Publications by authors named "Dror Sharon"

96 Publications

Senior- Løken Syndrome: A Case Series and Review of The Reno-Retinal Phenotype and Advances of Molecular Diagnosis.

Retina 2021 Jan 27. Epub 2021 Jan 27.

Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Israel Pediatric Nephrology Unit, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Israel St John of Jerusalem Eye Hospital Group, East Jerusalem, Israel Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.

Purpose: To report genetic and clinical findings in a case series of 10 patients from eight unrelated families diagnosed with Senior-Løken syndrome (SLS).

Methods: A retrospective study of patients with SLS. Data collected included clinical findings electroretinography and ocular imaging. Genetic analysis was based on molecular inversion probes (MIPs), whole-exome (WES) and Sanger sequencing.

Results: All patients who underwent electrophysiology (8/10) had widespread photoreceptor degeneration. Genetic analysis revealed two mutations in NPHP1, two mutations in NPHP4 and two mutations in IQCB1 (NPHP5). Five of the six mutations identified in the current study were found in a single family each in our cohort. The IQCB1- p.R461* mutation has been identified in three families. Patients harboring mutations in IQCB1 were diagnosed with Leber congenital amaurosis (LCA), while patients with NPHP4 and NPHP1 mutations showed early and sector retinitis pigmentosa (RP), respectively. ffERG was extinct for 6 out of 10 patients, moderately decreased for two and unavailable for another two subjects. Renal involvement was evident in 7/10 patients at the time of diagnosis. Kidney function was normal (based on serum creatinine) in patients younger than 10 years. Mutations in IQCB1 were associated with high hypermetropia whereas mutations in NPHP4 were associated with high myopia.

Conclusions: Patients presenting with infantile inherited retinal degeneration are not universally screened for renal dysfunction. Modern genetic tests can provide molecular diagnosis at an early age and therefore facilitate early diagnosis of renal disease with recommended periodic screening beyond childhood and family planning.
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http://dx.doi.org/10.1097/IAE.0000000000003138DOI Listing
January 2021

A new mouse model for retinal degeneration due to Fam161a deficiency.

Sci Rep 2021 Jan 21;11(1):2030. Epub 2021 Jan 21.

Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel.

FAM161A mutations are the most common cause of inherited retinal degenerations in Israel. We generated a knockout (KO) mouse model, Fam161a, lacking the major exon #3 which was replaced by a construct that include LacZ under the expression of the Fam161a promoter. LacZ staining was evident in ganglion cells, inner and outer nuclear layers and inner and outer-segments of photoreceptors in KO mice. No immunofluorescence staining of Fam161a was evident in the KO retina. Visual acuity and electroretinographic (ERG) responses showed a gradual decrease between the ages of 1 and 8 months. Optical coherence tomography (OCT) showed thinning of the whole retina. Hypoautofluorescence and hyperautofluorescence pigments was observed in retinas of older mice. Histological analysis revealed a progressive degeneration of photoreceptors along time and high-resolution transmission electron microscopy (TEM) analysis showed that photoreceptor outer segment disks were disorganized in a perpendicular orientation and outer segment base was wider and shorter than in WT mice. Molecular degenerative markers, such as microglia and CALPAIN-2, appear already in a 1-month old KO retina. These results indicate that a homozygous Fam161a frameshift mutation affects retinal function and causes retinal degeneration. This model will be used for gene therapy treatment in the future.
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http://dx.doi.org/10.1038/s41598-021-81414-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820261PMC
January 2021

KCNV2-associated Retinopathy: Genetics, Electrophysiology and Clinical Course - KCNV2 Study Group Report 1.

Am J Ophthalmol 2020 Dec 10. Epub 2020 Dec 10.

Moorfields Eye Hospital, 162 City Rd, London EC1V 2PD, United Kingdom; UCL Institute of Ophthalmology, University College London, 11-43 Bath St, London EC1V 9E, United Kingdom. Electronic address:

Purpose: To investigate genetics, electrophysiology and clinical course of KCNV2-associated retinopathy in a cohort of children and adults.

Study Design: Multicenter international clinical cohort study.

Methods: Review of clinical notes and molecular genetic testing. Full-field electroretinography (ERG) incorporating the international standards were reviewed and quantified and compared with age and recordings from control subjects.

Results: In total 230 disease-associated alleles were identified from 117 patients, corresponding to 75 different KCNV2 variants, with 28 being novel. The mean age of onset was 3.9 years old. All patients were symptomatic before the age of 12 years (age range: 0-11 years). Decreased visual acuity was present in all patients, and four other symptoms were common: reduced color vision (78.6%), photophobia (53.5%), nyctalopia (43.6%), and nystagmus (38.6%). After a mean follow of 8.4 years, the mean best corrected visual acuity (BCVA, ±SD) decreased from 0.81 LogMAR (0.27 LogMAR) to 0.90 LogMAR (0.31 LogMAR). Full-field ERGs showed pathognomonic waveform features. Quantitative assessment revealed a wide range of ERG amplitudes and peak times, with a mean rate of age-associated reduction indistinguishable from the control group. Mean amplitude reductions for the DA 0.01 ERG, DA 10 ERG a-wave, LA30Hz and LA3 ERG b-wave were 55%, 21%, 48% and 74% respectively. Peak times showed stability across 6 decades.

Conclusion: In KCNV2-retinopathy full-field ERGs are diagnostic, and consistent with largely stable peripheral retinal dysfunction. Report No.1 highlights the severity of the clinical phenotype and established a large cohort of patients, emphasizing the unmet need for trials of novel therapeutics.
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http://dx.doi.org/10.1016/j.ajo.2020.11.022DOI Listing
December 2020

Variable phenotype of Knobloch syndrome due to biallelic mutations in children.

Eur J Ophthalmol 2020 Nov 25:1120672120977343. Epub 2020 Nov 25.

Department of Ophthalmology, Hadassah University Medical Center, Faculty of Medicine, Hebrew University, Jerusalem, Israel.

Purpose: Knobloch syndrome is a rare, recessively inherited disorder classically characterized by high myopia, retinal detachment, and occipital encephalocele. Our aim is to report the clinical and genetic findings of four Israeli children affected by Knobloch syndrome.

Methods: Retrospective study of four patients diagnosed with Knobloch syndrome, who underwent full ophthalmic examination, electroretinography, and neuroradiologic imaging. Genetic analysis included whole exome sequencing (WES) and Sanger sequencing.

Results: The four patients included in this study had high myopia and nystagmus at presentation. Ocular findings included vitreous syneresis, macular atrophy, macular coloboma, and retinal detachment. One child had iris transillumination defects and an albinotic fundus, initially leading to an erroneous clinical diagnosis of albinism. Electroretinography revealed a marked cone-rod pattern of dysfunction in all four children. Brain imaging demonstrated none to severe occipital pathology. Cutaneous scalp changes were present in three patients. WES analysis, confirmed by Sanger sequencing revealed biallelic null mutations in all affected individuals, consistent with autosomal recessive inheritance.

Conclusions: This report describes variable features in patients with Knobloch syndrome, including marked lack of eye pigment similar to albinism in one child, macular coloboma in two children as well as advanced cone-rod dysfunction in all children. One patient had normal neuroradiologic findings, emphasizing that some affected individuals have isolated ocular disease. Awareness of this syndrome, with its variable phenotype may aid early diagnosis, monitoring for potential complications, and providing appropriate genetic counseling.
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http://dx.doi.org/10.1177/1120672120977343DOI Listing
November 2020

Unique combination of clinical features in a large cohort of 100 patients with retinitis pigmentosa caused by FAM161A mutations.

Sci Rep 2020 09 16;10(1):15156. Epub 2020 Sep 16.

Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University Jerusalem, Jerusalem, Israel.

FAM161A mutations are the most common cause of autosomal recessive retinitis pigmentosa in the Israeli-Jewish population. We aimed to characterize the spectrum of FAM161A-associated phenotypes and identify characteristic clinical features. We identified 114 bi-allelic FAM161A patients and obtained clinical records of 100 of these patients. The most frequent initial symptom was night blindness. Best-corrected visual acuity was largely preserved through the first three decades of life and severely deteriorated during the 4th-5th decades. Most patients manifest moderate-high myopia. Visual fields were markedly constricted from early ages, but maintained for decades. Bone spicule-like pigmentary changes appeared relatively late, accompanied by nummular pigmentation. Full-field electroretinography responses were usually non-detectable at first testing. Fundus autofluorescence showed a hyper-autofluorescent ring around the fovea in all patients already at young ages. Macular ocular coherence tomography showed relative preservation of the outer nuclear layer and ellipsoid zone in the fovea, and frank cystoid macular changes were very rare. Interestingly, patients with a homozygous nonsense mutation manifest somewhat more severe disease. Our clinical analysis is one of the largest ever reported for RP caused by a single gene allowing identification of characteristic clinical features and may be relevant for future application of novel therapies.
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http://dx.doi.org/10.1038/s41598-020-72028-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495424PMC
September 2020

Advancing Clinical Trials for Inherited Retinal Diseases: Recommendations from the Second Monaciano Symposium.

Transl Vis Sci Technol 2020 06 3;9(7). Epub 2020 Jun 3.

Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI, USA.

Major advances in the study of inherited retinal diseases (IRDs) have placed efforts to develop treatments for these blinding conditions at the forefront of the emerging field of precision medicine. As a result, the growth of clinical trials for IRDs has increased rapidly over the past decade and is expected to further accelerate as more therapeutic possibilities emerge and qualified participants are identified. Although guided by established principles, these specialized trials, requiring analysis of novel outcome measures and endpoints in small patient populations, present multiple challenges relative to study design and ethical considerations. This position paper reviews recent accomplishments and existing challenges in clinical trials for IRDs and presents a set of recommendations aimed at rapidly advancing future progress. The goal is to stimulate discussions among researchers, funding agencies, industry, and policy makers that will further the design, conduct, and analysis of clinical trials needed to accelerate the approval of effective treatments for IRDs, while promoting advocacy and ensuring patient safety.
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http://dx.doi.org/10.1167/tvst.9.7.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414644PMC
June 2020

A unique -associated variant in a Georgian Jewish family with probable North Carolina macular dystrophy and the possible contribution of a unique variant.

Mol Vis 2020 16;26:299-310. Epub 2020 Apr 16.

Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University Jerusalem, Jerusalem, Israel.

Purpose: North Carolina macular dystrophy (NCMD) is an autosomal dominant maculopathy that is considered a non-progressive developmental disorder with variable expressivity. Our study aimed to clinically and genetically characterize macular dystrophy in a family (MOL1154) consisting of six affected subjects with a highly variable maculopathy phenotype in which no correlation between age and severity exists.

Methods: Clinical characterization included visual acuity testing and electroretinography. Genetic analysis included Sanger sequencing and whole exome sequencing (WES).

Results: WES analysis performed on DNA samples from two individuals revealed a heterozygous deletion of six nucleotides [c.2247_2252del; p.(Leu750_Lys751del)] in the gene. Co-segregation analysis revealed that five of the six NCMD affected subjects carried this deletion, while one individual who had a relatively mild phenotype compatible with dry age-related macular degeneration (AMD) did not carry it. We subsequently analyzed the upstream region of that has previously been reported to be associated with NCMD and identified a unique heterozygous transversion (chr6:100040974A>C) located within the previously described suspected control region in all six affected individuals. This transversion is likely to cause NCMD.

Conclusions: NCMD has a wide spectrum of clinical phenotypes that can overlap with AMD, making it challenging to correctly diagnose affected individuals and family members. The DNA sequence variant we found in the gene of some of the affected family members may suggest some role as a modifier gene. However, this variant still does not explain the huge phenotypic variability of NCMD and needs to be studied in other and larger populations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245606PMC
April 2020

Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics.

Genet Med 2020 Jul 20;22(7):1235-1246. Epub 2020 Apr 20.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Purpose: Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands.

Methods: Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays.

Results: In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband.

Conclusion: Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases.
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http://dx.doi.org/10.1038/s41436-020-0787-4DOI Listing
July 2020

Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases.

Proc Natl Acad Sci U S A 2020 02 21;117(5):2710-2716. Epub 2020 Jan 21.

Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, 91120 Jerusalem, Israel;

One of the major questions in human genetics is what percentage of individuals in the general population carry a disease-causing mutation. Based on publicly available information on genotypes from six main world populations, we created a database including data on 276,921 sequence variants, present within 187 genes associated with autosomal recessive (AR) inherited retinal diseases (IRDs). Assessment of these variants revealed that 10,044 were categorized as disease-causing mutations. We developed an algorithm to compute the gene-specific prevalence of disease, as well as the mutational burden in healthy subjects. We found that the genetic prevalence of AR-IRDs corresponds approximately to 1 case in 1,380 individuals, with 5.5 million people expected to be affected worldwide. In addition, we calculated that unaffected carriers of mutations are numerous, ranging from 1 in 2.26 individuals in Europeans to 1 in 3.50 individuals in the Finnish population. Our analysis indicates that about 2.7 billion people worldwide (36% of the population) are healthy carriers of at least one mutation that can cause AR-IRD, a value that is probably the highest across any group of Mendelian conditions in humans.
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http://dx.doi.org/10.1073/pnas.1913179117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007541PMC
February 2020

An Ashkenazi Jewish founder mutation in causes retinal phenotype in both hemizygous males and heterozygous female carriers.

Ophthalmic Genet 2019 10 25;40(5):443-448. Epub 2019 Oct 25.

Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

: Mutations in have been mainly associated with X-linked incomplete congenital stationary night blindness (icCSNB). Variable phenotypic expression in females was reported in some families. We report here three non-related Ashkenazi Jewish families originating in Eastern Europe, that included males and a many affected females, initially diagnosed with variable retinal phenotypes.: Whole exome sequencing (WES), Sanger sequencing and microsatellite haplotyping were used for genetic analysis. Complete ophthalmologic examination was performed including visual acuity, refraction, colour vision, slit-lamp, fundoscopy and electroretinography (ERG).: We identified four affected males, showing moderate visual impairment, and seven female carriers, six of them presenting mild to moderate visual impairment. Infantile nystagmus was found in all affected males and in 5/7 females. Nyctalopia and myopia were common in both males and females. Initial clinical differential diagnosis included cone-dystrophy, cone-rod dystrophy, cone-dystrophy with supernormal rod response or CSNB based on ERG results. WES and Sanger sequencing revealed a previously described missense mutation c.2225T>G; p.(F742C) in (NM_001256789.2) in all three families, encompassed by a shared haplotype: Our data suggests that p.(F742C) in is an X-linked founder mutation in Ashkenazi Jews originating in Eastern Europe. This mutation causes a mild-to-moderate icCSNB phenotype, expressed in most female carriers. A targeted test for this variant in suspected patients may initiate diagnostic analysis. Our results highlight the relevance of WES in the clinic, allowing fast and accurate diagnosis for unclear and variable clinical phenotype and in pedigrees with multiple possible inheritance patterns.
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http://dx.doi.org/10.1080/13816810.2019.1681008DOI Listing
October 2019

Deep-intronic variants in CNGB3 cause achromatopsia by pseudoexon activation.

Hum Mutat 2020 01 30;41(1):255-264. Epub 2019 Sep 30.

Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.

Our comprehensive cohort of 1100 unrelated achromatopsia (ACHM) patients comprises a considerable number of cases (~5%) harboring only a single pathogenic variant in the major ACHM gene CNGB3. We sequenced the entire CNGB3 locus in 33 of these patients to find a second variant which eventually explained the patients' phenotype. Forty-seven intronic CNGB3 variants were identified in 28 subjects after a filtering step based on frequency and the exclusion of variants found in cis with pathogenic alleles. In a second step, in silico prediction tools were used to filter out those variants with little odds of being deleterious. This left three variants that were analyzed using heterologous splicing assays. Variant c.1663-1205G>A, found in 14 subjects, and variant c.1663-2137C>T, found in two subjects, were indeed shown to exert a splicing defect by causing pseudoexon insertion into the transcript. Subsequent screening of further unsolved CNGB3 subjects identified four additional cases harboring the c.1663-1205G>A variant which makes it the eighth most frequent CNGB3 variant in our cohort. Compound heterozygosity could be validated in ten cases. Our study demonstrates that whole gene sequencing can be a powerful approach to identify the second pathogenic allele in patients apparently harboring only one disease-causing variant.
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http://dx.doi.org/10.1002/humu.23920DOI Listing
January 2020

A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC).

Hum Mutat 2020 01 15;41(1):140-149. Epub 2019 Sep 15.

Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

Inherited retinal diseases (IRDs) cause visual loss due to dysfunction or progressive degeneration of photoreceptors. These diseases show marked phenotypic and genetic heterogeneity. The Israeli IRD consortium (IIRDC) was established in 2013 with the goal of performing clinical and genetic mapping of the majority of Israeli IRD patients. To date, we recruited 2,420 families including 3,413 individuals with IRDs. On the basis of our estimation, these patients represent approximately 40% of Israeli IRD patients. To the best of our knowledge, this is, by far, the largest reported IRD cohort, and one of the first studies addressing the genetic analysis of IRD patients on a nationwide scale. The most common inheritance pattern in our cohort is autosomal recessive (60% of families). The most common retinal phenotype is retinitis pigmentosa (43%), followed by Stargardt disease and cone/cone-rod dystrophy. We identified the cause of disease in 56% of the families. Overall, 605 distinct mutations were identified, of which 12% represent prevalent founder mutations. The most frequently mutated genes were ABCA4, USH2A, FAM161A, CNGA3, and EYS. The results of this study have important implications for molecular diagnosis, genetic screening, and counseling, as well as for the development of new therapeutic strategies for retinal diseases.
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http://dx.doi.org/10.1002/humu.23903DOI Listing
January 2020

TRPM1 Mutations are the Most Common Cause of Autosomal Recessive Congenital Stationary Night Blindness (CSNB) in the Palestinian and Israeli Populations.

Sci Rep 2019 08 19;9(1):12047. Epub 2019 Aug 19.

Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel.

Precise genetic and phenotypic characterization of congenital stationary night blindness (CSNB) patients is needed for future therapeutic interventions. The aim of this study was to estimate the prevalence of CSNB in our populations and to study clinical and genetic aspects of the autosomal recessive (AR) form of CSNB. This is a retrospective cohort study of Palestinian and Israeli CSNB patients harboring mutations in TRPM1 underwent comprehensive ocular examination. Genetic analysis was performed using homozygosity mapping and sequencing. 161 patients (from 76 families) were recruited for this study, leading to a prevalence of 1:6210 in the vicinity of Jerusalem, much higher than the worldwide prevalence. 61% of the families were consanguineous with AR inheritance pattern. Biallelic pathogenic TRPM1 mutations were identified in 36 families (72 patients). Two founder mutations explain the vast majority of cases: a nonsense mutation c.880A>T (p.Lys294*) identified in 22 Palestinian families and a large genomic deletion (36,445 bp) encompassing exons 2-7 of TRPM1 present in 13 Ashkenazi Jewish families. Most patients were myopic (with mean BCVA of 0.40 LogMAR) and all had absent rod responses in full field electroretinography. To the best of our knowledge, this is the largest report of a clinical and genetic analysis of patients affected with CSNB due to TRPM1 mutations.
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http://dx.doi.org/10.1038/s41598-019-46811-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700182PMC
August 2019

The combination of whole-exome sequencing and clinical analysis allows better diagnosis of rare syndromic retinal dystrophies.

Acta Ophthalmol 2019 Sep 29;97(6):e877-e886. Epub 2019 Mar 29.

Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Purpose: To identify the accurate clinical diagnosis of rare syndromic inherited retinal diseases (IRDs) based on the combination of clinical and genetic analyses.

Methods: Four unrelated families with various autosomal recessive syndromic inherited retinal diseases were genetically investigated using whole-exome sequencing (WES).

Results: Two affected subjects in family MOL0760 presented with a distinctive combination of short stature, developmental delay, congenital mental retardation, microcephaly, facial dysmorphism and retinitis pigmentosa (RP). Subjects were clinically diagnosed with suspected Kabuki syndrome. WES revealed a homozygous nonsense mutation (c.5492dup, p.Asn1831Lysfs*8) in VPS13B that is known to cause Cohen syndrome. The index case of family MOL1514 presented with both RP and liver dysfunction, suspected initially to be related. WES identified a homozygous frameshift mutation (c.1787_1788del, p.His596Argfs*47) in AGBL5, associated with nonsyndromic RP. The MOL1592 family included three affected subjects with crystalline retinopathy, skin ichthyosis, short stature and congenital adrenal hypoplasia, and were found to harbour a homozygous nonsense mutation (c.682C>T, p.Arg228Cys) in ALDH3A2, reported to cause Sjögren-Larsson syndrome (SLS). In the fourth family, SJ002, two siblings presented with hypotony, psychomotor delay, dysmorphic facial features, pathologic myopia, progressive external ophthalmoplegia and diffuse retinal atrophy. Probands were suspected to have atypical Kearns-Sayre syndrome, but were diagnosed with combined oxidative phosphorylation deficiency-20 due to a novel suspected missense variant (c.1691C>T, p.Ala564Val) in VARS2.

Conclusion: Our findings emphasize the important complement of WES and thorough clinical investigation in establishing precise clinical diagnosis. This approach constitutes the basis for personalized medicine in rare IRDs.
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http://dx.doi.org/10.1111/aos.14095DOI Listing
September 2019

Allele frequency analysis of variants reported to cause autosomal dominant inherited retinal diseases question the involvement of 19% of genes and 10% of reported pathogenic variants.

J Med Genet 2019 08 25;56(8):536-542. Epub 2019 Mar 25.

Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Background: Next generation sequencing (NGS) generates a large amount of genetic data that can be used to better characterise disease-causing variants. Our aim was to examine allele frequencies of sequence variants reported to cause autosomal dominant inherited retinal diseases (AD-IRDs).

Methods: Genetic information was collected from various databases, including PubMed, the Human Genome Mutation Database, RETNET and gnomAD.

Results: We generated a database of 1223 variants reported in 58 genes, including their allele frequency in gnomAD that contains NGS data of over 138 000 individuals. While the majority of variants are not represented in gnomAD, 138 had an allele count of >1 and were examined carefully for various aspects including cosegregation and functional analyses. The analysis revealed 122 variants that were reported pathogenic but unlikely to cause AD-IRDs. Interestingly, in some cases, these unlikely pathogenic variants were the only ones reported to cause disease in AD inheritance pattern for a particular gene, therefore raising doubt regarding the involvement of 11 (19%) of the genes in AD-IRDs.

Conclusion: We predict that these data are not limited to a specific disease or inheritance pattern since non-pathogenic variants were mistakenly reported as pathogenic in various diseases. Our results should serve as a warning sign for geneticists, variant database curators and sequencing panels' developers not to automatically accept reported variants as pathogenic but cross-reference the information with large databases.
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http://dx.doi.org/10.1136/jmedgenet-2018-105971DOI Listing
August 2019

Chromatic pupilloperimetry for objective diagnosis of Best vitelliform macular dystrophy.

Clin Ophthalmol 2019 5;13:465-475. Epub 2019 Mar 5.

Goldschleger Eye Institute, Sheba Medical Center, Tel Hashomer, Israel,

Purpose: To determine the pupil response of Best vitelliform macular dystrophy (BVMD) patients for focal blue and red light stimuli presented at 76 test points in a 16.2° visual field (VF) using a chromatic pupilloperimeter.

Methods: An observational study was conducted in 16 participants: 7 BVMD patients with a heterozygous BEST1 mutation and 9 similar-aged controls. All participants were tested for best-corrected visual acuity, chromatic pupilloperimetry and Humphrey perimetry. Percentage of pupil contraction (PPC), maximal pupil contraction velocity (MCV) and latency of MCV (LMCV) were determined.

Results: The mean PPC and MCV recorded in BVMD patients in response to red stimuli were lower by >2 standard errors (SEs) from the mean of controls in 47% and 43% of VF test points, respectively. The mean PPC and MCV recorded in the patients in response to blue stimuli were lower by >2 SEs from the mean of controls in 36% and 24% of VF test points, respectively. The patients' mean and median MCV recorded in response to red light correlated with their Humphrey mean deviation score (=-0.714, =0.071 and =-0.821, =0.023, respectively) and visual acuity (=0.709, =0.074 and =0.655, =0.111, respectively). A substantially shorter mean LMCV was recorded in BVMD patients compared to controls in 54% and 93% of VF test points in response to red and blue light, respectively. Receiver operating characteristic analysis for LMCV in response to red light identified a test point at the center of the VF with high diagnostic accuracy (area under the curve of 0.94).

Conclusion: Chromatic pupilloperimetry may potentially be used for objective noninvasive assessment of rod and cone cell function in different locations of the retina in BVMD patients.
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http://dx.doi.org/10.2147/OPTH.S191486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407903PMC
March 2019

Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F-mediated inherited retinal disorders.

Hum Mutat 2019 06 28;40(6):765-787. Epub 2019 Mar 28.

INSERM, CNRS, Institut de la Vision, Sorbonne Université, Paris, France.

Inherited retinal disorders (IRD) represent clinically and genetically heterogeneous diseases. To date, pathogenic variants have been identified in ~260 genes. Albeit that many genes are implicated in IRD, for 30-50% of the cases, the gene defect is unknown. These cases may be explained by novel gene defects, by overlooked structural variants, by variants in intronic, promoter or more distant regulatory regions, and represent synonymous variants of known genes contributing to the dysfunction of the respective proteins. Patients with one subgroup of IRD, namely incomplete congenital stationary night blindness (icCSNB), show a very specific phenotype. The major cause of this condition is the presence of a hemizygous pathogenic variant in CACNA1F. A comprehensive study applying direct Sanger sequencing of the gene-coding regions, exome and genome sequencing applied to a large cohort of patients with a clinical diagnosis of icCSNB revealed indeed that seven of the 189 CACNA1F-related cases have intronic and synonymous disease-causing variants leading to missplicing as validated by minigene approaches. These findings highlight that gene-locus sequencing may be a very efficient method in detecting disease-causing variants in clinically well-characterized patients with a diagnosis of IRD, like icCSNB.
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http://dx.doi.org/10.1002/humu.23735DOI Listing
June 2019

A novel intronic mutation of is a major cause of autosomal recessive retinitis pigmentosa among Caucasus Jews.

Mol Vis 2019 22;25:155-164. Epub 2019 Feb 22.

Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

Purpose: To identify the genetic basis for retinitis pigmentosa (RP) in a cohort of Jewish patients from Caucasia.

Methods: Patients underwent a detailed ophthalmic evaluation, including funduscopic examination, visual field testing, optical coherence tomography (OCT), and electrophysiological tests, electroretinography (ERG) and visual evoked potentials (VEP). Genetic analysis was performed with a combination of whole exome sequencing (WES) and Sanger sequencing. Bioinformatic analysis of the WES results was performed via a customized pipeline. Pathogenicity of the identified intronic variant was evaluated in silico using the web tool Human Splicing Finder, and in vitro, using a minigene-based splicing assay. Linkage disequilibrium (LD) analysis was used to demonstrate a founder effect, and the decay of LD over generations around the mutation in Caucasus Jewish chromosomes was modeled to estimate the age of the most recent common ancestor.

Results: In eight patients with RP from six unrelated families, all of Caucasus Jewish ancestry, we identified a novel homozygous intronic variant, located at position -9 of intron 15. The c.1921-9C>G variant was predicted to generate a novel acceptor splice site, nine bases upstream of the original splice site of intron 15. In vitro splicing assay demonstrated that this novel acceptor splice site is used instead of the wild-type site, leading to an 8-bp insertion into exon 16, which is predicted to cause a frameshift. The presence of a common ancestral haplotype in mutation-bearing chromosomes was compatible with a founder effect.

Conclusions: The c.1921-9C>G intronic mutation is a founder mutation that accounts for at least 40% (6/15 families) of autosomal recessive RP among Caucasus Jews. This result is highly important for molecular diagnosis, carrier screening, and genetic counseling in this population.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386512PMC
June 2019

[THE ISRAELI INHERITED RETINAL DISEASES CONSORTIUM (IIRDC)- CLINICAL-GENETIC MAPPING AND FUTURE PERSPECTIVES].

Harefuah 2019 Feb;158(2):91-95

Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa.

Introduction: The sense of vision is highly important for humans and its loss markedly affects function and quality of life. Many inherited retinal diseases (IRDs) cause visual loss due to dysfunction or progressive degeneration of photoreceptor cells. These diseases show clinical and genetic heterogeneity.

Aims: The Israeli IRD consortium (IIRDC) was established with the goal of performing clinical and genetic mapping of IRDs in the Israeli population.

Methods: Clinical evaluation is carried out at electroretinography (ERG) centers and ophthalmology departments, where the patients undergo a comprehensive eye exam, including testing of visual acuity, refractive error, imaging techniques and ERG tests. Genetic analysis is performed using Sanger sequencing, analysis of founder mutations, and whole exome sequencing.

Results: We recruited over 2,000 families including more than 3,000 individuals with IRDs. The most common inheritance pattern is autosomal recessive (65% of families). The most common retinal phenotype is retinitis pigmentosa (RP- 45% of families), followed by cone/cone-rod dystrophy, Stargardt Disease and Usher syndrome. We identified the cause of disease in 51% of families, mainly due to mutations in ABCA4, USH2A, FAM161A, CNGA3, and EYS. IIRDC researchers were involved in the identification of 16 novel IRD genes. In parallel, IIRDC members are involved in the development of therapeutic modalities for these currently incurable diseases.

Conclusions: IIRDC works in close collaborative efforts aiming to continue and recruit for the genotype - phenotype study from the vast majority of Israeli IRD families, to identify all disease-causing mutations, and to tailor therapeutic interventions to each IRD patient.
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February 2019

Photoreceptor Guanylate Cyclase () Mutations Cause Retinal Dystrophies by Severe Malfunction of Ca-Dependent Cyclic GMP Synthesis.

Front Mol Neurosci 2018 25;11:348. Epub 2018 Sep 25.

Department of Neuroscience, Biochemistry Group, University of Oldenburg, Oldenburg, Germany.

Over 100 mutations in that encodes the photoreceptor guanylate cyclase GC-E are known to cause two major diseases: autosomal recessive Leber congenital amaurosis (arLCA) or autosomal dominant cone-rod dystrophy (adCRD) with a poorly understood mechanism at the molecular level in most cases. Only few mutations were further characterized for their enzymatic and molecular properties. GC-E activity is under control of neuronal Ca-sensor proteins, which is often a possible route to dysfunction. We investigated five recently-identified GC-E mutants that have been reported in patients suffering from arLCA (one large family) and adCRD/maculopathy (four families). Microsatellite analysis revealed that one of the mutations, c.2538G > C (p.K846N), occurred . To better understand the mechanism by which mutations that are located in different GC-E domains develop different phenotypes, we investigated the molecular consequences of these mutations by expressing wildtype and mutant GC-E variants in HEK293 cells. Analyzing their general enzymatic behavior, their regulation by Ca sensor proteins and retinal degeneration protein 3 (RD3) dimerization domain mutants (p.E841K and p.K846N) showed a shift in Ca-sensitive regulation by guanylate cyclase-activating proteins (GCAPs). Mutations in the cyclase catalytic domain led to a loss of enzyme function in the mutant p.P873R, but not in p.V902L. Instead, the p.V902L mutation increased the guanylate cyclase activity more than 20-fold showing a high GCAP independent activity and leading to a constitutively active mutant. This is the first mutation to be described affecting the GC-E catalytic core in a complete opposite way.
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http://dx.doi.org/10.3389/fnmol.2018.00348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167591PMC
September 2018

Carrier frequency analysis of mutations causing autosomal-recessive-inherited retinal diseases in the Israeli population.

Eur J Hum Genet 2018 08 30;26(8):1159-1166. Epub 2018 Apr 30.

Department of Ophthalmology, Hadassah-Hebrew University Medical Center, 91120, Jerusalem, Israel.

Inherited retinal diseases (IRDs) are heterogeneous phenotypes caused by variants in a large number of genes. Disease prevalence and the frequency of carriers in the general population have been estimated in only a few studies, but are largely unknown. To this end, we developed two parallel methods to calculate carrier frequency for mutations causing autosomal-recessive (AR) IRDs in the Israeli population. We created an SQL database containing information on 178 genes from gnomAD (including genotyping of 5706 Ashkenazi Jewish (AJ) individuals) and our cohort of >2000 families with IRDs. Carrier frequency for IRD variants and genes was calculated based on allele frequency values and the Hardy-Weinberg (HW) equation. We identified 399 IRD-causing variants in 111 genes in Israeli patients and AJ controls. For the AJ subpopulation, gnomAD and HW-based regression analysis showed high correlation, therefore allowing one to use HW-based data as a reliable estimate of carrier frequency. Overall, carrier frequency per subpopulation ranges from 1/2.2 to 1/9.6 individuals, with the highest value obtained for the Arab-Muslim subpopulation in Jerusalem reaching an extremely high carrier rate of 44.7%. Carrier frequency per gene ranges from 1/31 to 1/11994 individuals. We estimate the total carrier frequency for AR-IRD mutations in the Israeli population as over 30%, a relatively high carrier frequency with marked variability among subpopulations. Therefore, these data are highly important for more reliable genetic counseling and genetic screening. Our method can be adapted to study other populations, either based on allele frequency data or cohort of patients.
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http://dx.doi.org/10.1038/s41431-018-0152-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057931PMC
August 2018

The Genetics of Usher Syndrome in the Israeli and Palestinian Populations.

Invest Ophthalmol Vis Sci 2018 02;59(2):1095-1104

Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Purpose: Usher syndrome (USH) is the most common cause for deaf-blindness. It is genetically and clinically heterogeneous and prevalent in populations with high consanguinity rate. We aim to characterize the set of genes and mutations that cause USH in the Israeli and Palestinian populations.

Methods: Seventy-four families with USH were recruited (23 with USH type 1 [USH1], 33 with USH2, seven with USH3, four with atypical USH, and seven families with an undetermined USH type). All affected subjects underwent a full ocular evaluation. A comprehensive genetic analysis, including Sanger sequencing for the detection of founder mutations, homozygosity mapping, and whole exome sequencing in large families was performed.

Results: In 79% of the families (59 out of 74), an autosomal recessive inheritance pattern could be determined. Mutation detection analysis led to the identification of biallelic causative mutations in 51 (69%) of the families, including 21 families with mutations in USH2A, 17 in MYO7A, and seven in CLRN1. Our analysis revealed 28 mutations, 11 of which are novel (including c.802G>A, c.8558+1G>T, c.10211del, and c.14023A>T in USH2A; c.285+2T>G, c.2187+1G>T, c.3892G>A, c.5069_5070insC, c.5101C>T, and c.6196C>T in MYO7A; and c.15494del in GPR98).

Conclusions: We report here novel homozygous mutations in various genes causing USH, extending the spectrum of causative mutations. We also prove combined sequencing techniques as useful tools to identify novel disease-causing mutations. To the best of our knowledge, this is the largest report of a genetic analysis of Israeli and Palestinian families (n = 74) with different USH subtypes.
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http://dx.doi.org/10.1167/iovs.17-22817DOI Listing
February 2018

A homozygous founder missense variant in arylsulfatase G abolishes its enzymatic activity causing atypical Usher syndrome in humans.

Genet Med 2018 09 4;20(9):1004-1012. Epub 2018 Jan 4.

Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Purpose: We aimed to identify the cause of disease in patients suffering from a distinctive, atypical form of Usher syndrome.

Methods: Whole-exome and genome sequencing were performed in five patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and sensorineural hearing loss. Functional analysis of the wild-type and mutant proteins was performed in human fibrosarcoma cells.

Results: We identified a homozygous founder missense variant, c.133G>T (p.D45Y) in arylsulfatase G (ARSG). All patients shared a distinctive retinal phenotype with ring-shaped atrophy along the arcades engirdling the fovea, resulting in ring scotoma. In addition, patients developed moderate to severe sensorineural hearing loss. Both vision and hearing loss appeared around the age of 40 years. The identified variant affected a fully conserved amino acid that is part of the catalytic site of the enzyme. Functional analysis of the wild-type and mutant proteins showed no basal activity of p.D45Y.

Conclusion: Homozygosity for ARSG-p.D45Y in humans leads to protein dysfunction, causing an atypical combination of late-onset Usher syndrome. Although there is no evidence for generalized clinical manifestations of lysosomal storage diseases in this set of patients, we cannot rule out the possibility that mild and late-onset symptoms may appear.
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http://dx.doi.org/10.1038/gim.2017.227DOI Listing
September 2018

Nonsyndromic Retinitis Pigmentosa in the Ashkenazi Jewish Population: Genetic and Clinical Aspects.

Ophthalmology 2018 05 22;125(5):725-734. Epub 2017 Dec 22.

Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Electronic address:

Purpose: To analyze the genetic and clinical findings in retinitis pigmentosa (RP) patients of Ashkenazi Jewish (AJ) descent, aiming to identify genotype-phenotype correlations.

Design: Cohort study.

Participants: Retinitis pigmentosa patients from 230 families of AJ origin.

Methods: Sanger sequencing was performed to detect specific founder mutations known to be prevalent in the AJ population. Ophthalmologic analysis included a comprehensive clinical examination, visual acuity (VA), visual fields, electroretinography, color vision testing, and retinal imaging by OCT, pseudocolor, and autofluorescence fundus photography.

Main Outcome Measures: Inheritance pattern and causative mutation; retinal function as assessed by VA, visual fields, and electroretinography results; and retinal structural changes observed on clinical funduscopy as well as by pseudocolor, autofluorescence, and OCT imaging.

Results: The causative mutation was identified in 37% of families. The most prevalent RP-causing mutations are the Alu insertion (c.1297_8ins353, p.K433Rins31*) in the male germ cell-associated kinase (MAK) gene (39% of families with a known genetic cause for RP) and c.124A>G, p.K42E in dehydrodolichol diphosphate synthase (DHDDS) (33%). Additionally, disease-causing mutations were identified in 11 other genes. Analysis of clinical parameters of patients with mutations in the 2 most common RP-causing genes revealed that MAK patients had better VA and visual fields at relatively older ages in comparison with DHDDS patients. Funduscopic findings of DHDDS patients matched those of MAK patients who were 20 to 30 years older. Patients with DHDDS mutations were referred for electrophysiologic evaluation at earlier ages, and their cone responses became nondetectable at a much younger age than MAK patients.

Conclusions: Our AJ cohort of RP patients is the largest reported to date and showed a substantial difference in the genetic causes of RP compared with cohorts of other populations, mainly a high rate of autosomal recessive inheritance and a unique composition of causative genes. The most common RP-causing genes in our cohort, MAK and DHDDS, were not described as major causative genes in other populations. The clinical data show that in general, patients with biallelic MAK mutations had a later age of onset and a milder retinal phenotype compared with patients with biallelic DHDDS mutations.
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http://dx.doi.org/10.1016/j.ophtha.2017.11.014DOI Listing
May 2018

Whole-exome sequencing reveals POC5 as a novel gene associated with autosomal recessive retinitis pigmentosa.

Hum Mol Genet 2018 02;27(4):614-624

Department of Otorhinolaryngology, Radboud University Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.

Retinitis pigmentosa (RP), the most common form of inherited retinal degeneration, is associated with different groups of genes, including those encoding proteins involved in centriole and cilium biogenesis. Exome sequencing revealed a homozygous nonsense mutation [c.304_305delGA (p. D102*)] in POC5, encoding the Proteome Of Centriole 5 protein, in a patient with RP, short stature, microcephaly and recurrent glomerulonephritis. The POC5 gene is ubiquitously expressed, and immunohistochemistry revealed a distinct POC5 localization at the photoreceptor connecting cilium. Morpholino-oligonucleotide-induced knockdown of poc5 translation in zebrafish resulted in decreased length of photoreceptor outer segments and a decreased visual motor response, a measurement of retinal function. These phenotypes could be rescued by wild-type human POC5 mRNA. These findings demonstrate that Poc5 is important for normal retinal development and function. Altogether, this study presents POC5 as a novel gene involved autosomal recessively inherited RP, and strengthens the hypothesis that mutations in centriolar proteins are important cause of retinal dystrophies.
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http://dx.doi.org/10.1093/hmg/ddx428DOI Listing
February 2018

Genotype-functional-phenotype correlations in photoreceptor guanylate cyclase (GC-E) encoded by GUCY2D.

Prog Retin Eye Res 2018 03 20;63:69-91. Epub 2017 Oct 20.

Department of Neuroscience, University of Oldenburg, D-26111 Oldenburg, Germany. Electronic address:

The GUCY2D gene encodes for the photoreceptor guanylate cyclase GC-E that synthesizes the intracellular messenger of photoreceptor excitation cGMP and is regulated by intracellular Ca-sensor proteins named guanylate cyclase-activating proteins (GCAPs). Over 140 disease-causing mutations have been described so far in GUCY2D, 88% of which cause autosomal recessive Leber congenital amaurosis (LCA) while heterozygous missense mutations cause autosomal dominant cone-rod degeneration (adCRD). Mutations in GUCY2D are one of the major causes of all LCA cases and are the major cause of adCRD. A single amino acid, arginine at position 838, is likely to be the most sensitive one in GC-E as four single mutations and two complex mutations were reported to affect R838. The biochemical effect of 45 GC-E variants was studied showing a clear genotype-phenotype correlation: LCA-causing mutations either show reduced ability or complete inability to synthesize cGMP from GTP, while CRD-causing mutations are functional, but shift the Ca-sensitivity of the GC-E - GCAP complex. Eight animal models of retinal guanylate cyclase deficiency have been reported including knockout (KO) mouse and chicken models. These two models were used for gene augmentation therapy that yielded promising results. Here we integrate the available information on the genetics, biochemistry and phenotype that is related to GUCY2D mutations. These data clearly show that mutation type (missense versus null) and localization (dimerization domain versus other protein domains) are correlated with the pattern of inheritance, impact on enzymatic function and retinal phenotype. Such clear correlation is unique to GUCY2D while mutations in many other retinal disease genes show variable phenotypes and lack of available biochemical assays.
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http://dx.doi.org/10.1016/j.preteyeres.2017.10.003DOI Listing
March 2018

Whole-Exome Sequencing Identifies Biallelic IDH3A Variants as a Cause of Retinitis Pigmentosa Accompanied by Pseudocoloboma.

Ophthalmology 2017 07 13;124(7):992-1003. Epub 2017 Apr 13.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands. Electronic address:

Purpose: To identify the genetic cause of and describe the phenotype in 4 families with autosomal recessive retinitis pigmentosa (arRP) that can be associated with pseudocoloboma.

Design: Case series.

Participants: Seven patients from 4 unrelated families with arRP, among whom 3 patients had bilateral early-onset macular pseudocoloboma.

Methods: We performed homozygosity mapping and whole-exome sequencing in 5 probands and 2 unaffected family members from 4 unrelated families. Subsequently, Sanger sequencing and segregation analysis were performed in additional family members. We reviewed the medical history of individuals carrying IDH3A variants and performed additional ophthalmic examinations, including full-field electroretinography, fundus photography, fundus autofluorescence imaging, and optical coherence tomography.

Main Outcome Measures: IDH3A variants, age at diagnosis, visual acuity, fundus appearance, visual field, and full-field electroretinography, fundus autofluorescence, and optical coherence tomography findings.

Results: We identified 7 different variants in IDH3A in 4 unrelated families, that is, 5 missense, 1 nonsense, and 1 frameshift variant. All participants showed symptoms early in life, ranging from night blindness to decreased visual acuity, and were diagnosed between the ages of 1 and 11 years. Four participants with biallelic IDH3A variants displayed a typical arRP phenotype and 3 participants were diagnosed with arRP and pseudocoloboma of the macula.

Conclusions: IDH3A variants were identified as a novel cause of typical arRP in some individuals associated with macular pseudocoloboma. We observed both phenotypes in 2 siblings carrying the same compound heterozygous variants, which could be explained by variable disease expression and warrants caution when making assertions about genotype-phenotype correlations.
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http://dx.doi.org/10.1016/j.ophtha.2017.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868413PMC
July 2017

OR2W3 sequence variants are unlikely to cause inherited retinal diseases.

Ophthalmic Genet 2016 12 18;37(4):366-368. Epub 2016 Feb 18.

b Department of Computational Biology , Unit of Medical Genetics, University of Lausanne , Lausanne , Switzerland.

Because of its formidable throughput, whole exome sequencing (WES) is significantly increasing the power of investigations in ophthalmic genetics. However, when applied to Mendelian conditions, WES results often contain many false positives, e.g. candidate mutations that are unrelated to the disease. For instance, highly polymorphic genes such as olfactory receptor genes carry a plethora of both common and rare alleles that are part of the normal set of variations of the human genome. Following a WES-based study, the heterozygous missense variant p.R142W in the olfactory receptor gene OR2W3 was recently reported as a pathogenic mutation causing autosomal dominant retinitis pigmentosa (RP). This variant, however, was not scored against data contained in public WES repositories, indicating that p.R142W is present in ~1 in 6500 control individuals. Therefore, if it really was pathogenic, it would be responsible for a percentage of dominant RP cases corresponding to the double of those recorded so far worldwide, or 2/3 of all RP cases (dominant, recessive, and X-linked). We therefore conclude that this sequence variant, and hence the OR2W3 gene, do not cause RP. Prompted by these findings and based on simple principles of population genetics, we suggest that WES studies should consider DNA variants as the possible cause of dominant RP only if they are present in less than 1:100,000 individuals from the general population. In addition, we propose that DNA variants belonging to highly polymorphic genes should be carefully analyzed at the functional level before inferring their pathogenicity, in RP or other genetic diseases.
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http://dx.doi.org/10.3109/13816810.2015.1081252DOI Listing
December 2016

Bi-allelic Truncating Mutations in CEP78, Encoding Centrosomal Protein 78, Cause Cone-Rod Degeneration with Sensorineural Hearing Loss.

Am J Hum Genet 2016 09;99(3):777-784

Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel. Electronic address:

Inherited retinal diseases (IRDs) are a diverse group of genetically and clinically heterogeneous retinal abnormalities. The present study was designed to identify genetic defects in individuals with an uncommon combination of autosomal recessive progressive cone-rod degeneration accompanied by sensorineural hearing loss (arCRD-SNHL). Homozygosity mapping followed by whole-exome sequencing (WES) and founder mutation screening revealed two truncating rare variants (c.893-1G>A and c.534delT) in CEP78, which encodes centrosomal protein 78, in six individuals of Jewish ancestry with CRD and SNHL. RT-PCR analysis of CEP78 in blood leukocytes of affected individuals revealed that the c.893-1G>A mutation causes exon 7 skipping leading to deletion of 65bp, predicted to result in a frameshift and therefore a truncated protein (p.Asp298Valfs(∗)17). RT-PCR analysis of 17 human tissues demonstrated ubiquitous expression of different CEP78 transcripts. RNA-seq analysis revealed three transcripts in the human retina and relatively higher expression in S-cone-like photoreceptors of Nrl-knockout retina compared to rods. Immunohistochemistry studies in the human retina showed intense labeling of cone inner segments compared to rods. CEP78 was reported previously to interact with c-nap1, encoded by CEP250 that we reported earlier to cause atypical Usher syndrome. We conclude that truncating mutations in CEP78 result in a phenotype involving both the visual and auditory systems but different from typical Usher syndrome.
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http://dx.doi.org/10.1016/j.ajhg.2016.07.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011076PMC
September 2016