September 2009
Volume 50, Issue 9
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Retina  |   September 2009
Correlation of Genetic and Clinical Findings in Spanish Patients with X-linked Juvenile Retinoschisis
Author Affiliations
  • Rosa Riveiro-Alvarez
    From the Departments of Genetics,
    Centro de Investigacion Biomedica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III (ISCIII), Madrid, Spain; the
  • Maria-Jose Trujillo-Tiebas
    From the Departments of Genetics,
    Centro de Investigacion Biomedica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III (ISCIII), Madrid, Spain; the
  • Ascension Gimenez-Pardo
    From the Departments of Genetics,
    Centro de Investigacion Biomedica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III (ISCIII), Madrid, Spain; the
  • Maria Garcia-Hoyos
    From the Departments of Genetics,
    Centro de Investigacion Biomedica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III (ISCIII), Madrid, Spain; the
  • Miguel-Angel Lopez-Martinez
    From the Departments of Genetics,
    Centro de Investigacion Biomedica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III (ISCIII), Madrid, Spain; the
  • Jana Aguirre-Lamban
    From the Departments of Genetics,
    Centro de Investigacion Biomedica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III (ISCIII), Madrid, Spain; the
  • Blanca Garcia-Sandoval
    Ophthalmology, and
  • Silvia Vazquez-Fernandez del Pozo
    Epidemiology, Fundacion Jimenez Diaz, Madrid, Spain;
  • Diego Cantalapiedra
    From the Departments of Genetics,
    Centro de Investigacion Biomedica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III (ISCIII), Madrid, Spain; the
  • Almudena Avila-Fernandez
    From the Departments of Genetics,
    Centro de Investigacion Biomedica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III (ISCIII), Madrid, Spain; the
  • Montserrat Baiget
    Genetics Department, Hospital Sant Pau, Barcelona, Spain; and
    CIBER de Enfermedades Raras, ISCIII, Barcelona, Spain.
  • Carmen Ramos
    From the Departments of Genetics,
    Centro de Investigacion Biomedica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III (ISCIII), Madrid, Spain; the
  • Carmen Ayuso
    From the Departments of Genetics,
    Centro de Investigacion Biomedica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III (ISCIII), Madrid, Spain; the
Investigative Ophthalmology & Visual Science September 2009, Vol.50, 4342-4350. doi:10.1167/iovs.09-3418
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      Rosa Riveiro-Alvarez, Maria-Jose Trujillo-Tiebas, Ascension Gimenez-Pardo, Maria Garcia-Hoyos, Miguel-Angel Lopez-Martinez, Jana Aguirre-Lamban, Blanca Garcia-Sandoval, Silvia Vazquez-Fernandez del Pozo, Diego Cantalapiedra, Almudena Avila-Fernandez, Montserrat Baiget, Carmen Ramos, Carmen Ayuso; Correlation of Genetic and Clinical Findings in Spanish Patients with X-linked Juvenile Retinoschisis. Invest. Ophthalmol. Vis. Sci. 2009;50(9):4342-4350. doi: 10.1167/iovs.09-3418.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

purpose. X-linked juvenile retinoschisis (XLRS) is one of the most common causes of juvenile macular degeneration in males, characterized by microcystic changes, splitting within the inner retinal layer (schisis), and the presence of vitreous veils. This study was conducted to describe and further correlate specific genetic variation in Spanish patients with XLRS with clinical characteristics and additional ophthalmic complications.

methods. The study was performed in 34 Spanish families with XLRS, comprising 51 affected males. Thorough clinical ophthalmic and electrophysiological examinations were performed. The coding regions of the RS1 gene were amplified by polymerase chain reaction and directly sequenced. Haplotype analyses were also performed.

results. Twenty different mutations were identified. Ten of the 20 were novel and 3 were de novo mutational events. The most common mutation (p.Gln154Arg; 6/20) presented a common haplotype. RS1 variants did not correlate with ophthalmic findings and were not associated with additional ophthalmic complications.

conclusions. The prevalent p.Gln154Arg mutation is first reported in this work and presents a common origin in Spanish patients with XLRS. In addition, de novo mutations mainly occur in CG dinucleotides. Despite the large mutational spectrum and variable phenotypes, no genotype–phenotype correlations were found. Identifying the causative mutation is helpful in confirming diagnosis and counseling, but cannot provide a prognosis.

X-linked juvenile retinoschisis (XLRS; OMIM 312700; Online Mendelian Inheritance in Man; http://www.ncbi.nlm.nih.gov/Omim/ provided in the public domain by the National Center for Biotechnology Information, Bethesda, MD) is one of the most common causes of juvenile macular degeneration in males. 1 This X-linked trait affects only males; female carriers rarely have vision morbidity. 2 3  
XLRS is a symmetrical bilateral macular disorder with onset in the first decade of life, in some cases, as early as 3 months of age. Fundus examination shows microcystic changes of the macular region of the retina and areas of splitting within the nerve fiber layer, or schisis, 4 5 giving the impression of a spoked-wheel pattern, and the presence of vitreous veils, which are neural sheets that float in the vitreous cavity. Severe cases involve full-thickness retinal detachment. 4 6 More advanced stages of the disease are complicated by vitreous hemorrhage, retinal detachment, and neovascular glaucoma, 7 which may induce severe loss of vision. The electroretinograms (ERGs) of most affected males demonstrate normal or near-normal a-waves characteristic of photoreceptor function but often substantially reduced b-waves, originating from inner retinal cell activity. 8  
The RS1 gene maps to chromosome Xp22.2-22.1, contains six exons, and encodes a 224-amino-acid protein called Retinoschisin, 9 with an N-terminal secretory leader peptide sequence 10 11 and a discoidin domain in exons four to six. Discoidin domains are highly conserved across species, 12 are found in a large family of secreted or membrane-bound proteins and have been implicated in cell adhesion and cell–cell interactions. 13  
It is known that Retinoschisin associates with retinal cell surface membranes, 14 15 acting as a cellular scaffold for the retinal architecture. Recently, Molday et al. 14 indicated that Retinoschisin forms a complex with Na/K-ATPase and SARM1, therefore being implicated in a novel signaling pathway important in the photoreceptor–bipolar synaptic structure and function and retinal cell organization. 
Extensive investigations have led to the identification of numerous disease-causing mutations in the RS1 gene, including missense, nonsense, deletions, insertions, and splice site mutations (www.hgmd.org/ Human Gene Mutation Database provided in the public domain by the Institute of Medical Genetics, Cardiff, Wales, UK). The correlation between the phenotype and genotype of XLRS remained unclear, according to reports. 16 17  
The purpose of this systematic screening was two-fold: to describe specific genetic variation in Spanish patients with XLRS and to further correlate the most frequent RS1 variants with clinical characteristics and specific ophthalmic complications: retinal detachment, vitreous hemorrhage, and strabismus. 
Methods
Ascertainment of Patients
This molecular study was reviewed and approved by the Ethics Committee of Fundacion Jimenez Diaz, and it was performed according to the tenets of the Declaration of Helsinki and further reviews (Edinburgh, 2000; www.wma.net). Thirty-four Spanish families presenting with XLRS due to mutations in the RS1 gene were studied. The patient group consisted of 51 affected males. 
The age at onset was defined as either the patient’s age at which visual loss was first noted or the age documented in an ophthalmic record of the first diagnosis. In all cases, thorough clinical ophthalmic and electrophysiological examinations were performed, including a comprehensive ophthalmic and family history, funduscopic examination after pupillary dilation, static perimetry and best corrected visual acuity examination. For some patients, optical coherence tomography (OCT) images were obtained, which provided high-resolution, cross-sectional images of the macular region. Electrophysiological assessment included full-field electroretinogram (ERG), according to standards of the International Society for Clinical Electrophysiology of Vision (ISCEV). 18 19  
Ascertainment of Control Subjects
Healthy control individuals were recruited from anonymous male blood donors referred by the Blood Service of the Hospital. Subjects previously provided a signed informed consent, as well as their nationality, age, and sex. Thus, the ethnic background of recently immigrated individuals was ruled out. The control group was free of any ocular disease. 
Molecular Analysis
DNA Extraction.
Peripheral blood samples with EDTA anticoagulant were collected from each member of the family. Genomic DNA was extracted using an automated DNA extractor (BioRobot EZ1; Qiagen, Hilden, Germany). Before use, DNA samples were preserved frozen. 
Direct Sequencing.
The six exons of the RS1 gene, including intron–exon junctions were amplified by PCR with published primers. 9 These fragments were electrophoresed in a 3% agarose gel and purified with a DNA extraction kit (QIA-quick Gel Extraction Kit; Qiagen, Hilden, Germany). Sequencing reactions were performed with a four-dye terminator, cycle-sequencing, ready-reaction kit (BigDye DNA Sequencing Kit; Applied Biosystems, Inc., Foster City, CA). Sequence products were purified through fine columns (Sephadex G-501; Princetown Separations, Adelphia, NJ) and resolved on a sequencer (ABI Prism 3130; Applied Biosystems). 
In addition, the presence of novel mutations located on exons 4, 5, and 6 of the RS1 gene were analyzed in 100 male control chromosomes by direct sequencing. 
Haplotype Analysis
Haplotypes were generated by using three microsatellite markers flanking the RS1 gene (TEL-DXS9911-RS1-DXS999-DXS989-CEN). In several patients, four additional microsatellite markers were amplified (TEL-DXS8022-DXS1053-DXS8019-DXS9911-RS1-DXS999-DXS1226-DXS989-CEN) to determine whether they shared a common haplotype. After amplification by PCR, fluorescent-labeled products were mixed and electrophoresed (ABI Prism 3130; Applied Biosystems, Inc.). For haplotype reconstruction, an informatic program was used (Cyrillic ver. 2.1; Cyrillic Software, Wallingford, UK). 
Statistical Analysis
For genotype–phenotype correlation studies, a χ2 test was performed to examine the correlation between specific RS1 variants, p.Gln154Arg, p.Glu72Lys, p.His194fsX263 and p.Pro203Leu, and specific ophthalmic complications: retinal detachment, vitreous hemorrhage, and strabismus. In addition, visual acuity was further compared among patients who did or did not have any of these complications. Statistical analyses were performed on computer (SPSS 10.0 Software; SPSS, Chicago, IL), and P < 0.05 was considered a statistically significant difference. 
Results
Molecular Findings
Thirty-four Spanish families with XLRS, comprising 51 male patients, were evaluated, and 20 different hemizygous nucleotide substitutions were detected. Most disease alleles carried missense mutations (17/20; 85.0%). However, frameshift variants (2/20; 10.0%) and one nonsense mutation (1/20; 5.0%) were also identified in XLRS chromosomes. All mutations were clustered in exons 4, 5, and 6 encoding the discoidin domain. Most of the mutations detected have been reported as XLRS-associated variants, namely: p.Glu72Lys, p.Tyr89Cys, p.Arg141Cys, p.His194fsX263, p.Arg197Cys, p.Pro203Leu, p.Arg209His, p.Arg213Gln, p.Glu215Gln, and p.Leu216Pro. In addition, 10 novel disease-associated variants were identified: p.Gln80Ter, p.Leu137Pro, p.Thr138fsX, p.Gln154Arg, p.Pro192Leu, p.Ile194Asn, p.Arg197Ser, p.Arg200Ser, p.His207Asp, and p.Glu215Val (Table 1) . These alleles were absent in 100 Spanish ethnically matched control chromosomes, and cosegregated within the families, suggesting that they are pathologic. 
Common Haplotypes
The most frequent RS1 variant in the Spanish XLRS population was the missense p.Gln154Arg (c.461A>G) mutation, being present in 17.64% (6/34) families. Haplotype analyses with seven microsatellite markers (TEL-DXS8022-DXS1053-DXS8019-DXS9911-RS1-DXS999-DXS1226-DXS989-CEN), spanning over 12.65 cM, were amplified in affected members from these six families. This molecular study showed that the common piece of DNA comprises 6.32 cM between the DXS1053 and DXS999 markers, which suggests a founder effect (Fig. 1A)
The missense p.Tyr89Cys mutation in exon 4 of the RS1 gene was identified in two Spanish families. Allelic segregation analysis was performed in the index case of XLRS-44 and in all family members from XLRS-306. A common haplotype was demonstrated between the markers DXS8022 and DXS989 (12.65 cM), suggesting a common ancestry (Fig. 1B)
Recurrent Mutations
The second most frequent mutation was p.Glu72Lys (c.214G>A), 20 which was identified in five families. Nevertheless, these cohorts seemed not to be related, since they did not exhibit the same haplotype (Fig. 2A)
The third most frequent mutation was the p.His194fsX263 variant, which was identified in three unrelated families and most likely was of independent origin (Fig. 2B)
The novel missense p.Glu215Val (c.644A>T) mutation, in exon 6 of the RS1 gene was identified in families XLRS-101 and XLRS-320. Allelic segregation analysis was performed in all family members, and the disease-associated haplotype segregated within the families. In addition, haplotype construction demonstrated an independent origin (Fig. 2C)
De Novo Mutational Events
In XLRS-108, a novel nonsense mutation was identified in an affected child: a C-to-T change at nucleotide 238 in exon 4 of the RS1 gene, where glutamine was replaced by a stop codon at codon 80 (p.Gln80Ter [c.238C>T]) (Table 1) . This change was not detected in his mother, indicating a de novo event. In addition, p.Glu72Lys was detected as a de novo mutation in XLRS-43. In this family, this variant occurred for the first time in a carrier mother who had two affected male twins (Fig. 2A) . The p.Pro203Leu variant was identified in two families. Haplotype analysis demonstrated independent origin for this RS1 mutation. Similar to family XLRS-43, in family XLRS-199, this mutation was described for the first time in a carrier mother of two affected twins (Fig. 2D) . Of interest, these de novo mutations were located on CG dinucleotides (Table 1)
Genotype–Phenotype Correlation
The summary of clinical and genetic findings is presented in Table 2 2 . In general, clinical data demonstrated intra- and interfamilial variability (i.e., age at onset ranged from congenital to the 2nd decade of life). Also, patients’ visual acuity varied from counting fingers to 60/100, or a wide variation was observed between both eyes. 
Three main general symptoms were observed: (1) Retinal schisis: 92.7% of the patients presented macular schisis, whereas only 24.4% also showed peripheral schisis; (2) vitreous abnormalities: 46.3% of the affected individuals presented vitreoretinal proliferation, vitreous degeneration, or persistent hyperplastic primary vitreous; (3) abnormal ERG: in every patient in whom ERG was performed, it showed alterations, mainly in the b-wave amplitude, ranging from reduced to extinguished. Besides, additional ophthalmic findings were observed in less proportion: cataracts (31.8%), amblyopia (31.8%), scotomas—mainly associated with schisis areas—(31.8%), photophobia (27.3%), or nyctalopia (27.3%). Finally, in elder subjects (>40 years old), retinal pigment epithelium (RPE) atrophy, pigment spots, optic pallor, and vascular abnormalities were observed. 
In family XLRS-112, we identified two brothers bearing the p.Arg209His (c.626G>A) mutation. Of interest, one of them presented with typical retinoschisis symptoms, whereas his brother was asymptomatic at the age of 39. 
Despite typical clinical features of XLRS—macular schisis, microcysts, and vitreous veils—additional ophthalmic findings of retinal detachment, vitreous hemorrhage, and strabismus were evaluated in patients presenting the most frequent RS1 variants: p.Gln154Arg, p.Glu72Lys, p.His194fsX263, and p.Pro203Leu. To determine whether these retinal complications were associated with specific mutations in the patients, we further compared both parameters by χ2 test (P = 0.05). This analysis revealed that RS1 variants did not correlate with these ophthalmologic complications and were not associated with retinal detachment, vitreous hemorrhage, or strabismus. 
Discussion
In this study, we examined RS1 gene mutations from 51 affected males belonging to 34 Spanish families and evaluated genotype–phenotype correlations in these patients. Twenty different hemizygous nucleotide substitutions in the coding region of the gene were identified, of which 14 were found only once. The majority of these (17/20) were missense mutations, although nonsense mutations (1/20), insertions (1/20), and deletions (1/20) have all been found. Of these 20 variants, 10 were not previously reported. 
All mutations were not distributed randomly over the gene, as all them were found in exons 4, 5, and 6 encoding the discoidin domain, which extends from amino acids 63-219 21 and has been considered critical for RS1 function. Our mutation analysis also revealed a high prevalence of mutations involving cysteine residues, pointing to sites important in the tertiary folding and protein function (Table 1)
Common Ancestries versus Hot Spots
The most frequent substitution was the novel p.Gln154Arg variant, identified in six Spanish families, affecting five males and one carrier female. Once haplotypes were constructed, all affected members demonstrated a common haplotype, therefore suggesting identity by descent (Fig. 1A) . Of interest, only another nucleotide change has been described at codon 154, p.Gln154Ter, in one family from the UK. 21 As these variants do not lie on a CpG dinucleotide, this site may be less frequently hit by mutations. Consequently, we suspected that once it was mutated, p.Gln154Arg was inherited from a common ancestor. This finding may indicate the possibility of a founder effect in the Spanish population. Five (71.4%) of the seven patients carrying the p.Gln154Arg mutation presented symptoms early in life, and three (42.8%) of them also showed such ophthalmic complications as retinal detachment (2/7), vitreous hemorrhage (1/7), and strabismus (1/7; Table 2 2 ). 
Besides, the p.Tyr89Cys variant was identified in two unrelated families (Fig. 1B) . Affected members from both cohorts shared a larger piece of DNA (12.65 cM) than did the p.Gln154Arg families (6.32 cM). Therefore, a more recent origin for p.Tyr89Cys was suspected. 
Hot Spots and De Novo Mutational Events
The second most frequent alteration was p.Glu72Lys, which was identified in five unrelated Spanish families. As previously described, p.Glu72Lys is the most common RS founder mutation in Finland 20 and has also been reported numerous times in many different populations. 21 Nevertheless, in our population this variant resembled a recurrent mutational event rather than a founder effect, as haplotypes demonstrated independent origins. Moreover, this mutation arose de novo in a carrier woman who had two affected twins (Fig. 2A) . The patients presented various ages at onset, ranging from a few months to >20 years. Of them, 28.5% showed vascular abnormalities and 57.1% presented additional complications that required treatment: surgical correction of retinal detachment and strabismus and photocoagulation for vitreous hemorrhage (Table 2) 2
The third most frequent variant was the c.578_579insC (p.His194fsX263) frameshift mutation, identified in three Spanish families presenting different haplotypes (Fig. 2B) . This insertion has been described in three unrelated families from Austria, the United Kingdom, and the United States. Moreover, in this stretch of cytosine nucleotides (positions 574-579) another five different mutations have been additionally identified in 18 unrelated families. 21 These recurrent mutational events across populations further suggest that this tract is a definite hot spot in RS1
Finally, the missense p.Glu215Val substitution was observed in two Spanish families. Although this mutation was first described in these cohorts and a possible common ancestor was possible, haplotype analysis demonstrated independent origins (Fig. 2C)
De Novo Mutational Events and CpG Dinucleotides
Three de novo mutations were identified in our set of families, representing a frequency of 8.8% (3/34; Table 1 ). These three variants—p.Gln80Ter (c.238C>T); p.Glu72Lys (c.214G>A); and p.Pro203Leu (c.608C>T)—lie on CG dinucleotides. 
RS1 contains 26 CpG dinucleotides, accounting for ∼7.7% of the coding sequence of the gene. We analyzed all point mutations identified in RS1 so far (www.hgdm.cf.ac.uk) and we found that ∼18.5% of them occur at these sites. This percentage could suggest one of the main causes for mutational events in the RS1 gene, therefore providing direct evidence of multiple origins of XLRS and different mutation frequencies across populations. 
In conclusion, we observed that RS1 mutations identified in two or more families and presenting different haplotypes, occurred at CG dinucleotides in 50% of the cases. Nevertheless, de novo mutations occurred in CG dinucleotides in 100% of the cases. 
Phenotype–Genotype Correlation
In our Spanish patients with XLRS, we found that the RS1 mutation spectrum is large. Their phenotype is relatively uniform for three main ophthalmic findings—retinal schisis, vitreous abnormalities, and altered ERG b-wave amplitude—although showed wide inter- and intrafamilial variation in terms of age of onset and progression. Moreover, this study revealed that RS1 variants did not correlate with additional ophthalmic complications, being not significantly associated with retinal detachment, vitreous hemorrhage, or strabismus. Nevertheless, the knowledge of Spanish mutational spectrum led to the identification of a founder effect for a novel RS1 variant (p.Gln154Arg), which mainly causes early onset of the disease. 
Thus, identifying the causative mutation in patients with XLRS is helpful for confirming diagnosis and counseling of family members, although an asymptomatic male is reported in this work, but cannot predict the likely course of the disease for an individual patient. 
Although crucial, extensive phenotyping of Spanish patients with XLRS did not allow the assessment of a certain prognosis for the wide spectrum of RS1 variants, since no genotype–phenotype correlation was demonstrated. Nevertheless, patients could receive accurate counseling and be informed about possible ophthalmic complications that can be surgically treated (i.e., retinopexia for retinal detachment, surgical correction of strabismus). Therefore, patient education and close follow-up are the only clinical alternatives for early identification and treatment of vision-threatening complications. 
To our knowledge, this study represents the first report of RS1 mutations in Spanish patients with XLRS and provides further evidence of different mutation frequency across populations. 
 
Table 1.
 
Summarized RS1 Mutations in Spanish X-Linked Juvenile Retinoschisis Pedigrees
Table 1.
 
Summarized RS1 Mutations in Spanish X-Linked Juvenile Retinoschisis Pedigrees
Pedigrees n Exon Nucleotide Change Amino Acid Change Predicted Effect Frequency (%)
43*, 93, 104, 185, 189 5 4 c.2I4G>A p.Glu72Lys Missense 14.70
108* 1 4 c.238C>T p.Gln80Ter Nonsense 2.94
44, 306 2 4 c.266A>G p.Tyr89Cys Missense 5.90
102 1 5 c.410T>C p.Leu137Pro Missense 2.94
250 1 5 c.412_421del p.Thr138fsX145 Frameshift 2.94
95 1 5 c.421C>T p.Arg141Cys Missense 2.94
30, 70, 97, 143, 161, 219 6 5 c.461A>G p.Gln154Arg Missense 17.64
217 1 6 c.575C>T p.Pro192Leu Missense 2.94
53, 55, 124 3 6 c.578_579insC p.His194fsX263 Frameshift 8.82
321 1 6 c.581T>A p.Ile194Asn Missense 2.94
162bis 1 6 c.589C>A p.Arg197Ser Missense 2.94
145 1 6 c.589C>T p.Arg197Cys Missense 2.94
322 1 6 c.598C>A p.Arg200Ser Missense 2.94
199*, 268 2 6 c.608C>T p.Pro203Leu Missense 5.90
276 1 6 c.619C>G p.His207Asp Missense 2.94
112 1 6 c.626G>A p.Arg209His Missense 2.94
45 1 6 c.638G>A p.Arg213Gln Missense 2.94
29 1 6 c.643G>C p.Glu215Gln Missense 2.94
101, 320 2 6 c.644A>T p.Glu215Val Missense 5.90
107 1 6 c.647T>C p.Leu216Pro Missense 2.94
Total 34
Figure 1.
 
XLRS pedigrees presenting common haplotypes for p.Gln154Arg and p.Tyr89Cys variants. (A) Haplotype analyses from p.Gln154Arg affected males and one carrier woman (simplified pedigrees). The displayed region shows seven microsatellite markers spanning over 12.65 cM. p.Gln154Arg-mutation-bearing patients shared a common piece of 6.32-cM DNA (between the markers DXS1053 and DXS999), whereas the distal markers (DXS8022, DXS1226, and DXS989) differed among them. In family XLRS-219, the DXS8019 marker (153 bp) differed by two base pairs from that in the remaining families (155 bp) which could be explained by microsatellite instability. (B) The missense p.Tyr89Cys mutation, in exon 4 of the RS1 gene, was identified in two Spanish families (simplified pedigree from XLRS-44). Haplotype construction demonstrated a common haplotype between DXS8022 and DXS989, suggesting a common ancestry. In family XLRS-306, we observed two sisters, one carrier (I:2) and one noncarrier (I:3), who shared the same haplotype. A de novo mutational event is possible in the carrier. However, it cannot be ruled out that markers were not informative for the women’s parents.
Figure 1.
 
XLRS pedigrees presenting common haplotypes for p.Gln154Arg and p.Tyr89Cys variants. (A) Haplotype analyses from p.Gln154Arg affected males and one carrier woman (simplified pedigrees). The displayed region shows seven microsatellite markers spanning over 12.65 cM. p.Gln154Arg-mutation-bearing patients shared a common piece of 6.32-cM DNA (between the markers DXS1053 and DXS999), whereas the distal markers (DXS8022, DXS1226, and DXS989) differed among them. In family XLRS-219, the DXS8019 marker (153 bp) differed by two base pairs from that in the remaining families (155 bp) which could be explained by microsatellite instability. (B) The missense p.Tyr89Cys mutation, in exon 4 of the RS1 gene, was identified in two Spanish families (simplified pedigree from XLRS-44). Haplotype construction demonstrated a common haplotype between DXS8022 and DXS989, suggesting a common ancestry. In family XLRS-306, we observed two sisters, one carrier (I:2) and one noncarrier (I:3), who shared the same haplotype. A de novo mutational event is possible in the carrier. However, it cannot be ruled out that markers were not informative for the women’s parents.
Figure 2.
 
Pedigrees from Spanish families presenting the same RS1 variants but different haplotypes. (A) Pedigrees from families having the p.Glu72Lys mutation (bold). Haplotypes indicated an independent origin for this variant. *Individual II:2 from XLRS-43, with a de novo mutational event. (B) Pedigrees from families presenting the p.His194fsX263 mutation (bold). Haplotypes indicate an independent origin for this variant. (C) The novel missense p.Glu215Val (c.644A>T) mutation (bold), in exon 6 of the RS1 gene was identified in families XLRS-101 and XLRS-320. Allelic segregation analysis was performed in all family members, and the disease-associated haplotype segregated within the families. In addition, haplotype construction demonstrated an independent origin. (D) The p.Pro203Leu (c.608C>T) variant was identified in two families (bold). Haplotype analysis demonstrated independent origin for this RS1 mutation. *Individual II:2 from XLRS-199, with a de novo mutational event. (A, B, C, D) Arrows indicate the index case.
Figure 2.
 
Pedigrees from Spanish families presenting the same RS1 variants but different haplotypes. (A) Pedigrees from families having the p.Glu72Lys mutation (bold). Haplotypes indicated an independent origin for this variant. *Individual II:2 from XLRS-43, with a de novo mutational event. (B) Pedigrees from families presenting the p.His194fsX263 mutation (bold). Haplotypes indicate an independent origin for this variant. (C) The novel missense p.Glu215Val (c.644A>T) mutation (bold), in exon 6 of the RS1 gene was identified in families XLRS-101 and XLRS-320. Allelic segregation analysis was performed in all family members, and the disease-associated haplotype segregated within the families. In addition, haplotype construction demonstrated an independent origin. (D) The p.Pro203Leu (c.608C>T) variant was identified in two families (bold). Haplotype analysis demonstrated independent origin for this RS1 mutation. *Individual II:2 from XLRS-199, with a de novo mutational event. (A, B, C, D) Arrows indicate the index case.
Table 2.
 
Summarized Clinical and Genetic Data of 43 Male Patients Belonging to 34 Spanish XLRS Families
Table 2.
 
Summarized Clinical and Genetic Data of 43 Male Patients Belonging to 34 Spanish XLRS Families
Mutation Family Age at Onset Age (y) Visual Acuity (RE/LE) Vitreous Findings Vascular Abnormalities Macular Findings Peripheral Schisis
Number Subject
p.Glu72Lys XLRS-43* Proband 4 Months 10 20/100 Normal Yes Normal Yes
p.Glu72Lys XLRS-93 Proband 12 Years 36 50/100 Vitreous veils No Macular microcysts Yes
p.Glu72Lys XLRS-104 Proband 8 Years 19 10/100 Vitreous veils No Macular schisis, macular cycts Yes
p.Glu72Lys XLRS-104 Cousin 7 Years 11 40/100 Normal No Macular schisis No
p.Glu72Lys XLRS-185 Proband 6 Months 4 Vitreous veils No Normal Yes
p.Glu72Lys XLRS-189 Proband 21 Years 59 10/100 Vitreous veils Retinal vasculitis Macular schisis No
p.Glu72Lys XLRS-189 Brother 12 Years 42 Normal Macular schisis No
p.Gln80Ter XLRS-108* Proband 9 Years 9
p.Tyr89Cys XLRS-44 Proband 10 Years 54 10/100 Vitreous veils No Macular RPE atrophy, optic pallor No
p.Tyr89Cys XLRS-306 Proband 16 Years 25 20/100 Vitreous veils No Macular schisis No
p.Leu137Pro XLRS-102 Proband 6 Years 24 20/100 Normal No Macular schisis, macular cysts Yes
p.Thr138fsX145 XLRS-250 Proband Congenital 48 10/100 Vitreoretinal degeneration No Macular schisis No
p.Arg141Cys XLRS-95 Proband 4 Years 42 10/100 Vitreoretinal degeneration Dendritiform blood vessels Macular RPE atrophy, chorioretinal atrophy, pigment spots No
p.Gln154Arg XLRS-30 Proband 18 Months 24 Vitreoretinal proliferation No Schisis of the macula, cavities in the inner retina No
p.Gln154Arg XLRS-30 Grandfather 15 Years 10/100 Normal No Macular schisis No
p.Gln154Arg XLRS-70 Son 1 Year 5 Vitreous veils Peripheral exudates Microcystic macular degeneration, separation of the inner retinal layers No
p.Gln154Arg XLRS-97 Proband 6 Months 6 Vitreous veils No Macular schisis Yes
p.Gln154Arg XLRS-143 Proband 2 Years 9 20/100 Normal No Macular schisis Yes
p.Gln154Arg XLRS-161 Proband 1 Year 5 Normal No Macular schisis No
p.Gln154Arg XLRS-219 Proband 11 Years 15 70/100 Vitreous veils No Normal Yes
p.Pro192Leu XLRS-217 Proband 2 Years 4 Normal No Macular schisis No
p.His194fsX263 XLRS-53 Proband 3 Years 12 30/100 Macular folds No Macular schisis No
p.His194fsX263 XLRS-53 Brother 15 Months 14 50/100; CF Macular folds Yes Macular schisis No
p.His194fsX263 XLRS-53 Uncle 5 Years 33
p.His194fsX263 XLRS-55 Proband 4 Years 45 5/100 Vitreoretinal degeneration Thin vessels Optic pallor, peripheral pigment spots No
p.His194fsX263 XLRS-124 Proband 7 Years 17 60/100; 70/100 Normal No Macular schisis No
p.Ile194Asn XLRS-321 Proband 12 Years 13 40/100 Normal No Macular schisis No
p.Arg197Ser ARRP-162bis Proband 7 Years 49 10/100 Normal Thin vessels Optic pallor, pigment spots, macular microcysts No
p.Arg197Ser ARRP-162bis Brother 25 Years 45 40/100; CF Vitreous veils No Macular schisis, macular cysts No
p.Arg197Cys XLRS-145 Proband 3 Years 27 40/100 Normal No Macular schisis No
p.Arg200Ser XLRS-322 Proband 10 Years 11 5/100; 40/100 Normal No Macular schisis No
p.Arg200Ser XLRS-322 Brother 14 Years 14 Normal No Macular schisis No
p.Pro203Leu XLRS-199* Proband 7 Years 10 40/100 Normal No Radial pattern of macular schisis, macular cycts No
p.Pro203Leu XLRS-199* Brother 7 Years 10 40/100 Normal No Radial pattern of macular schisis, macular cysts No
p.Pro203Leu XLRS-268 Proband 6 Months 2 Normal No Macular cysts Yes
p.His207Asp XLRS-276 Proband 3 Years 15 30/100 Vitreous veils No Radial pattern of macular schisis, macular cysts No
p.Arg209His XLRS-112 Proband Congenital 36 2/100 Persistent hyperplastic primary vitreous No Macular schisis No
p.Arg213Gln XLRS-45 Proband 7 Years 20 10/100 Normal No Macular schisis Yes
p.Glu215Gln XLRS-29 Proband 5 Years 23 20/100; 10/100 Normal No Microcysts in maculas No
p.Glu215Gln XLRS-29 Second uncle 28 Years 55 10/100 Normal No Microcysts in maculas No
p.Glu215Val XLRS-101 Proband 2 Years 25 30/100; 40/100 Normal No Bilateral macular lesion No
p.Glu215Val XLRS-320 Proband 8 Years 9 50/100 Normal No Macular schisis No
p.Leu216Pro XLRS-107 Proband 13 Years 28 30/100; 20/100 Vitreous veils No Macular schisis No
Table 2A.
Table 2A.
Electroretinogram Others Additional Ophthalmic Complications
Retinal Detachment Age of Surgical Correction Vitreous Hemorrhage Age at Surgical Correction Strabismus Age at Surgical Correction
Reduced Astigmatism, hypermetropia Yes 4 Months No Yes 5 Months
Amblyopia No Yes 14 Years Yes Childhood
Reduced b-wave amplitude No Yes 14 Years No
No No No
Amblyopia Yes 1 Year No Yes 4 Months
Cystoid macular edema, dyschromatopsia, photophobia No No No
No No No
No recordable b-wave Cataracts, absolute scotomas No No No
Reduced a-wave and b-wave ampitudes No No No
No recordable b-wave No Yes 6 Years No
Myopia Yes 46 Years No No
Extinguished Cataracts No No No
Extinguished Yes 18 Months Yes 2 Years No
Cataracts Yes 15 Years No No
Reduced b-wave amplitude Hypermetropia, strabismus No No No
No No Yes 6 Months
Reduced b-wave amplitude No No No
Reduced b-wave amplitude No No No
Reduced b-wave amplitude Amblyopia, astigmatism, myopia, scotomas No No No
No No No
Hyperopia No No Yes 3 Years
No Yes 15 Months No
Reduced Amblyopia, myopia, mystagmus, scotomas No No No
No recordable b-wave Dyschromatopsia, photophobia No No No
No No No
Extinguished Cataract, dyschromatopsia, nyctalopia, photophobia Yes 7 Years No No
No recordable b-wave Amblyopia, nyctalopia, photophobia, scotomas No No Yes 32 Years
Reduced b-wave amplitude No No No
Congenital cataracts No No No
Congenital cataracts No No No
No No No
No No No
No No No
No No No
Congenital cataracts No No No
Reduced b-wave amplitude Nyctalopia No No No
No recordable b-wave Amblyopia, nyctalopia, photophobia, scotomas No Yes 5 Years No
No recordable b-wave Nyctalopia, hemeralopia, photophobia, scotomas No No No
Extinguished Amblyopia, nyctalopia, photophobia, strabismus No No No
No No No
Reduced b-wave amplitude No No No
The authors thank Rafael Navarro for the clinical evaluation of patients, the Blood Service of the Fundacion Jimenez Diaz Hospital for their efforts in obtaining blood samples from control individuals, and all the patients who participated in the study. 
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Figure 1.
 
XLRS pedigrees presenting common haplotypes for p.Gln154Arg and p.Tyr89Cys variants. (A) Haplotype analyses from p.Gln154Arg affected males and one carrier woman (simplified pedigrees). The displayed region shows seven microsatellite markers spanning over 12.65 cM. p.Gln154Arg-mutation-bearing patients shared a common piece of 6.32-cM DNA (between the markers DXS1053 and DXS999), whereas the distal markers (DXS8022, DXS1226, and DXS989) differed among them. In family XLRS-219, the DXS8019 marker (153 bp) differed by two base pairs from that in the remaining families (155 bp) which could be explained by microsatellite instability. (B) The missense p.Tyr89Cys mutation, in exon 4 of the RS1 gene, was identified in two Spanish families (simplified pedigree from XLRS-44). Haplotype construction demonstrated a common haplotype between DXS8022 and DXS989, suggesting a common ancestry. In family XLRS-306, we observed two sisters, one carrier (I:2) and one noncarrier (I:3), who shared the same haplotype. A de novo mutational event is possible in the carrier. However, it cannot be ruled out that markers were not informative for the women’s parents.
Figure 1.
 
XLRS pedigrees presenting common haplotypes for p.Gln154Arg and p.Tyr89Cys variants. (A) Haplotype analyses from p.Gln154Arg affected males and one carrier woman (simplified pedigrees). The displayed region shows seven microsatellite markers spanning over 12.65 cM. p.Gln154Arg-mutation-bearing patients shared a common piece of 6.32-cM DNA (between the markers DXS1053 and DXS999), whereas the distal markers (DXS8022, DXS1226, and DXS989) differed among them. In family XLRS-219, the DXS8019 marker (153 bp) differed by two base pairs from that in the remaining families (155 bp) which could be explained by microsatellite instability. (B) The missense p.Tyr89Cys mutation, in exon 4 of the RS1 gene, was identified in two Spanish families (simplified pedigree from XLRS-44). Haplotype construction demonstrated a common haplotype between DXS8022 and DXS989, suggesting a common ancestry. In family XLRS-306, we observed two sisters, one carrier (I:2) and one noncarrier (I:3), who shared the same haplotype. A de novo mutational event is possible in the carrier. However, it cannot be ruled out that markers were not informative for the women’s parents.
Figure 2.
 
Pedigrees from Spanish families presenting the same RS1 variants but different haplotypes. (A) Pedigrees from families having the p.Glu72Lys mutation (bold). Haplotypes indicated an independent origin for this variant. *Individual II:2 from XLRS-43, with a de novo mutational event. (B) Pedigrees from families presenting the p.His194fsX263 mutation (bold). Haplotypes indicate an independent origin for this variant. (C) The novel missense p.Glu215Val (c.644A>T) mutation (bold), in exon 6 of the RS1 gene was identified in families XLRS-101 and XLRS-320. Allelic segregation analysis was performed in all family members, and the disease-associated haplotype segregated within the families. In addition, haplotype construction demonstrated an independent origin. (D) The p.Pro203Leu (c.608C>T) variant was identified in two families (bold). Haplotype analysis demonstrated independent origin for this RS1 mutation. *Individual II:2 from XLRS-199, with a de novo mutational event. (A, B, C, D) Arrows indicate the index case.
Figure 2.
 
Pedigrees from Spanish families presenting the same RS1 variants but different haplotypes. (A) Pedigrees from families having the p.Glu72Lys mutation (bold). Haplotypes indicated an independent origin for this variant. *Individual II:2 from XLRS-43, with a de novo mutational event. (B) Pedigrees from families presenting the p.His194fsX263 mutation (bold). Haplotypes indicate an independent origin for this variant. (C) The novel missense p.Glu215Val (c.644A>T) mutation (bold), in exon 6 of the RS1 gene was identified in families XLRS-101 and XLRS-320. Allelic segregation analysis was performed in all family members, and the disease-associated haplotype segregated within the families. In addition, haplotype construction demonstrated an independent origin. (D) The p.Pro203Leu (c.608C>T) variant was identified in two families (bold). Haplotype analysis demonstrated independent origin for this RS1 mutation. *Individual II:2 from XLRS-199, with a de novo mutational event. (A, B, C, D) Arrows indicate the index case.
Table 1.
 
Summarized RS1 Mutations in Spanish X-Linked Juvenile Retinoschisis Pedigrees
Table 1.
 
Summarized RS1 Mutations in Spanish X-Linked Juvenile Retinoschisis Pedigrees
Pedigrees n Exon Nucleotide Change Amino Acid Change Predicted Effect Frequency (%)
43*, 93, 104, 185, 189 5 4 c.2I4G>A p.Glu72Lys Missense 14.70
108* 1 4 c.238C>T p.Gln80Ter Nonsense 2.94
44, 306 2 4 c.266A>G p.Tyr89Cys Missense 5.90
102 1 5 c.410T>C p.Leu137Pro Missense 2.94
250 1 5 c.412_421del p.Thr138fsX145 Frameshift 2.94
95 1 5 c.421C>T p.Arg141Cys Missense 2.94
30, 70, 97, 143, 161, 219 6 5 c.461A>G p.Gln154Arg Missense 17.64
217 1 6 c.575C>T p.Pro192Leu Missense 2.94
53, 55, 124 3 6 c.578_579insC p.His194fsX263 Frameshift 8.82
321 1 6 c.581T>A p.Ile194Asn Missense 2.94
162bis 1 6 c.589C>A p.Arg197Ser Missense 2.94
145 1 6 c.589C>T p.Arg197Cys Missense 2.94
322 1 6 c.598C>A p.Arg200Ser Missense 2.94
199*, 268 2 6 c.608C>T p.Pro203Leu Missense 5.90
276 1 6 c.619C>G p.His207Asp Missense 2.94
112 1 6 c.626G>A p.Arg209His Missense 2.94
45 1 6 c.638G>A p.Arg213Gln Missense 2.94
29 1 6 c.643G>C p.Glu215Gln Missense 2.94
101, 320 2 6 c.644A>T p.Glu215Val Missense 5.90
107 1 6 c.647T>C p.Leu216Pro Missense 2.94
Total 34
Table 2.
 
Summarized Clinical and Genetic Data of 43 Male Patients Belonging to 34 Spanish XLRS Families
Table 2.
 
Summarized Clinical and Genetic Data of 43 Male Patients Belonging to 34 Spanish XLRS Families
Mutation Family Age at Onset Age (y) Visual Acuity (RE/LE) Vitreous Findings Vascular Abnormalities Macular Findings Peripheral Schisis
Number Subject
p.Glu72Lys XLRS-43* Proband 4 Months 10 20/100 Normal Yes Normal Yes
p.Glu72Lys XLRS-93 Proband 12 Years 36 50/100 Vitreous veils No Macular microcysts Yes
p.Glu72Lys XLRS-104 Proband 8 Years 19 10/100 Vitreous veils No Macular schisis, macular cycts Yes
p.Glu72Lys XLRS-104 Cousin 7 Years 11 40/100 Normal No Macular schisis No
p.Glu72Lys XLRS-185 Proband 6 Months 4 Vitreous veils No Normal Yes
p.Glu72Lys XLRS-189 Proband 21 Years 59 10/100 Vitreous veils Retinal vasculitis Macular schisis No
p.Glu72Lys XLRS-189 Brother 12 Years 42 Normal Macular schisis No
p.Gln80Ter XLRS-108* Proband 9 Years 9
p.Tyr89Cys XLRS-44 Proband 10 Years 54 10/100 Vitreous veils No Macular RPE atrophy, optic pallor No
p.Tyr89Cys XLRS-306 Proband 16 Years 25 20/100 Vitreous veils No Macular schisis No
p.Leu137Pro XLRS-102 Proband 6 Years 24 20/100 Normal No Macular schisis, macular cysts Yes
p.Thr138fsX145 XLRS-250 Proband Congenital 48 10/100 Vitreoretinal degeneration No Macular schisis No
p.Arg141Cys XLRS-95 Proband 4 Years 42 10/100 Vitreoretinal degeneration Dendritiform blood vessels Macular RPE atrophy, chorioretinal atrophy, pigment spots No
p.Gln154Arg XLRS-30 Proband 18 Months 24 Vitreoretinal proliferation No Schisis of the macula, cavities in the inner retina No
p.Gln154Arg XLRS-30 Grandfather 15 Years 10/100 Normal No Macular schisis No
p.Gln154Arg XLRS-70 Son 1 Year 5 Vitreous veils Peripheral exudates Microcystic macular degeneration, separation of the inner retinal layers No
p.Gln154Arg XLRS-97 Proband 6 Months 6 Vitreous veils No Macular schisis Yes
p.Gln154Arg XLRS-143 Proband 2 Years 9 20/100 Normal No Macular schisis Yes
p.Gln154Arg XLRS-161 Proband 1 Year 5 Normal No Macular schisis No
p.Gln154Arg XLRS-219 Proband 11 Years 15 70/100 Vitreous veils No Normal Yes
p.Pro192Leu XLRS-217 Proband 2 Years 4 Normal No Macular schisis No
p.His194fsX263 XLRS-53 Proband 3 Years 12 30/100 Macular folds No Macular schisis No
p.His194fsX263 XLRS-53 Brother 15 Months 14 50/100; CF Macular folds Yes Macular schisis No
p.His194fsX263 XLRS-53 Uncle 5 Years 33
p.His194fsX263 XLRS-55 Proband 4 Years 45 5/100 Vitreoretinal degeneration Thin vessels Optic pallor, peripheral pigment spots No
p.His194fsX263 XLRS-124 Proband 7 Years 17 60/100; 70/100 Normal No Macular schisis No
p.Ile194Asn XLRS-321 Proband 12 Years 13 40/100 Normal No Macular schisis No
p.Arg197Ser ARRP-162bis Proband 7 Years 49 10/100 Normal Thin vessels Optic pallor, pigment spots, macular microcysts No
p.Arg197Ser ARRP-162bis Brother 25 Years 45 40/100; CF Vitreous veils No Macular schisis, macular cysts No
p.Arg197Cys XLRS-145 Proband 3 Years 27 40/100 Normal No Macular schisis No
p.Arg200Ser XLRS-322 Proband 10 Years 11 5/100; 40/100 Normal No Macular schisis No
p.Arg200Ser XLRS-322 Brother 14 Years 14 Normal No Macular schisis No
p.Pro203Leu XLRS-199* Proband 7 Years 10 40/100 Normal No Radial pattern of macular schisis, macular cycts No
p.Pro203Leu XLRS-199* Brother 7 Years 10 40/100 Normal No Radial pattern of macular schisis, macular cysts No
p.Pro203Leu XLRS-268 Proband 6 Months 2 Normal No Macular cysts Yes
p.His207Asp XLRS-276 Proband 3 Years 15 30/100 Vitreous veils No Radial pattern of macular schisis, macular cysts No
p.Arg209His XLRS-112 Proband Congenital 36 2/100 Persistent hyperplastic primary vitreous No Macular schisis No
p.Arg213Gln XLRS-45 Proband 7 Years 20 10/100 Normal No Macular schisis Yes
p.Glu215Gln XLRS-29 Proband 5 Years 23 20/100; 10/100 Normal No Microcysts in maculas No
p.Glu215Gln XLRS-29 Second uncle 28 Years 55 10/100 Normal No Microcysts in maculas No
p.Glu215Val XLRS-101 Proband 2 Years 25 30/100; 40/100 Normal No Bilateral macular lesion No
p.Glu215Val XLRS-320 Proband 8 Years 9 50/100 Normal No Macular schisis No
p.Leu216Pro XLRS-107 Proband 13 Years 28 30/100; 20/100 Vitreous veils No Macular schisis No
Table 2A.
Table 2A.
Electroretinogram Others Additional Ophthalmic Complications
Retinal Detachment Age of Surgical Correction Vitreous Hemorrhage Age at Surgical Correction Strabismus Age at Surgical Correction
Reduced Astigmatism, hypermetropia Yes 4 Months No Yes 5 Months
Amblyopia No Yes 14 Years Yes Childhood
Reduced b-wave amplitude No Yes 14 Years No
No No No
Amblyopia Yes 1 Year No Yes 4 Months
Cystoid macular edema, dyschromatopsia, photophobia No No No
No No No
No recordable b-wave Cataracts, absolute scotomas No No No
Reduced a-wave and b-wave ampitudes No No No
No recordable b-wave No Yes 6 Years No
Myopia Yes 46 Years No No
Extinguished Cataracts No No No
Extinguished Yes 18 Months Yes 2 Years No
Cataracts Yes 15 Years No No
Reduced b-wave amplitude Hypermetropia, strabismus No No No
No No Yes 6 Months
Reduced b-wave amplitude No No No
Reduced b-wave amplitude No No No
Reduced b-wave amplitude Amblyopia, astigmatism, myopia, scotomas No No No
No No No
Hyperopia No No Yes 3 Years
No Yes 15 Months No
Reduced Amblyopia, myopia, mystagmus, scotomas No No No
No recordable b-wave Dyschromatopsia, photophobia No No No
No No No
Extinguished Cataract, dyschromatopsia, nyctalopia, photophobia Yes 7 Years No No
No recordable b-wave Amblyopia, nyctalopia, photophobia, scotomas No No Yes 32 Years
Reduced b-wave amplitude No No No
Congenital cataracts No No No
Congenital cataracts No No No
No No No
No No No
No No No
No No No
Congenital cataracts No No No
Reduced b-wave amplitude Nyctalopia No No No
No recordable b-wave Amblyopia, nyctalopia, photophobia, scotomas No Yes 5 Years No
No recordable b-wave Nyctalopia, hemeralopia, photophobia, scotomas No No No
Extinguished Amblyopia, nyctalopia, photophobia, strabismus No No No
No No No
Reduced b-wave amplitude No No No
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