ABSTRACT
Purpose: To report a rare clinical finding of preretinal granules associated with atypical familial exudative vitreoretinopathy (FEVR) and perform a review of the literature. Observations: An asymptomatic 18-year-old male was referred for unilateral peripheral avascular retina evaluation in association with presumed FEVR. He was first noted to have white preretinal granules on fundus examination at five years of age. The lesions remained unchanged over the subsequent years. Genetic testing did not reveal a pathogenic or likely pathogenic variant in a known FEVR gene. A review of the literature revealed five other cases of FEVR with similar findings. Conclusions and Importance: Literature review suggests preretinal granules may present rarely in FEVR. Negative genetic screening of known FEVR genes in our patient with atypical FEVR suggests either a molecularly distinct etiology supporting the rarity of this association with FEVR or, alternatively, the presence of granules in developmental retinal vascular anomalies that are not specific to FEVR. Future study and genetic testing is necessary to better understand the cause of these preretinal granules and the clinical manifestations of FEVR.
ABSTRACT
PURPOSE: Prematurely born children are at risk of numerous complications that affect the visual system. Retinopathy of prematurity (ROP) and cerebral visual impairment (CVI) are among two major causes of childhood blindness and visual impairment in industrialized nations, and large countries with emerging economies are seeing increasing childhood blindness from ROP alone, adding to the burden of disease worldwide. The purpose of this paper is to review the long-term impacts of prematurity, ROP and CVI on vision in children who were born preterm. METHOD: The topics in this review of the literature include the burden of vision loss in prematurely born children world-wide, a description of ROP and CVI, effects on visual acuity, refractive errors, strabismus and binocularity, visual fields and contrast sensitivity, and risk factors for visual complications. RESULTS: Children who are most at risk of visual complications are those with the smallest gestational age at birth and birth weight in general. Although ROP severity and the presence of neurological impairments including CVI play a large role in the development of poor visual outcomes, premature birth alone without CVI or severe ROP increases the risk of future visual complications. Awareness of signs and symptoms of CVI are important in the management of affected children. CONCLUSION: Children born preterm are at increased risk of reduced visual acuity, refractive errors, strabismus and amblyopia, complications of ROP, CVI, visual field abnormalities and reduced contrast sensitivity. Awareness of risk factors warranting close monitoring and signs and symptoms of CVI are critical to optimize the visual outcomes and overall development.
Subject(s)
Premature Birth , Refractive Errors , Retinopathy of Prematurity , Strabismus , Infant, Newborn , Child , Pregnancy , Female , Humans , Infant, Premature , Vision Disorders/etiology , Blindness/complications , Strabismus/complications , Retinopathy of Prematurity/diagnosisABSTRACT
This study reports variants in BBS1 and BBS7 in patients with Bardet-Biedl syndrome from the Canadian Maritime provinces. The BBS1 variant NM_024649.5:c.1169T>G was identified as a recurrent variant in Prince Edward Island.
Subject(s)
Bardet-Biedl Syndrome , Microtubule-Associated Proteins , Humans , Canada , Microtubule-Associated Proteins/genetics , Mutation , Prince Edward IslandABSTRACT
Importance: Familial exudative vitreoretinopathy (FEVR) is a nonsyndromic autosomal dominant retinal disorder commonly caused by variants in the FZD4 gene. This study investigates the potential role beyond ocular abnormalities for FZD4 gene variants in patients with FEVR. Objective: To evaluate the role of FZD4 in symptoms beyond those associated with FEVR through a patient with biallelic variants in FZD4. Design, Setting, and Participants: This case series included the DNA testing and phenotyping of 1 patient proband and her parents, combined with signaling assays, to determine the association of patient-derived compound heterozygous variants on FZD4 signaling and biologic function. Main Outcomes and Measures: FZD4 genes were tested using next-generation sequencing and Sanger sequencing. Cell-based assays measured the effect of the variants on FZD4 signaling. Results: The proband presented with absent red reflexes from complete tractional retinal detachments diagnosed at 3 days of age and failed the newborn screening hearing test. Auditory brainstem response at 6 months of age showed bilateral mild to moderate high-frequency sensorineural hearing loss. The patient manifested developmental delays in speech and walking. Intravenous fluorescein angiography (IVFA) of the patient's parents detected stage 1 FEVR. Genetic testing revealed 2 FZD4 variants in the patient, each variant found in 1 parent. Signaling assays confirmed that the presence of both variants was associated with significantly worse signaling activity compared with the heterozygous state. Conclusions and Relevance: Results of this case series suggest that extraocular syndromic FEVR was associated with FZD4 variants. The decrease in FZD4 signaling owing to the biallelic nature of the disease resulted in hearing deficits, developmental delays, and a more severe retinal phenotype.
Subject(s)
Biological Products , Eye Diseases, Hereditary , Hearing Loss, Sensorineural , Retinal Diseases , DNA/genetics , DNA Mutational Analysis , Eye Diseases, Hereditary/diagnosis , Eye Diseases, Hereditary/genetics , Familial Exudative Vitreoretinopathies , Female , Frizzled Receptors/genetics , Hearing Loss, Sensorineural/diagnosis , Hearing Loss, Sensorineural/genetics , Humans , Mutation , Pedigree , Retinal Diseases/diagnosisABSTRACT
Due to resource restrictions related to the COVID-19 pandemic, many pediatric patients are facing substantial delays for surgery, potentially resulting in additional distress for caregivers. We aimed to assess the experiences and psychosocial distress of parents during COVID-19 as they relate to the pandemic, waiting for surgery, and the combined effects of both events. The was a cross-sectional qualitative study. Parents with children who faced treatment delays during the initial wave of the COVID-19 pandemic for elective, non-emergent procedures across a variety of surgical specialties were recruited. Semi-structured telephone interviews and thematic analysis were utilized. Thematic saturation was reached with eighteen participants. Four themes were identified: coping with COVID-19, distress levels, quality and nature of communication with the surgical team, and the experience of COVID-19 related hospital restrictions. Participants reported varying levels of distress due to the delay in surgery, such as the fear of developmental delay or disease progression for their child. They also indicated their own physical and mental health had been impacted by emotional distress related to both COVID-19 and delays in treatment. Most participants experienced the COVID-19-related hospital restrictions as distressing. This related predominantly to limiting in-hospital caregivers to only one caregiver. Participants were found to have substantial levels of psychosocial distress. Targeted social and emotional support may be helpful in reducing parental distress as the pandemic timeframe continues. Within the limits of individual health systems, reducing restrictions to the number of allowed care givers may help allay distress felt by parents.
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OBJECTIVE: Retinopathy of prematurity (ROP) is a leading cause of childhood visual impairment. Treatment options for severe ROP include laser and/or anti-vascular endothelial growth factor (anti-VEGF) injections. Previous studies have compared the 2 treatments for functional outcomes including visual acuity, amblyopia, and strabismus. The purpose of this study was to evaluate the influence of treatment on binocularity. METHODS: In this masked, cross-sectional study, binocularity was measured using Bagolini lenses and the Frisby stereotest in children aged 3-8 years with a history of ROP treatment in 2 Canadian centres. Events associated with disruption of binocularity including amblyopia, anisometropia, and strabismus, were recorded and analyzed as secondary outcomes. RESULTS: A total of 42 children were recruited: 19 were treated with laser and 23 with an anti-VEGF agent. The mean age at the time of assessment in the laser group was 81.2 (6.8 years) ± 16.2 months versus 63 (5.25 years) ± 15.7 months in the anti-VEGF group (p < 0.001). No statistically significant difference in rates of binocularity was detected (68% laser vs 82% anti-VEGF, pâ¯=â¯0.27). Laser-treated participants experienced a greater number of cumulative insults to binocularity (pâ¯=â¯0.01). CONCLUSIONS: Patients with a history of ROP treated with laser or anti-VEGF agents require long-term follow-up to address binocularity-disrupting factors. Although we did not detect a difference in rates and level of binocularity between treatment groups, we did find an increased rate of cumulative binocularity disrupting events in the laser-treated group.
Subject(s)
Retinopathy of Prematurity , Angiogenesis Inhibitors/therapeutic use , Bevacizumab/therapeutic use , Canada , Child , Cross-Sectional Studies , Humans , Infant, Newborn , Intravitreal Injections , Laser Coagulation , Retinopathy of Prematurity/diagnosis , Retinopathy of Prematurity/drug therapy , Vascular Endothelial Growth Factor AABSTRACT
BACKGROUND: Familial exudative vitreoretinopathy (FEVR) is a rare congenital disorder characterized by a lack of blood vessel growth to the periphery of the retina with secondary fibrovascular proliferation at the vascular-avascular junction. These structurally abnormal vessels cause leakage and hemorrhage, while the fibroproliferative scarring results in retinal dragging, detachment and blindness. Mutations in the FZD4 gene represent one of the most common causes of FEVR. METHODS: A loss of function mutation resulting from a 10-nucleotide insertion into exon 1 of the zebrafish fzd4 gene was generated using transcription activator-like effector nucleases (TALENs). Structural and functional integrity of the retinal vasculature was examined by fluorescent microscopy and optokinetic responses. RESULTS: Zebrafish retinal vasculature is asymmetrically distributed along the dorsoventral axis, with active vascular remodeling on the ventral surface of the retina throughout development. fzd4 mutants exhibit disorganized ventral retinal vasculature with discernable tubular fusion by week 8 of development. Furthermore, fzd4 mutants have impaired optokinetic responses requiring increased illumination. CONCLUSION: We have generated a visually impaired zebrafish FEVR model exhibiting abnormal retinal vasculature. These fish provide a tractable system for studying vascular biology in retinovascular disorders, and demonstrate the feasibility of using zebrafish for evaluating future FEVR genes identified in humans.
Subject(s)
Frizzled Receptors/physiology , Retina/pathology , Retinal Vessels/pathology , Vascular Remodeling/genetics , Zebrafish Proteins/physiology , Animals , Animals, Genetically Modified , Body Patterning/genetics , Disease Models, Animal , Embryo, Nonmammalian , Familial Exudative Vitreoretinopathies/diagnosis , Familial Exudative Vitreoretinopathies/genetics , Familial Exudative Vitreoretinopathies/pathology , Feasibility Studies , Frizzled Receptors/genetics , Humans , Neovascularization, Pathologic/embryology , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/physiopathology , Retina/diagnostic imaging , Retina/embryology , Retina/metabolism , Retinal Diseases/genetics , Retinal Diseases/pathology , Retinal Vessels/embryology , Retinal Vessels/physiology , Zebrafish/embryology , Zebrafish/genetics , Zebrafish Proteins/geneticsABSTRACT
We have optimized point mutation knock-ins into zebrafish genomic sites using clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 reagents and single-stranded oligodeoxynucleotides. The efficiency of knock-ins was assessed by a novel application of allele-specific polymerase chain reaction and confirmed by high-throughput sequencing. Anti-sense asymmetric oligo design was found to be the most successful optimization strategy. However, cut site proximity to the mutation and phosphorothioate oligo modifications also greatly improved knock-in efficiency. A previously unrecognized risk of off-target trans knock-ins was identified that we obviated through the development of a workflow for correct knock-in detection. Together these strategies greatly facilitate the study of human genetic diseases in zebrafish, with additional applicability to enhance CRISPR-based approaches in other animal model systems.
Subject(s)
CRISPR-Cas Systems , Gene Editing/methods , Gene Knock-In Techniques/methods , Point Mutation/genetics , Zebrafish/genetics , Animals , Animals, Genetically Modified , Clustered Regularly Interspaced Short Palindromic Repeats , Embryo, Nonmammalian , Microinjections , Mutagenesis, Site-Directed/methods , Zebrafish/embryologyABSTRACT
Mutations in genes that code for components of the Norrin-FZD4 ligand-receptor complex cause the inherited childhood blinding disorder familial exudative vitreoretinopathy (FEVR). Statistical evidence from studies of patients at risk for the acquired disease retinopathy of prematurity (ROP) suggest that rare polymorphisms in these same genes increase the risk of developing severe ROP, implying that decreased Norrin-FZD4 activity predisposes patients to more severe ROP. To test this hypothesis, we measured the development and recovery of retinopathy in wild type and Fzd4 heterozygous mice in the absence or presence of ocular ischemic retinopathy (OIR) treatment. Avascular and total retinal vascular areas and patterning were determined, and vessel number and caliber were quantified. In room air, there was a small delay in retinal vascularization in Fzd4 heterozygous mice that resolved as mice reached maturity suggestive of a slight defect in retinal vascular development. Subsequent to OIR treatment there was no difference between wild type and Fzd4 heterozygous mice in the vaso-obliterated area following exposure to high oxygen. Importantly, after return of Fzd4 heterozygous mice to room air subsequent to OIR treatment, there was a substantial delay in retinal revascularization of the avascular area surrounding the optic nerve, as well as delayed vascularization toward the periphery of the retina. Our study demonstrates that a small decrease in Norrin-Fzd4 dependent retinal vascular development lengthens the period during which complications from OIR could occur.
Subject(s)
Frizzled Receptors/genetics , Oxygen/toxicity , Retinopathy of Prematurity/etiology , Animals , Disease Models, Animal , Female , Frizzled Receptors/metabolism , Genotype , Haploinsufficiency , Male , Mice , Microscopy, Fluorescence , Optic Nerve/blood supply , Retina/metabolism , Retina/pathology , Retinal Neovascularization , Retinal Vessels/growth & development , Retinal Vessels/metabolism , Retinopathy of Prematurity/geneticsABSTRACT
OBJECTIVE: We explore the stability of parental attitudes to the ethical issues raised by the return of genomic research results. METHODS: A 19-item questionnaire was mailed to participants in a large genome research consortium 18 months following a baseline survey. We describe the stability of parental attitudes to (a) sharing of genomic research results, (b) endorsement of children in genomic research, (c) responsibilities of researchers, and (d) responsibilities to extended family. We also explore their experience in receiving results. RESULTS: Of 170 original participants, 154 (91%) responded. Most participants expressed positive rights to receive incidental genomic research findings (85%), including when ameliorative therapy was unknown (85%). Only 3% found it acceptable to delegate the decision to return results to an independent committee. Researchers, either with a parent (42%) or physician (17%), were felt to be responsible to convey research results to children when they reach adulthood. Most participants (74%) indicated that results should be shared with potentially affected extended family. These results are very similar to those of the baseline survey. All participants who received genomic results would do so again and reported actions similar to their expressed attitudes. CONCLUSIONS: The opinions of parents regarding genomic research remain stable over time. Guidelines on the return of results should incorporate these findings.
Subject(s)
Attitude to Health , Genomics/ethics , Human Experimentation/ethics , Parents/psychology , Adolescent , Adult , Aged , Child , Ethics, Research , Family , Female , Follow-Up Studies , Genetic Research/ethics , Genome/ethics , Humans , Incidental Findings , Male , Middle Aged , Physicians/ethics , Research Personnel/ethics , Social Behavior , Social Responsibility , Surveys and Questionnaires , Young AdultABSTRACT
The birth of a bilaterally blind child is catastrophic for families and a challenging diagnostic and management problem for ophthalmologists. Early identification of the underlying cause and its genetic basis helps initiate possible treatment, delineate prognosis, and identify risks for future pregnancies. In some cases, an early diagnosis can also influence the treatment of other family members. We report two sisters with bilateral retinal detachment and retro-lental masses from birth with no detectable NDP or FZD4 mutations. They were born to parents without detectable retinal anomalies. At 1 year of age, the elder sister had low impact bone fractures, and further evaluation identified severe osteopenia and multiple spinal compression fractures. Molecular testing identified biallelic lipoprotein receptor-related protein 5 (LRP5) mutations (NM_002335.3:c. [889dupA]; [2827 + 1G > A]) confirming a diagnosis of osteoporosis-pseudoglioma (OPPG) syndrome. After this diagnosis, the father and mother were found to have low bone mass and the father started on therapy. We conclude that early detection of LRP5 mutations is important for initiation of treatment of reduced bone density in the patients and their carrier relatives.
Subject(s)
Low Density Lipoprotein Receptor-Related Protein-5/genetics , Mutation , Osteogenesis Imperfecta/genetics , Retinal Detachment/congenital , DNA Mutational Analysis , Female , Fractures, Compression/diagnostic imaging , Heterozygote , Humans , Infant , Radiography , Retinal Detachment/diagnostic imaging , Siblings , UltrasonographyABSTRACT
IMPORTANCE: Retinal detachment with avascularity of the peripheral retina, typically associated with familial exudative vitreoretinopathy (FEVR), can result from mutations in KIF11, a gene recently identified to cause microcephaly, lymphedema, and chorioretinal dysplasia (MLCRD) as well as chorioretinal dysplasia, microcephaly, and mental retardation (CDMMR). Ophthalmologists should be aware of the range of presentations for mutations in KIF11 because the phenotypic distinction between FEVR and MLCRD/CDMMR portends management implications in patients with these conditions. OBJECTIVE: To identify gene mutations in patients who present with a FEVR phenotype and explore the spectrum of ocular and systemic abnormalities caused by KIF11 mutations in a cohort of patients with FEVR or microcephaly in conjunction with chorioretinopathy or FEVR. DESIGN, SETTING, AND PARTICIPANTS: Clinical data and DNA were collected from each participant between 1998 and 2013 from the clinical practices of ophthalmologists and clinical geneticists internationally. Twenty-eight FEVR probands with diagnoses made by the referring physician and without a known FEVR gene mutation, and 3 with microcephaly and chorioretinopathy, were included. At least 1 patient in each pedigree manifested 1 or more of the following: macular dragging, partial retinal detachment, falciform folds, or total retinal detachment. EXPOSURES: Whole-exome sequencing was conducted on affected members in multiplex pedigrees, and Sanger sequencing of the 22 exons of the KIF11 gene was performed on singletons. Clinical data and history were collected and reviewed. MAIN OUTCOMES AND MEASURES: Identification of mutations in KIF11. RESULTS: Four novel heterozygous KIF11 mutations and 1 previously published mutation were identified in probands with FEVR: p.A218Gfs*15, p.E470X, p.R221G, c.790-1G>T, and the previously described heterozygous p.R47X. Documentation of peripheral avascular areas on intravenous fluorescein angiography was possible in 2 probands with fibrovascular proliferation demonstrating phenotypic overlap with FEVR. CONCLUSIONS AND RELEVANCE: Mutations in KIF11 cause a broader spectrum of ocular disease than previously reported, including retinal detachment. The KIF11 gene likely plays a role in retinal vascular development and mutations in this gene can lead to clinical overlap with FEVR. Cases of FEVR should be carefully inspected for the presence of microcephaly as a marker for KIF11-related disease to enhance the accuracy of the prognosis and genetic counseling.
Subject(s)
Kinesins/genetics , Lymphedema/genetics , Microcephaly/genetics , Mutation , Retinal Dysplasia/genetics , Base Sequence , Child , Child, Preschool , DNA Mutational Analysis , Electrophysiology , Exons/genetics , Eye Diseases, Hereditary , Facies , Familial Exudative Vitreoretinopathies , Female , Fluorescein Angiography , Humans , Lymphedema/diagnosis , Male , Microcephaly/diagnosis , Molecular Sequence Data , Pedigree , Phenotype , Polymerase Chain Reaction , Retinal Diseases/diagnosis , Retinal Diseases/genetics , Retinal Dysplasia/diagnosisABSTRACT
OBJECTIVE: Idiopathic intracranial hypertension (IIH) in children is an uncommon but significant cause of morbidity, including permanent visual loss. It is important to understand if, like obesity, IIH in children is on the rise and is related to that increase. The aim of this study is to compare the recent incidence rate of pediatric IIH in a tertiary care hospital with earlier data published from that same hospital. DESIGN: Retrospective chart review. PARTICIPANTS: All children aged 2 to 16 years diagnosed with IIH at the IWK Health Centre in Halifax between 1997 and 2007. METHODS: Charts of eligible patients were reviewed to ensure all diagnostic criteria for IIH were met. Incidence and obesity rates were calculated based on data from Statistics Canada. RESULTS: Twelve cases (5 males, 7 females) fulfilling the diagnostic criteria for IIH were identified, for an annual incidence of 0.6 cases per 100,000 children with no sex predilection (p = 0.51). Obesity was noted in 75% of patients examined (9/12). Children older than 12 years were more likely to be obese (6/6, 100%) compared with those younger than 12 years (3/6, 50%). CONCLUSIONS: The calculated incidence is lower than that found in an earlier study for the same geographic region (0.9 cases per 100,000 children) despite increasing obesity rates. This decrease may be a reflection of improved diagnostic techniques or may indicate that factors other than obesity govern IIH predilection in younger children.
Subject(s)
Pediatric Obesity/epidemiology , Pseudotumor Cerebri/epidemiology , Adolescent , Body Mass Index , Child , Child, Preschool , Female , Humans , Incidence , Intracranial Pressure , Male , Nova Scotia/epidemiology , Retrospective Studies , Visual Acuity/physiology , Visual Fields/physiologyABSTRACT
PURPOSE: We describe parental attitudes toward the return of targeted and incidental genomic research results in the setting of high-risk pediatric cancer and inherited childhood diseases. METHODS: A validated 36-item questionnaire was mailed to participants in three large-scale genome research consortia examining attitudes toward receipt of genomic research results and the influence of certainty, severity, and onset of the condition, in addition to responsibilities to extended family and provision of results even after death of the proband. RESULTS: Of the 563 participants who were sent questionnaires, 362 (64%) responded. Most of them stated a positive right to receive results related to the target condition (97%) or to incidental findings (86%); no difference was found in results between participants with cancer and those with orphan diseases. Furthermore, 92% indicated that genomic research for childhood-onset conditions should occur. The majority wanted incidental results predicting susceptibility even to untreatable fatal conditions (83%), to multiple conditions (87%), or to those with uncertain impact (70%). Most felt sibling genomic results showing serious conditions, whether treatable (93%) or not (88%), and/or results discovered after death of the proband should be shared with family (74%). CONCLUSION: Many parents of children in pediatric genomic research indicated a strong desire to receive a broader range of results than is described in consensus recommendations. Clear delineation of what will be offered should be established at the time of consent.
Subject(s)
Genomics , Health Knowledge, Attitudes, Practice , Incidental Findings , Parents/psychology , Adult , Canada , Child , Female , Genetic Research , Humans , Male , Middle Aged , Surveys and QuestionnairesABSTRACT
AIM: The aim of this study is to assess the role of Frizzled-4 (FZD4) in familial exudative vitreoretinopathy (FEVR) and Coats disease. METHODS: Tissue samples were collected for DNA extraction and automated DNA sequencing of the two coding exons of FZD4 in both directions. Cases carrying a FZD4 mutation and demonstrating extreme disease severity were selected for direct automated sequencing of all coding exons of LRP5, NDP and TSPAN12. Clinical data were obtained for the purpose of identifying genotype-phenotype correlations. RESULTS: 68 probands were diagnosed as having autosomal dominant or sporadic FEVR. Eleven FZD4 mutations (five missense, three deletions, one insertion, two nonsense) were identified. Six of these mutations are novel, and none were found in 346 control chromosomes. In 16 cases of Coats disease, one polymorphism combination was found in two samples: no mutations were detected. No genotype-phenotype correlation emerged. Three severely affected cases with FZD4 mutations failed to show additional mutations in the three other FEVR genes. CONCLUSION: The authors identified 12 FEVR probands with FZD4 mutations. FZD4 mutation screening can be a useful tool especially in mild or atypical cases of FEVR. Germ-line mutations in FZD4 do not appear to be a common cause of Coats disease.
Subject(s)
Eye Diseases, Hereditary/genetics , Frizzled Receptors/genetics , Mutation/genetics , Receptors, G-Protein-Coupled/genetics , Retinal Telangiectasis/genetics , Vitreoretinopathy, Proliferative/genetics , Adolescent , Adult , Aged , Child , Child, Preschool , Exons , Female , Genetic Association Studies , Humans , Male , Middle Aged , Pedigree , Vitreoretinopathy, Proliferative/diagnosis , Young AdultABSTRACT
PURPOSE: To determine whether mutations in the FZD4 gene are a risk factor for developing severe ROP. METHODS: Three Canadian tertiary care centers recruited premature infants prospectively and retrospectively, and assigned affectation status based on the maximum degree of severity of ROP recorded in both eyes. Mutation screening of the FZD4 gene was performed using direct sequencing. All sequence changes were evaluated for functional significance. RESULTS: Two novel FZD4 mutations (Ala370Gly or Lys203Asn) were identified in two infants from the severe ROP group (n=71). No mutation was detected in the mild to no ROP group (n=33), and the two novel mutations were absent in 173 random Caucasian samples. Mutation Ala370Gly was also found in one sibling and one parent of the affected infant, but no signs of familial exudative vitreoretinopathy (FEVR), a condition with phenotypic overlap with ROP known to be caused by FZD4 mutations, were present in either family member. CONCLUSIONS: Mutations in the FZD4 gene in this group of premature infants supports a role for the FZD4 pathway in the development of severe ROP and accounts for approximately 3% of severe ROP in Caucasian premature infants.
Subject(s)
Frizzled Receptors/genetics , Mutation , Receptors, G-Protein-Coupled/genetics , Retinopathy of Prematurity/genetics , Amino Acid Sequence , Animals , Birth Weight , Female , Genetic Predisposition to Disease , Gestational Age , Humans , Infant, Newborn , Male , Molecular Sequence Data , Prospective Studies , Retrospective Studies , Risk Factors , Sequence Homology, Amino AcidABSTRACT
BACKGROUND: In families segregating a monogenic genetic disorder with a single disease gene introduction, patients share a mutation-carrying chromosomal interval with identity-by-descent (IBD). Such a shared chromosomal interval or haplotype, surrounding the actual pathogenic mutation, is typically detected and defined by multipoint linkage and phased haplotype analysis using microsatellite or SNP genotype data. High-density SNP genotype data presents a computational challenge for conventional genetic analyses. A novel non-parametric method termed Homozygosity Haplotype (HH) was recently proposed for the genome-wide search of the autosomal segments shared among patients using high density SNP genotype data. METHODOLOGY/PRINCIPAL FINDINGS: The applicability and the effectiveness of HH in identifying the potential linkage of disease causative gene with high-density SNP genotype data were studied with a series of monogenic disorders ascertained in eastern Canadian populations. The HH approach was validated using the genotypes of patients from a family affected with a rare autosomal dominant disease Schnyder crystalline corneal dystrophy. HH accurately detected the approximately 1 Mb genomic interval encompassing the causative gene UBIAD1 using the genotypes of only four affected subjects. The successful application of HH to identify the potential linkage for a family with pericentral retinal disorder indicates that HH can be applied to perform family-based association analysis by treating affected and unaffected family members as cases and controls respectively. A new strategy for the genome-wide screening of known causative genes or loci with HH was proposed, as shown the applications to a myoclonus dystonia and a renal failure cohort. CONCLUSIONS/SIGNIFICANCE: Our study of the HH approach demonstrates that HH is very efficient and effective in identifying potential disease linked region. HH has the potential to be used as an efficient alternative approach to sequencing or microsatellite-based fine mapping for screening the known causative genes in genetic disease study.
Subject(s)
Chromosome Mapping/methods , Haplotypes , Polymorphism, Single Nucleotide , Algorithms , Chromosome Mapping/statistics & numerical data , Corneal Dystrophies, Hereditary/genetics , Dystonic Disorders/genetics , Female , Genotype , Homozygote , Humans , Male , Pedigree , Retinal Degeneration/geneticsABSTRACT
PURPOSE: To describe a severe familial exudative vitreoretinopathy (FEVR) phenotype seen in infancy that resembles persistent fetal vasculature (PFV) caused by mutations in the FZD4 gene in two pedigrees with high intrafamilial variability. METHODS: Three infants presented with features compatible with bilateral PFV. Eye examinations from the affected children and their relatives were reviewed retrospectively (follow-up:18 months-9 years). Mutation screening was performed using direct sequencing of the FZD4, LRP5 and NDP genes. RESULTS: Bilateral retinal folds extending from the optic nerve to the inferotemporal aspect of the lens mimicing PFV were observed in two of the three affected children before the age of two months. The third child was examined at birth, and the avascular peripheral retina treated with diode laser within one week of age, with subsequent arrest of the disease process. A FZD4 mutation, M493_W494del, was identified in one affected child in pedigree 1, and a novel missense mutation, I114T, was detected in 2 affected children in pedigree 2; while no mutations were found in NDP or LRP5 genes in the 3 affected children. In both pedigrees, at least one affected relative was asymptomatic and failed to show the characteristic avascular changes of FEVR. CONCLUSIONS: The clinical features in the three children and their relatives with a documented FZD4 mutation support the previous reports of a high degree of intrafamilial and interfamilial variability in FEVR. In extreme cases with very early onset, the development of a retinal fold can mimic PFV, a non-hereditary condition with rare exception.