCA were retrospectively correlated with genetic testing results. Genetic diagnostic yield was [...] Read more.
The diagnostic yield of genetic testing for ocular/oculocutaneous albinism (OA/OCA) in a diverse pediatric population in the United States (U.S.) is unclear. Phenotypes of 53 patients who presented between 2006–2022 with OA/OCA were retrospectively correlated with genetic testing results. Genetic diagnostic yield was defined as detection of pathogenic/likely pathogenic variant(s) matching the anticipated inheritance for that gene–disease relationship. Variant reclassifications of those with variants of uncertain significance (VUS) and without positive diagnostic yield were completed. Overall initial genetic diagnostic yield of OA/OCA was 66%. There was no significant difference (p = 0.59) between race and ethnicities (Black (78%), White (59%), Hispanic/Latino (64%)); however, the diagnostic yield of OA (33%) was significantly lower (p = 0.007) than OCA (76%). Causative variants in OCA2 (28%) and TYR (20%) were most common. Further, Hermansky–Pudlak syndrome variants were identified in 9% of patients. Re-classification of VUS in non-diagnostic cases resulted in genetic diagnoses for 29% of individuals and increased overall diagnostic yield to 70% of all subjects. There is a high diagnostic yield of genetic testing of patients overall with OA/OCA in a diverse U.S. based pediatric population. Presence or absence of cutaneous involvement of albinism significantly affects genetic diagnostic yield. Full article
(This article belongs to the Special Issue Genetics of Eye Development and Disease)
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13 pages, 4784 KiB  
Case Report
Specific Deoxyceramide Species Correlate with Expression of Macular Telangiectasia Type 2 (MacTel2) in a SPTLC2 Carrier HSAN1 Family
by Lindsey M. Q. Wilson, Sadaf Saba, Jun Li, Lev Prasov and Jason M. L. Miller
Genes 2023, 14(4), 931; https://doi.org/10.3390/genes14040931 - 18 Apr 2023
Viewed by 1559
Abstract
Hereditary sensory and autonomic neuropathy type 1 (HSAN1/HSN1) is a peripheral neuropathy most commonly associated with pathogenic variants in the serine palmitoyltransferase complex (SPTLC1, SPTLC2) genes, which are responsible for sphingolipid biosynthesis. Recent reports have shown that some HSAN1 patients also develop macular [...] Read more.
Hereditary sensory and autonomic neuropathy type 1 (HSAN1/HSN1) is a peripheral neuropathy most commonly associated with pathogenic variants in the serine palmitoyltransferase complex (SPTLC1, SPTLC2) genes, which are responsible for sphingolipid biosynthesis. Recent reports have shown that some HSAN1 patients also develop macular telangiectasia type 2 (MacTel2), a retinal neurodegeneration with an enigmatic pathogenesis and complex heritability. Here, we report a novel association of a SPTLC2 c.529A>G p.(Asn177Asp) variant with MacTel2 in a single member of a family that otherwise has multiple members afflicted with HSAN1. We provide correlative data to suggest that the variable penetrance of the HSAN1/MacTel2-overlap phenotype in the proband may be explained by levels of certain deoxyceramide species, which are aberrant intermediates of sphingolipid metabolism. We provide detailed retinal imaging of the proband and his HSAN1+/MacTel2- brothers and suggest mechanisms by which deoxyceramide levels may induce retinal degeneration. This is the first report of HSAN1 vs. HSAN1/MacTel2 overlap patients to comprehensively profile sphingolipid intermediates. The biochemical data here may help shed light on the pathoetiology and molecular mechanisms of MacTel2. Full article
(This article belongs to the Special Issue Genetics of Eye Development and Disease)
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10 pages, 2944 KiB  
Case Report
Characteristics of a Three-Generation Family with Stickler Syndrome Type I Carrying Two Different COL2A1 Mutations
by Adam Jacobson, Cagri G. Besirli and Brenda L. Bohnsack
Genes 2023, 14(4), 847; https://doi.org/10.3390/genes14040847 - 31 Mar 2023
Cited by 1 | Viewed by 1500
Abstract
Stickler Syndrome is typically characterized by ophthalmic manifestations including vitreous degeneration and axial lengthening that predispose to retinal detachment. Systemic findings consist of micrognathia, cleft palate, sensorineural hearing loss, and joint abnormalities. COL2A1 mutations are the most common, however, there is a lack [...] Read more.
Stickler Syndrome is typically characterized by ophthalmic manifestations including vitreous degeneration and axial lengthening that predispose to retinal detachment. Systemic findings consist of micrognathia, cleft palate, sensorineural hearing loss, and joint abnormalities. COL2A1 mutations are the most common, however, there is a lack of genotype-phenotype correlations. Retrospective, single-center case series of a three-generation family. Clinical features, surgical requirements, systemic manifestations, and genetic evaluations were collected. Eight individuals clinically displayed Stickler Syndrome, seven of whom had genetic confirmation, and two different COL2A1 mutations (c.3641delC and c.3853G>T) were identified. Both mutations affect exon 51, but display distinct phenotypes. The c.3641delC frameshift mutation resulted in high myopia and associated vitreous and retinal findings. Individuals with the c.3853G>T missense mutation exhibited joint abnormalities, but mild ocular manifestations. One individual in the third generation was biallelic heterozygous for both COL2A1 mutations and showed ocular and joint findings in addition to autism and severe developmental delay. These COL2A1 mutations exhibited distinct eye vs. joint manifestations. The molecular basis for these phenotypic differences remains unknown and demonstrates the need for deep phenotyping in patients with Stickler syndrome to correlate COL2A1 gene function and expression with ocular and systemic findings. Full article
(This article belongs to the Special Issue Genetics of Eye Development and Disease)
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