A novel homozygous MYO7A mutation involved in a Venezuelan population with high frequency of USHER1B

Background: Macanao’s population in Venezuela has perhaps the greatest incidence of USH1B known in Latin America (79 cases per 100,000 population); however, until now no mutation in the MYO7A gene had been reported for this population.

Materials and Methods: This study aimed to evaluate the entire coding region of the MYO7A gene by direct sequencing of PCR products obtained from patients clinically diagnosed with USH1B.

Results: A novel mutation named c.6079_6081del was detected on exon 45 of the MYO7A gene, causing the loss of a single histidine amino acid at codon 2027 (p.H2027del) located within the second FERM domain of the human protein myosin VIIA. Three patients with clinical diagnosis of USH1B were detected positive in homozygosis for the c.6079_6081del mutation; whereas six people from the same affected family were heterozygotes and three other family members were negative.

Conclusion: We suggest that this new mutation named c.6079_6081del (p.H2027del) is the main cause of deaf-blindness found in this family clinically diagnosed as USH1B. Additional studies should be performed on this population to determine whether the c.6079_6081del mutation is the main cause of USH1B for the rest of the population.     

Investigation of the Rho-kinase Gene Polymorphism in Primary Open-angle Glaucoma

Purpose: Genetic factors are shown to have a role in the development of primary open-angle glaucoma (POAG). The aim of this study was to determine the effects of genetic polymorphisms of Rho-kinase (ROCK) genes on the risk of POAG in a Turkish population.

Methods: Genomic DNA was extracted from leukocytes of the peripheral blood, and 8 single nucleotide polymorphisms in the ROCK1 and ROCK2 genes were analysed in 179 patients with POAG and in 182 healthy controls of similar age by using BioMark HD dynamic array system.

Results: Neither genotype distributions nor the allele frequencies for the ROCK1 (rs35996865) and ROCK2 [rs2290156, rs965665, rs10178332, rs2230774 (Thr431Asn), rs2230774 (Thr431Ser), rs6755196, and rs726843] gene polymorphisms showed a significant difference between the groups. There were also no marked associations between the haplotype frequencies and POAG.

Conclusions: This is the first study to examine the involvement of ROCK1 and ROCK2 gene variations in the risk of POAG development. This study demonstrated that the polymorphisms studied are not associated with the increased risk of development of POAG in the Turkish population.     

Characteristics of Undiagnosed Primary Open-Angle Glaucoma: The Tajimi Study

Purpose: To evaluate the characteristics of patients with previously undiagnosed primary open-angle glaucoma (POAG) in the Tajimi Study.

Methods: Background and ophthalmic examination data from 111 patients previously undiagnosed with POAG from the Tajimi Study, a population-based survey of glaucoma, were analyzed and compared with those of eight patients with previously diagnosed glaucoma.

Results: The mean deviation (MD) and vertical cup-to-disc ratio (vC/D) of the worse eye of each patient averaged ?5.5 decibels (dB) and 0.72 and ?10.4?dB and 0.83, respectively, in undiagnosed and diagnosed POAG. In undiagnosed POAG, arcuate and partial arcuate patterns accounted for 50% of the pattern of the visual field (VF) damage, and 95% of patients presented with intraocular pressure of 21?mmHg or less (normal tension glaucoma). The undiagnosed group had better MD and smaller vC/D values in the worse eye and less involvement of bilateral VFs than the diagnosed group (p?=?0.004–0.050 with Bonferroni correction), while other factors, including mean sensitivity of the binocular VF, showed no intergroup difference.

Conclusion: The characteristics of Japanese patients with previously undiagnosed POAG indicated that bilateral evaluation of the optic disc and VF are important for identifying individuals with glaucoma.     

Analysis of toll-like receptor rs4986790 polymorphism in Saudi patients with primary open angle glaucoma

Background: To investigate whether SNP rs4986790 in toll-like receptors (TLRs) is a risk factor for primary open angle glaucoma (POAG) in a Saudi population.

Materials and methods: A cohort of 85 unrelated POAG patients and 95 unrelated control subjects from Saudi Arabia were genotyped utilizing Taq-Man® assay. The association between mutant genotypes and various clinical indices important for POAG was investigated.

Results: Among cases, the normal pattern (A/A) was detected in 70 (82.4%) of the subjects, A/G in 14 (16.5%) and G/G in one subject only (1.2%). Among controls, prevalence of the genotype (A/A) was detected in 86 (90.5%), the (A/G) genotype in 8 (8.4%) and homozygous mutated genotype (G/G) in 1 (1.1%) subjects. Comparing cases to controls, the odds ratio of having heterozygous mutation (A/G) was 2.15 [95% CI: 0.853–5.417], which was not significant (p = 0.114). The odds ratio of having homozygous mutation (G/G) was 1.22 [95% CI: 0.075–19.99], which was statistically non-significant (p = 0.568). Likewise, the presence of the mutated allele (G) was non-significantly different between cases and controls (p = 0.154). Comparing cases to controls as regards co-morbidity with other systemic diseases, there were no statistically significant differences between groups in all assessed diseases except for a family history of glaucoma (p = 0.014)

Conclusions: In conclusion, we could not detect any direct link between genotypes or allele frequencies of SNP rs4986790 in the TLR4 gene and POAG. In contrast, genotype (A/A) may be protective against POAG especially among individuals with no family history of glaucoma.     

Clinical and genetic characterization of a large primary open angle glaucoma pedigree

Purpose: To both characterize the clinical features of large primary open angle glaucoma (POAG) pedigree from a village in southern India and to investigate the genetic basis of their disease.

Materials and methods: Eighty-four members of a large pedigree received complete eye examinations including slit lamp examination, tonometry, gonioscopy, and ophthalmoscopy. Some were further studied with perimetry. Those diagnosed with POAG were tested for disease-causing mutations in the myocilin and optineurin genes with Sanger sequencing.

Results: Fourteen of 84 family members were diagnosed with POAG, while eight were clinically judged to be POAG-suspects. The family structure and the pattern of glaucoma in the pedigree are complex. Features of glaucoma in this pedigree include relatively early age at diagnosis (mean 50 ± 14 years) and maximum intraocular pressures ranging from 14 to 36 mm Hg with a mean of 23 mm Hg ± 6.5 mm Hg. Patients had an average central corneal thickness (mean 529 ± 37.8 microns) and moderate cup-to-disc ratios (0.74 ± 0.14). No mutations were detected in myocilin, optineurin, or TANK binding kinase 1 (TBK1).

Conclusions: We report a five-generation pedigree with a complex pattern of POAG inheritance that includes 22 POAG patients and glaucoma suspects. Although the familial clustering of POAG in this pedigree is consistent with dominant inheritance of a glaucoma-causing gene, mutations were not detected in genes previously associated with autosomal dominant glaucoma, suggesting the involvement of a novel disease-causing gene in this pedigree.     

Undiagnosed Primary Open-Angle Glaucoma in Korea: The Korean National Health and Nutrition Examination Survey 2008–2009

Purpose: To evaluate the characteristics of patients with previously undiagnosed primary open-angle glaucoma (POAG) in Korea.

Methods: This study examined data from 391 subjects obtained from the 2008–2009 Korean National Health and Nutrition Examination Survey (KNHANES). The KNHANES is a population-based, cross-sectional epidemiological survey. Participants aged 19 years or older completed standardized interviews and dilated ocular examinations, including measurement of intraocular pressure, visual fields with frequency doubling perimetry, and fundus photography. Data from the 361 patients with previously undiagnosed POAG were analyzed and compared with data from the 30 patients with previously diagnosed glaucoma.

Results: A total of 92.3% of POAG cases were undiagnosed before this study. Adjusted for age and sex, the strongest risk factor for undiagnosed glaucoma was longer elapsed time since last eye doctor visit. Glaucoma patients who had not visited an eye specialist in the last 3 years were 22 times (95% confidence interval, CI, 4.49–105.64, p < 0.001) more likely to have undiagnosed disease compared with patients who had visited an eye specialist in the last month. Another significant factor for previously undiagnosed glaucoma was smaller cup-to-disc ratio (odds ratio, OR, 0.60/0.1 units, 95% CI 0.43–0.85/0.1 units, p = 0.004). The higher vertical cup-to-disc ratio of a subject’s two eyes was significantly different between those with previously undiagnosed (0.69) and diagnosed (0.78) POAG (p = 0.001).

Conclusions: The undiagnosed POAG group had a longer interval from last eye doctor visit and smaller vertical cup-to-disc ratio compared to the diagnosed group.     

A novel homozygous variant in the SMOC1 gene underlying Waardenburg anophthalmia syndrome

Background: Waardenburg anophthalmia syndrome (WAS), also known as ophthalmo-acromelic syndrome or anophthalmia-syndactyly, is a rare congenital disorder that segregates in an autosomal recessive pattern. Clinical features of the syndrome include malformation of the eyes and the skeleton. Mostly, WAS is caused by mutations in the SMOC-1 gene.

Materials and methods: The present report describes a large consanguineous family of Pakistani origin segregating Waardenburg anophthalmia syndrome in an autosomal recessive pattern. Genotyping followed by Sanger sequencing was performed to search for a candidate gene.

Results: SNP genotyping using AffymetrixGeneChip Human Mapping 250K Nsp array established a single homozygous region among affected members on chromosome 14q23.1-q24.3 harboring the SMOC1 gene. Sequencing of the gene revealed a novel homozygous missense mutation (c.812G>A; p.Cys271Tyr) in the family.

Conclusion: This is the first report of Waardenburg anophthalmia syndrome caused by a SMOC1 variant in a Pakistani population. The mutation identified in the present investigation extends the body of evidence implicating the gene SMOC-1 in causing WAS.     

Clinical and Genetic Identification of a Large Chinese Family with Autosomal Dominant Retinitis Pigmentosa

Background: Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by night blindness, progressive peripheral visual field loss, and loss of central vision. Fifty-three RP pathogenic genes are responsible for RP. Pre-mRNA processing factor 31(PRPF31) gene is the third most common cause of autosomal dominant retinitis pigmentosa (adRP), and so far more than 40 mutations in PRPF31 have been detected.

Purpose: To identify the underlying genetic defect in a five-generation Chinese family affected with adRP and to study the genotype-phenotype relationship of this family.

Methods: Detailed clinical investigations were undertaken and peripheral blood samples were collected from 25 individuals. Microsatellite (STR) markers tightly linked to genes known to be responsible for adRP were selected for linkage analysis. Exons and adjacent splice junctions of the candidate gene were amplified and sequenced.

Results: This adRP family exhibited an incomplete penetrance of the RP phenotype. In affected individuals, age of disease onset was from infancy to 4 years of age. Typical RP features were associated with this mutation. Linkage analysis identified a maximum two-point LOD score of 3.20 with D19S418, which is close to PRPF31. A mutation PRPF31: (c.358-359 del AA) was identified by linkage analysis.

Conclusions: A PRPF31 mutation was identified to be responsible for adRP in a large Chinese family. Our findings expand the mutation spectrum of RP in the Chinese population.     

Association of single-nucleotide polymorphisms in non-coding regions of the TLR4 gene with primary open angle glaucoma in a Mexican population

Background: Toll-like receptor 4 (TLR4) non-coding polymorphisms are associated to primary open angle glaucoma (POAG), normal tension glaucoma, and pseudoexfoliation glaucoma. This study was performed to determine whether non-coding single nucleotide polymorphisms (SNPs) in the TLR4 gene contribute to POAG in a Mexican population.

Material and methods: A total of 187 unrelated Mexican patients with POAG and 109 control subjects were included. Allelic, genotypic, and haplotypic diversity was assessed for the non-coding polymorphisms rs11536889, rs1927911, rs12377632, and rs2149356 of the TLR4 gene. Genotyping of target SNPs was performed by 5′ exonuclease allelic discrimination assays.

Results: Strong linkage disequilibrium was observed among the SNPs (D’ > 0.818), which were located in one haplotype block. The rs11536889 polymorphism was not associated to POAG in any case. The frequency of the minor allele of rs2149356 was significantly higher in the glaucoma group, conferring an increased risk of POAG (p = 0.0018, OR = 1.803, 95% CI 1.2556–2.5890) whereas minor allele of rs12377632 was significantly lower, attributing a protective effect (p = 0.0001, OR = 0.6662, 95% CI 0.4753–0.9339). Subjects with genotypes carrying the minor allele of rs1927911 and rs2149356 shown an increased risk for POAG (p = 0.03, OR = 1.78, 95% CI 1.10–2.87, and p < 0.0004, OR =2.62, 95%CI 1.61–4.27 respectively). Finally, we found significant risk haplotypes. The GTT haplotype (constituted by rs1927911, rs12377632, and rs2149356) reached the higher OR (p = 0.0026, OR = 4.70, 95% CI 1.73–12.77).

Conclusions: We have identified intronic TLR4 SNPs as genetic susceptibility alleles for POAG in a Mexican population. Our findings support the association of the TLR4 gene with POAG.     

Genetic factors influencing the reduction of central corneal thickness in disorders affecting the eye

Background: The aim was to summarize and discuss the current knowledge about genetic factors influencing the reduction of central corneal thickness (CCT) in disorders affecting the eye, such as primary open-angle glaucoma (POAG), brittle cornea syndrome (BCS), keratoconus (KTCN), Ehlers–Danlos syndrome (EDS; types I, II, and VI), osteogenesis imperfecta (OI), and myopia.

Materials and methods: A review of the published literature by use of key databases such as PubMed was undertaken in accordance with PRISMA guidelines and experience based on own research findings was applied.

Results: The differences in CCT measurements among those affected with diverse disorders and healthy individuals were evaluated. Then we considered the influence of genetic factors on CCT reduction. Disorders were compared based on phenotypes and sequence variants found in patients.

Conclusions: Specific sequence variants in COL8A2, PRDM5 and ZNF469, COL5A1 and ZNF469, and COL5A1 and COL5A2 could probably contribute to a CCT reduction in POAG, BCS, KTCN, and EDS, respectively. Similar sequence variants and phenotypes were identified and assessed in more than one disease.     

Recessive Mutations in LEPREL1 Underlie a Recognizable Lens Subluxation Phenotype

Purpose: To uncover the homozygous recessive gene mutation underlying familial lens subluxation and/or juvenile lens opacities in four sisters from a consanguineous family.

Methods: Prospective family study (clinical phenotyping; homozygosity-analysis-guided candidate gene testing).

Results: The proband was a 14-year-old girl with long-standing poor vision, bilateral temporal lens subluxation, lens opacities, and axial high myopia. There were no syndromic findings, and fibrillin-1 sequencing was normal. Three sisters, also non-syndromic, had undergone bilateral juvenile lens surgery (two for juvenile cataract, 1 for lens subluxation) within the first two decades of life. Both sisters who had cataract surgery developed bilateral post-operative retinal detachments and one had documented lens instability during cataract surgery. Genetic analysis revealed the phenotype to segregate with a novel homozygous recessive mutation in LEPREL1 (c.292delC; p.Gly100Alafs*104). Recessive mutations in this gene were recently highlighted as a cause for axial myopia and early-onset cataract in two families for whom some affected members also had ectopia lentis and/or post-operative retinal detachments.

Conclusions: Recessive LEPREL1 mutations should be recognized as part of the differential diagnosis of lens subluxation. The associated phenotype is non-syndromic and distinguishable from other causes of ectopia lentis in the context of its additional features: juvenile lens opacities, axial myopia, and a predisposition to retinal tears/detachment following intraocular surgery.     

De novo Mutations in the Cone-rod Homeobox Gene Associated with Leber Congenital Amaurosis in Chinese Patients

Background: The cone-rod homeobox (CRX) gene plays an important role in photoreceptor development. Recently, mutant alleles of the CRX gene have been associated with autosomal dominant Leber congenital amaurosis (LCA) and cone-rod dystrophy. The purpose of this study was to analyze the CRX mutations in a cohort of Chinese patients with LCA or early-onset severe retinal dystrophy (EOSRD) and to provide the clinical features of these patients.

Methods: Patients with LCA or EOSRD were enrolled from 2003 to 2012. Detailed ocular examinations including optical coherence tomography (OCT) and standardized electrophysiology were performed. Genomic DNA was isolated with standard methods of genetic diagnosis. All three exons of CRX were amplified with PCR and screened for mutations through direct DNA sequencing. A total of 200 unrelated healthy Chinese subjects were screened to exclude nonpathogenic polymorphisms. Offspring-parent relationship was tested to confirm de novo mutation.

Results: A total of 109 probands from 109 unrelated families were selected for mutation screening of the CRX gene. Two individuals with LCA were confirmed to carry de novo CRX mutations c.421delT (p.Ser141Pro fsX46) and c.571delT (p.Tyr191Met fsX3), respectively. The daughter of Case 1 also carried the same CRX mutation (c.421delT) and had LCA symptoms. Pigmentary retinopathy in the peripheral retina and macular atrophy were observed in the two probands. Macular atrophy without normal lamination structure was the retina phenotype under OCT.

Conclusions: Two de novo mutations in CRX were found in Chinese patients with LCA. The CRX mutation might create a dominantly inherited trait.     

Intraretinal cystoid spaces in a patient with retinitis pigmentosa due to mutation in the MAK gene

Background: Cystoid macular edema (CME) and non-leaking intraretinal cystoid spaces (ICS) have different pathophysiologic mechanisms.

Materials and methods: We report a patient with retinitis pigmentosa (RP) with ICS due to a mutation in the male germ cell-associated kinase (MAK) gene.

Results: A 41-year-old Ashkenazi Jewish male was referred for abnormal visual field revealed by regular optometric examination. His visual acuity was 20/20 in each eye. Dilated examination revealed typical finding of RP. Optical coherence tomography showed cystoid changes in each fovea. Photoreceptors were also degenerated. Intravenous fluorescein angiography showed no leakage. Genetic testing identified a homozygous mutation in the MAK gene: a 353-bp Alu insertion (K429insAlu).

Conclusions: Mak regulates microtubule stability via phosphorylating RP1. Abnormal Mak may impact retinal photoreceptor ciliary length and subcompartmentalization. Mak is required for the survival of photoreceptors in mice. ICS has been reported in other ciliopathies. We report the first case of ICS due to mutation in MAK.     

A Novel NOD2-associated Mutation and Variant Blau Syndrome: Phenotype and Molecular Analysis

Purpose: To describe the clinical and molecular implications of a novel mutation in the NOD2/CARD15 gene on a family and its seven affected members.

Methods: We reviewed the clinical presentations of family members who came to our center for refractory uveitis. Genetic testing and molecular testing was performed.

Results: All affected members had adult onset recurrent non-granulomatous panuveitis. The inheritance pattern suggested an autosomal dominant disease and genetic analysis identified a novel mutation in the NOD2 gene that converted amino acid 600 from glutamate to alanine (E600A). Transfection of the E600A NOD2 into human embryonic kidney-293 (HEK293) cells revealed constitutive activation and a reduced ability to respond to the NOD2 ligand, muramyl dipeptide (MDP) as compared with wild-type NOD2.

Conclusions: The E600A mutation in the NOD2 gene may confer a higher penetrance of uveitis but a later onset of milder forms of non-ocular involvement.     

Autosomal-dominant Leber Congenital Amaurosis Caused by a Heterozygous CRX Mutation in a Father and Son

Background: Leber congenital amaurosis (LCA) is most often an autosomal recessive disorder. We report a father and son with autosomal dominant LCA due to a mutation in the CRX gene.

Materials and Methods: DNA screening using an allele specific assay of 90 of the most common LCA-causing variations in the coding sequences of AIPL1, CEP290, CRB1, CRX, GUCY2D, RDH12 and RPE65 was performed on the father. Automated DNA sequencing of his son examining exon 3 of the CRX gene was subsequently performed.

Results: Both father and son have a heterozygous single base pair deletion of an adenine at codon 153 in the coding sequence of the CRX gene resulting in a frameshift mutation.

Conclusion: Mutations involving the CRX gene may demonstrate an autosomal dominant inheritance pattern for LCA.     

Homozygous SLC4A11 mutation in a large Irish CHED2 pedigree

Background: Congenital hereditary endothelial dystrophy (CHED) is a genetic disorder of corneal endothelial cells resulting in corneal clouding and visual impairment. Autosomal dominant (CHED1) and autosomal recessive (CHED2) forms have been reported and map to distinct loci on chromosome 20. CHED2 is caused by mutations in the SLC4A11 gene which encodes a membrane transporter protein.

Materials and methods: Members of a large CHED2 family were recruited for clinical and genetic studies. Genomic DNA was sequenced for the exons and intron-exon boundaries of the SLC4A11 gene.

Results: Twelve family members were recruited, of which eight were diagnosed with CHED. A homozygous SLC4A11 mutation (Leu843Pro) was detected in the eight patients; a single copy of the mutation was present in three unaffected carriers.

Conclusions: A missense SLC4A11 mutation (Leu843Pro) is responsible for CHED2 in this family; this is the first report of this mutation in a homozygous state.     

A novel mutation in the dominantly inherited TOPORS gene supports haploinsufficiency as the mechanism of retinitis pigmentosa

Background: Inherited retinal degenerations are a major cause of untreatable blindness in the younger age group. Recent advances in gene therapy using adeno-associated viral (AAV) vectors have raised the possibility of slowing or stopping retinal degenerations with gene replacement in cases of gene deficiency.

Materials and methods: In this report, we present a family with autosomal dominant retinitis pigmentosa. A screen for common ADRP genes was performed with 105 genes targeted. Next generation sequencing was used to identify the mutation which was next confirmed by bidirectional Sanger sequencing.

Results: A novel mutation of the TOPORS gene was identified, c.2539C>T p.(Arg847Ter), resulting in a premature termination codon and suggesting haploinsufficiency as the pathological mechanism.

Conclusions: Since the cDNA encoding TOPORS is 3,135 nucleotides (within the coding capacity of AAV vectors) and haploinsufficiency is a mechanism relating to inadequate gene expression, gene replacement therapy may be an option for patients with this condition.     

Use of Intravitreal Bevacizumab in a 9-Year-Old Child with Choroidal Neovascularization Associated with Autosomal Recessive Bestrophinopathy

Introduction: Bestrophinopathies result from mutations within the BEST1 gene; although multiple gene mutations have been identified, the recessive form is often the form which gives rise to the rarer complication of choroidal neovascularization. We describe a child with treated choroidal neovascularization secondary to Best disease with a newly identified genetic mutation.

Methods: Case report.

Results: A 9-year-old child reported unilateral blurred vision; the acuity deteriorated over the following months to 3/18 due to the development of a choroidal neovascular membrane. She was treated with three injections of bevacizumab with recovery to 6/12 vision and no subsequent recurrence over the follow-up period of 2 years, and no secondary complications from the drug. Genetic analysis revealed a novel heterozygous mutation in the BEST1 gene, with no evidence of disease in the family.

Conclusions: We describe a novel mutation within the BEST1 gene of the heterozygous form giving rise to vitelliform lesions and secondary neovascularization successfully treated in a child with a course of bevacizumab. The genetic testing has implications on genetic counseling in such patients and the genetic analysis of all such patients ought to be routinely considered.     

Congenital Achromatopsia and Macular Atrophy Caused by a Novel Recessive PDE6C Mutation (p.E591K)

Purpose: We have previously reported clinical features of two siblings, a sister with complete achromatopsia (ACHM) and a brother with incomplete ACHM, in a consanguineous Japanese family. With the current study, we intended to identify a disease-causing mutation in the siblings and to investigate why the phenotypes of the siblings differed.

Methods: We performed a comprehensive ophthalmic examination for each sibling and parent. Whole-exome and Sanger sequencing were performed on genomic DNA. Molecular modeling was analyzed in an in silico study.

Results: The ophthalmic examination revealed severe macular atrophy in the older female sibling at 30 years of age and mild macular atrophy in the brother at 26 years of age. The genetic analysis identified a novel homozygous PDE6C mutation (p.E591K) as the disease-causing allele in the siblings. Each parent was heterozygous for the mutation. Molecular modeling showed that the mutation could cause a conformational change in the PDE6C protein and result in reduced phosphodiesterase activity. We also identified an OPN1SW mutation (p.G79R), which is associated with congenital tritan deficiencies, in the sister and the father but not in the brother.

Conclusions: A novel homozygous PDE6C mutation was identified as the cause of ACHM. In addition, we identified an OPN1SW mutation in the sibling with complete ACHM, which might explain the difference in phenotype (complete versus incomplete ACHM) between the siblings.     

A family harboring homozygous FZD4 deletion supports the existence of recessive FZD4-related familial exudative vitreoretinopathy

Purpose: To document recessive FZD4-related familial exudative vitreoretinopathy.

Methods: Retrospective case series.

Results: Two brothers, the only two males among five siblings, had bilateral infantile retinal detachments and were referred for genetic counseling. Next-generation sequencing uncovered a homozygous FZD4 frameshift deletion in both affected brothers (c.40_49delCCCGGGGGCG; p.Pro14Serfs*44). None of the other immediate family members had clinical evidence for retinal disease, including the three family members who underwent confirmatory genetic testing and were found to be heterozygous for the mutation (both parents and one sister).

Conclusions: The findings in this family support the concept that some mutated FZD4 alleles can be associated with recessive rather than dominant disease.