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Background: Patients with Xp22.3 interstitial and terminal deletions have been shown to be affected by intellectual disability (ID) or autism. Previously, "VCX-A" (variably charged protein X-A), located at Xp22.3, was introduced as a gene for ID and its presence was suggested to be sufficient to maintain normal mental development. Recent reports suggest that mutations in "NLGN4" (neuroligin 4), located at that same region, are involved in autistic disorders and ID. Methods: In the current case study, we clinically and molecularly describe a pedigree of three generations affected by contiguous gene syndrome that includes features of X-linked ichthyosis and Kallmann syndrome. Results: Molecular analysis revealed the presence of an interstitial deletion spanning approximately 4.5Mb at Xp22.3. The centromeric breakpoint was localized between markers DXS1467 and DXS8051, proximal to "KAL-1." The telomeric breakpoint was localized between markers DXS89 and DXS1060, distal to "NLGN4." The deletion of "VCX-A" and "NLGN4" in this family prompted us to examine the cognitive functions of our two adult patients using comprehensive intellectual and neurocognitive assessment. Normal intellectual function was found in one patient and mild ID was revealed in the other. Neither patient met any Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition criteria for a pervasive developmental disorder such as autism. Conclusions: These findings suggest that deletion of "VCX-A" and "NLGN4" can result in variable phenotypic features and that normal mental development can be achieved despite this deletion, emphasizing the importance of environmental factors and possible modifier genes.

Objectives: To evaluate the yield and utility of the routine use of chromosomal microarray analysis (CMA) for prenatal genetic diagnosis in a large cohort of pregnancies with normal ultrasound (US) at the time of genetic testing, compared with pregnancies with abnormal US findings.Methods: We reviewed all prenatal CMA results in our center between November 2013 and December 2018. The prevalence of different CMA results in pregnancies with normal US at the time of genetic testing ('low-risk pregnancies'), was compared with that in pregnancies with abnormal US findings ('high-risk pregnancies'). Medical records were searched in order to evaluate subsequent US follow-up and the outcome of pregnancies with a clinically relevant copy-number variant (CNV), i.e. a pathogenic or likely pathogenic CNV or a susceptibility locus for disease with > 10% penetrance, related to early-onset disease in the low-risk group.Results: In a cohort of 6431 low-risk pregnancies that underwent CMA, the prevalence of a clinically significant CNV related to early-onset disease was 1.1% (72/6431), which was significantly lower than the prevalence in high-risk pregnancies (4.9% (65/1326)). Of the low-risk pregnancies, 0.4% (27/6431) had a pathogenic or likely pathogenic CNV, and another 0.7% (45/6431) had a susceptibility locus with more than 10% penetrance. Follow-up of the low-risk pregnancies with a clinically significant early-onset CNV revealed that 31.9% (23/72) were terminated, while outcome data were missing in 26.4% (19/72). In 16.7% (12/72) of low-risk pregnancies, an US abnormality was discovered later on in gestation, after genetic testing had been performed.Conclusion: Although the background risk of identifying a clinically significant early-onset abnormal CMA result in pregnancies with a low a-priori risk is lower than that observed in high-risk pregnancies, the risk is substantial and should be conveyed to all pregnant women. © 2020 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

We aimed to assess the indications for late amniocentesis, safety, genetic test results (especially chromosomal microarray) and pregnancy outcome. The indications for the procedure, any complications, CMA results and pregnancy outcome were recorded and analysed. Nine fetuses were diagnosed with aneuploidy (3%) and another nine had a pathogenic copy number variation (3%) suggesting that CMA doubled the diagnostic yield of chromosomal analysis. [Extracted from the article]

To explore the indications and diagnostic outcomes of fetal exome sequencing analyses performed in a single referral centre. IINT showed that exome analysis did not reveal any known or probable pathogenic variants in IINT cases, whereas among fetuses with anatomic malformation, a molecular diagnosis was reached in 16/65 (25%). [Extracted from the article]

Purpose: Bilateral pediatric cataract (BPC) is one of the most common causes of childhood visual impairment and blindness worldwide. A significant percentage of pediatric cataracts are caused by genetic alterations. We aim to characterize the set of genes and variants that cause BPC in the Israeli and Palestinian populations and to assess genotype-phenotype correlation., Methods: Retrospective study in a multidisciplinary center for visual impairment, located in a tertiary medical center. Medical charts of families who underwent genetic counseling because of BPC in a family member were reviewed. Clinical characteristics and genetic tests results were obtained from medical records of affected subjects., Results: Twenty-two families (47 patients) underwent genetic counseling and completed genetic testing. Causative variants were identified in 18/22 (81.8%) of the families, including 3 novel variants. Genetic testing used included mainly panel for congenital cataracts and whole exome sequencing. Eleven families performed genetic testing with the intention of future pregnancy planning. Main causative genes identified were crystalline genes followed by transcription factor genes. BCOR gene variants were associated with persistent fetal vasculature (PFV) cataract in two of three families., Conclusions: Combined molecular techniques are useful in identifying variants causing pediatric cataracts and showed a high detection rate in our population. BCOR gene variants might be associated with PFV type of cataracts. The study of pathogenic variants may aid in family planning and prevention of pediatric cataracts in future pregnancies. Additionally, in certain cases, it assists in diagnosing non-suspected syndromic types of pediatric cataracts., (© 2024. The Author(s).)

Background: Chromosomal-microarray-analysis (CMA) may reveal susceptibility-loci (SL) of varied penetrance for autism-spectrum-disorder (ASD) and other neurodevelopmental conditions. Attitudes of women/parents to disclosure of SL during pregnancy are understudied., Methods: A multiple-choice questionnaire was distributed to postpartum women. Data were collected on women's interest to receive prenatal genetic information with various levels of penetrance., Results: Women's (n = 941) disclosure choices were dependent on the magnitude of risk: approximately 70% supported disclosure of either full or 40% penetrance, 53% supported disclosure at a 20% risk threshold, and 40% supported disclosure at 10% or less. Although most women supported, rejected or were indecisive about disclosure consistently across all risk levels, nearly one-quarter (24%) varied their responses based on penetrance, and this was associated with religiosity, education, parity and concern about fetal health (p-values <0.04). Among those who varied their choices, the risk threshold was lower among secular women (20%) than among ultraorthodox women (40%). In a multivariable analysis, ultraorthodox women were much less likely to vary their choices on ASD disclosure compared with secular women (aOR = 0.37, p < 0.001)., Conclusion: Women's attitudes toward disclosure are influenced by the level of risk and their individual characteristics. We therefore encourage engaging women/couples in disclosure decisions regarding uncertain and probabilistic results from prenatal genomic tests., (© 2024 John Wiley & Sons Ltd.)

Background: To assess the main causes leading to childhood visual impairment/blindness in a center for low vision in Israel and to analyze the literature on pediatric blinding diseases in developed countries., Methods: Retrospective study based on observational case series. Data were obtained from medical records of visually impaired children, seen at a national referral low vision center. Children were divided into two groups: moderate visual impairment (6/18 to 6/60) and severe visual impairment (SVI)/blindness (<6/60). Inherited eye diseases (IED) were grouped together for analysis. Data from the Israeli blind registry from the same period of time were analyzed for comparison. A review of literature on childhood blindness in developed countries since 2000 was conducted., Results: A total of 1393 children aged 0-18 years were included in the study. Moderate visual impairment was seen in 1025 (73.6%) and SVI/blindness in 368 (26.4%) of the studied children. Among blind children, IED accounted for at least 51% of all diagnoses, including mainly albinism and retinal dystrophies. IED prevalence was equally high in both main ethnic groups (Jewish and Arab Muslims). Non-IED (22.6%) included mainly patients with cerebral visual impairment and retinopathy of prematurity., Conclusions: The leading cause of childhood visual impairment and blindness in our patient cohort was IED. Analyses of the literature from the last two decades show that IED are a major cause for SVI/childhood blindness in other developed countries as well. Updated patterns of global childhood blindness may suggest a need for new approach for screening programs and modern tactics for prevention., (© 2021. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Hermansky-Pudlak syndrome (HPS) is a group of rare autosomal recessive disorders characterized by oculocutaneous albinism (OCA) and bleeding diathesis. To date, 11 HPS types have been reported (HPS-1 to HPS-11), each defined by disease-causing variants in specific genes. Variants in the HPS1 gene were found in approximately 15% of HPS patients, most of whom harbor the Puerto Rican founder mutation. In this study, we report six affected individuals from three nonconsanguineous families of Ashkenazi Jewish descent, who presented with OCA and multiple ecchymoses and had normal platelet number and size. Linkage analysis indicated complete segregation to HPS3 . Sequencing of the whole coding region and the intron boundaries of HPS3 revealed a heterozygous c.1163+1G>A variant in all six patients. Long-range PCR amplification revealed that all affected individuals also carry a 14,761bp deletion that includes the 5'UTR and exon 1 of HPS3 , encompassing regions with long interspersed nuclear elements. The frequency of the c.1163+1G>A splice site variant was found to be 1:200 in the Ashkenazi Jewish population, whereas the large deletion was not detected in 300 Ashkenazi Jewish controls. These results present a novel HPS3 deletion mutation and suggest that the prevalence of HPS-3 in Ashkenazi Jews is more common than previously thought., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Marek-Yagel, Abudi-Sinreich, Macarov, Veber, Shalva, Philosoph, Pode-Shakked, Malicdan and Anikster.)

Background: Advanced prenatal genomic technologies can identify risks for adult-onset (AO) conditions in the fetus, challenging the traditional purpose of prenatal testing. Professional guidelines commonly support disclosure of high-penetrance AO actionable conditions, yet attitudes of women/parents to these findings and factors affecting their attitudes are understudied., Methods: We explored 941 (77% response rate) postpartum women's attitudes towards receiving prenatal genetic information, and associations of sociodemographic, medical and psychological characteristics with their choices, focusing on AO conditions., Results: Women largely support the disclosure of actionable AO findings (58.4%), in line with professional guidelines. A third of the women also supported the disclosure of non-actionable AO conditions. Stronger religious observance (p < 0.001) and higher psychological distress (p = 0.024) were associated with decreased interest in receiving actionable AO conditions, whereas higher concern for fetal health yielded increased interest (p = 0.032). Attitudes towards disclosure were strongly associated with women's perceived benefit of such information for their own, partner's, and future child's health. Termination of pregnancy based on such information received very little support., Conclusion: In-light of the demonstrated understanding of nuanced genetic information and the observed diversity in attitudes, a culturally competent opt-in/out policy could be considered. If full-disclosure is practiced, support should be provided to those expressing higher levels of distress., (© 2022 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

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 COL18A1 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.

Purpose: To report genetic and clinical findings in a case series of 10 patients from eight unrelated families diagnosed with Senior-Løken syndrome., Methods: A retrospective study of patients with Senior-Løken syndrome. Data collected included clinical findings electroretinography and ocular imaging. Genetic analysis was based on molecular inversion probes, whole-exome sequencing (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 3 families. Patients harboring mutations in IQCB1 were diagnosed with Leber congenital amaurosis, while patients with NPHP4 and NPHP1 mutations showed early and sector retinitis pigmentosa, respectively. Full-field electroretinography was extinct for 6 of 10 patients, moderately decreased for two, and unavailable for another 2 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., Conclusion: 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.

Purpose: Although most (or even all) genes that can cause achromatopsia (ACHM) when mutated are known, some patients are still negative for mutations even after screening the coding sequence of all known genes. Our aim was to characterize the genetic and clinical aspects of a deep intronic (c.1663-1205G>A, IVS14-1205G>A) CNGB3 variant., Methods: Clinical evaluation included visual acuity testing, refractive error, a full clinical eye exam, full-field electroretinography (ffERG), color vision testing, and retinal imaging. Genetic analysis of CNGB3 exons, as well as part of intron 14, was performed by Sanger sequencing of PCR products., Results: Screening for the CNGB3 c.1663-1205G>A variant revealed 17 patients belonging to 12 unrelated families who were either homozygous for this variant (7 cases, 5 families) or heterozygous in combination with another heterozygous known CNGB3 mutation (10 cases, 7 families). All patients were diagnosed with cone-dominated disease, mainly complete ACHM. In all cases, the disease had an early, congenital onset. Visual acuity was markedly impaired, ranging between 0.07 and 0.32 on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale (logarithm of the minimum angle of resolution [LogMAR] +1.18 to +0.50), with a mean visual acuity of 0.15 ETDRS (LogMAR +0.80). Additional typical signs of ACHM, including impaired color vision, light aversion, and nystagmus, were also noted in all patients. As is common in ACHM, fundus exams were largely unremarkable in most patients, with mild foveal RPE changes seen in some cases at older ages. ERG was available for 14 out of 17 patients, and in all of them-including infants from the age of 6 months-cone responses were nondetectable. In a few cases, rod involvement was also evident, with a mild reduction of amplitudes. Optical coherence tomography (OCT) imaging showed irregularity of the ellipsoid zone in the foveal area in some patients., Conclusions: CNGB3 is the most common cause of ACHM in patients of European descent; this is mainly due to a panethnic founder mutation, c.1148del. Here, we report on an intronic CNGB3 variant that is more frequent than the c.1148del mutation in our cohort of Jewish patients. Among our ACHM cohort, 63.7% of patients had biallelic CNGA3 mutations and 26.4% had biallelic CNGB3 mutations. The phenotype of patients harboring the intronic mutation falls largely within the spectrum commonly seen in ACHM. Since gene therapy for CNGB3 is currently under investigation, these patients might benefit from this promising therapy. Given that this variant is not detectable by current commonly used genetic testing platforms, these patients could easily be missed., (Copyright © 2021 Molecular Vision.)

Objective: Israel is one of the first countries to incorporate chromosomal microarray analysis into routine prenatal care. We explored attitudes of Israeli healthcare professionals (HCPs) towards the disclosure of challenging findings: variants of uncertain clinical significance (VUS), susceptibility loci (SL) for neurodevelopmental disorders and variants associated with adult-onset (AO) conditions. Particularly, we sought their views on providing parental choice regarding the disclosure of these findings., Methods: Twenty-nine in-depth interviews were conducted with genetic counselors (n = 19), medical geneticists (n = 4), medical geneticists that are trained in and practice fetal medicine (n = 3), and fetal medicine experts (n = 3)., Results: Most participants (n = 24) supported parental choice regarding uncertain genetic information. Engaging parents in disclosure decisions allows avoidance from potentially anxiety-provoking information, practicing parental autonomy, and better preparation in cases where uncertain findings are identified. HCPs believed that given appropriate preparation, parents can make informed decisions. Four participants believed that disclosure should be based on professional judgment and one supported full-disclosure. Unlike VUS or SL, all interviewees agreed that in cases of medically actionable AO conditions, the benefit of disclosure outweighs the damage., Conclusion: HCPs attitudes are largely in-line with the Israeli practice of involving parents in disclosure decisions regarding uncertain information. This may mitigate disclosure dilemmas and allow personalized disclosure based on parents' views., (© 2021 John Wiley & Sons Ltd.)

Inherited eye diseases (IED) are among the most common causes for childhood and young adulthood blindness in developed countries. Genetic counseling and testing have become an essential part of caregiving for families affected by one of these severe ocular pathologies. The objective of our study is to describe our experience during the 2020 (COVID-19) pandemic, following a practice protocol of safe genetic counseling for inherited ophthalmic diseases. We conducted a review of the genetic counseling practices from January until December 2020 in a multidisciplinary clinic for patients with visual impairment, in a tertiary hospital. The new protocol covered patient screening, required personal protective equipment, and the implementation of telemedicine. One hundred and eighty-three counseling sessions were done in this period of time; 33/183 were telemedicine counseling. The results of this study indicate that the practice of genetic counseling in regard to inherited eye diseases in the era of COVID-19 is effective and safe. Despite the high risk of infectivity that threatened healthcare professionals, safety measures adopted to reduce the risk of infection allowed us to prevent the cancelation of routine counseling, while keeping patient care our priority. The use of telemedicine was a very useful tool for providing counseling during lockdown periods in 2020., (© 2021 National Society of Genetic Counselors.)

Nonsyndromic hearing loss is genetically heterogeneous. Despite comprehensive genetic testing, many cases remain unsolved because the clinical significance of identified variants is uncertain or because biallelic pathogenic variants are not identified for presumed autosomal recessive cases. Common synonymous variants are often disregarded. Determining the pathogenicity of synonymous variants may improve genetic diagnosis. We report a synonymous variant c.9861 C > T/p.(Gly3287=) in MYO15A in homozygosity or compound heterozygosity with another pathogenic or likely pathogenic MYO15A variant in 10 unrelated families with nonsyndromic sensorineural hearing loss. Biallelic variants in MYO15A were identified in 21 affected and were absent in 22 unaffected siblings. A mini-gene assay confirms that the synonymous variant leads to abnormal splicing. The variant is enriched in the Ashkenazi Jewish population. Individuals carrying biallelic variants involving c.9861 C > T often exhibit progressive post-lingual hearing loss distinct from the congenital profound deafness typically associated with biallelic loss-of-function MYO15A variants. This study establishes the pathogenicity of the c.9861 C > T variant in MYO15A and expands the phenotypic spectrum of MYO15A-related hearing loss. Our work also highlights the importance of multicenter collaboration and data sharing to establish the pathogenicity of a relatively common synonymous variant for improved diagnosis and management of hearing loss.

Mutations in more than 150 genes are responsible for inherited hearing loss, with thousands of different, severe causal alleles that vary among populations. The Israeli Jewish population includes communities of diverse geographic origins, revealing a wide range of deafness-associated variants and enabling clinical characterization of the associated phenotypes. Our goal was to identify the genetic causes of inherited hearing loss in this population, and to determine relationships among genotype, phenotype, and ethnicity. Genomic DNA samples from informative relatives of 88 multiplex families, all of self-identified Jewish ancestry, with either non-syndromic or syndromic hearing loss, were sequenced for known and candidate deafness genes using the HEar-Seq gene panel. The genetic causes of hearing loss were identified for 60% of the families. One gene was encountered for the first time in human hearing loss: ATOH1 (Atonal), a basic helix-loop-helix transcription factor responsible for autosomal dominant progressive hearing loss in a five-generation family. Our results show that genomic sequencing with a gene panel dedicated to hearing loss is effective for genetic diagnoses in a diverse population. Comprehensive sequencing enables well-informed genetic counseling and clinical management by medical geneticists, otolaryngologists, audiologists, and speech therapists and can be integrated into newborn screening for deafness., (© 2020 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Objective: To examine the choices of women with both high-risk and low-risk pregnancies who are undergoing prenatal chromosomal microarray analysis in a clinical setting regarding three challenging types of findings: variants of uncertain clinical significance, susceptibility loci for neurodevelopmental disorders, and copy number variants associated with risks for adult-onset conditions. We assessed whether women's choices were associated with indications for testing or with one-on-one pretest genetic counseling., Methods: In this cross-sectional study, medical records of women who underwent invasive prenatal chromosomal microarray analysis testing (N=1,070) at Hadassah Medical Center between June 2017 and February 2018 were examined for testing indications, choices regarding chromosomal microarray analysis findings, and type of pretest genetic counseling. Multivariable analyses to assess associations with testing indication and prior genetic counseling were carried out using logistic regression models., Results: In total, 56% of women (n=593) chose to be informed of all three types of findings and 20% (n=218) chose not to be informed of any of the findings beyond high-penetrance childhood-onset pathogenic findings. Variants of uncertain clinical significance as a single choice was the least-selected finding (2.5%, n=27). Low-risk pregnancies (ie, those with normal biochemical screening and fetal ultrasound examinations) were associated with increased interest in receiving genetic information about adult-onset conditions (adjusted odds ratio [aOR] 1.7; 95% CI 1.18-2.33) and susceptibility loci (aOR 1.5; 95% CI 1.08-2.10)., Conclusion: Women with both high-risk and low-risk pregnancies were generally more likely to choose to receive additional genetic information, albeit differences in preferences depend on testing indication and type of pretest counseling.

Background : Mutations in CACNA1F 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. Materials and Methods : 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). Results : 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 CACNA1F (NM&#95;001256789.2) in all three families, encompassed by a shared haplotype Conclusions : Our data suggests that p.(F742C) in CACNA1F 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.

Purpose: Aniridia is a rare panocular disorder caused by mutations in the PAX6 gene and characterized mainly by iris hypoplasia. Here, we present six families with a history of low vision/blindness with a previously undiagnosed mild aniridia phenotype with minimal iris changes., Methods: Retrospective case series of patients diagnosed with a subtle aniridia phenotype characterized by minimal iris abnormalities, foveal hypoplasia, and an identified mutation in PAX6. Data collection from patient's charts included ocular examination findings, visual acuity, refraction, and clinical pictures when available. Genetic analysis was performed by isolation of genomic DNA from peripheral blood. The main outcome was the identification of patients with mild aniridia harboring a PAX6 mutation., Results: In all six families, the phenotype included minimal corectopia and foveal hypoplasia; nystagmus was present in 10 out of 11 patients. A PAX6 mutation was identified in all six families; three of these mutations were identified previously, and three are novel mutations. All the mutations are located within the conventional 128-residue paired domain of PAX6., Conclusions: A mild form of aniridia should be considered in the differential diagnosis of patients with low vision associated with mild iris abnormalities, nystagmus, and foveal hypoplasia. To ensure an accurate diagnosis of aniridia, minimal pupillary changes and/or incipient keratopathy should be examined. The broad phenotypic heterogeneity among aniridia leads to the fact that eye care clinicians must have a high index of suspicion for the disease when seeing undiagnosed low vision patients, because proper diagnosis can improve management as well as facilitate genetic testing and counselling.

Background: In developed countries, genetically inherited eye diseases are responsible for a high percentage of childhood visual impairment. We aim to report our experience using preimplantation genetic diagnostics (PGD) in order to avoid transmitting a genetic form of eye disease associated with childhood visual impairment and ocular cancer., Material and Methods: Retrospective case series of women who underwent in vitro fertilization (IVF) and PGD due to a familial history of inherited eye disease and/or ocular cancer, in order to avoid having a child affected with the known familial disease. Each family underwent genetic testing in order to identify the underlying disease-causing mutation. IVF and PGD treatment were performed; unaffected embryos were implanted in their respective mothers., Results: Thirty-five unrelated mothers underwent PGD, and the following hereditary conditions were identified in their families: albinism (10 families); retinitis pigmentosa (7 families); retinoblastoma (4 families); blue cone monochromatism, achromatopsia, and aniridia (2 families each); and Hermansky-Pudlak syndrome, Leber congenital amaurosis, Norrie disease, papillorenal syndrome, primary congenital cataract, congenital glaucoma, Usher syndrome type 1F, and microphthalmia with coloboma (1 family each). Following a total of 88 PGD cycles, 18 healthy (i.e., unaffected) children were born., Conclusions: Our findings underscore the importance an ophthalmologist plays in informing patients regarding the options now available for using prenatal and preimplantation genetic diagnosis to avoid having a child with a potentially devastating genetic form of eye disease or ocular cancer. This strategy is highly relevant, particularly given the limited options currently available for treating these conditions.

Autosomal recessive polycystic kidney disease (ARPKD) is usually detected late in pregnancies in embryos with large echogenic kidneys accompanied by oligohydramnios. Hundreds of private pathogenic variants have been identified in the large PKHD1 gene in various populations. Yet, because of the large size of the gene, segregation analysis of microsatellite polymorphic markers residing in the PKDH1 locus has commonly been utilized for prenatal diagnosis. Keeping in mind the limitations of this strategy, we utilized it for testing 7 families with affected fetuses or newborns, of which in 5 at least one parent was Ashkenazi, and identified that the same haplotype was shared by the majority of the Ashkenazi parents (7/9). This led us to suspect that they carry the same founder mutation. Whole Exome analysis of DNA from a fetus of one of the families detected an already known pathogenic variant c.3761&#95;3762delCCinsG, an indel variant resulting in frameshift (p.Ala1254GlyfsX49). This variant was detected in 9 parents (5 families), of them 7 individuals were Ashkenazi and one Moroccan Jew who shared the same haplotype, and one Ashkenazi, who carried the same variant on a recombinant haplotype. Screening for this variant in 364 Ashkenazi individuals detected 2 carriers. These findings suggest that although c.3761&#95;3762delCCinsG is considered one of the frequent variants detected in unrelated individuals, and was thought to have occurred independently on various haplotypes, it is in fact a founder mutation in the Ashkenazi population., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

The cellular response to DNA damage is essential for maintenance of genomic stability. MDC1 is a key member of the DNA damage response. It is an adaptor protein that binds and recruits proteins to sites of DNA damage, a crucial step for a proper response. MDC1 contains several protein-protein interacting modules, including a tandem BRCT domain that mediates various interactions involving MDC1. Here we demonstrate that MDC1 binds directly to RAP80, which is a DNA damage response protein that recruits BRCA1 to sites of damage. The interaction between MDC1 and RAP80 requires the tandem BRCT domain of MDC1 and the ubiquitin-interacting motifs of RAP80. Moreover, the interaction depends on UBC13, an E2 ubiquitin ligase that catalyzes K63-linked poly-ubiquitin chain formation. The results highly propose that the interaction between MDC1 and RAP80 depends on a ubiquitylation event, which we found to take place on K-1977 of MDC1. This study provides the first evidence that interactions involving MDC1 can be regulated by ubiquitylation., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Kindler syndrome (OMIM 173650) is an autosomal recessive condition characterized by skin blistering, skin atrophy, photosensitivity, colonic inflammation and mucosal stenosis. Fewer than 100 cases have been described in the literature. First reported in 1954, the molecular basis of Kindler syndrome was elucidated in 2003 with the discovery of FERMT1 (KIND1) loss-of-function mutations in affected individuals. The FERMT1 gene encodes kindlin-1 (also known as fermitin family homologue 1), a 77 kDa protein that localizes at focal adhesions, where it plays an important role in integrin signalling. In the current study, we describe five novel and three recurrent loss-of-function FERMT1 mutations in eight individuals with Kindler syndrome, and provide an overview of genotype-phenotype correlation in this disorder.

In Israel, Krabbe disease is frequent in two Moslem Arab villages in the Jerusalem area. In this paper we present our experience of almost four decades with diagnosis of Krabbe disease, carrier screening and prenatal diagnosis. The screening program is well accepted by the community, and there is a clear trend towards premarital testing. The screening program and prenatal diagnosis have led to a decrease in the incidence of Krabbe disease from 1.6 per 1,000 live births to 0.82 per 1,000., (Copyright © 2011 Wiley-Liss, Inc.)