Publications by authors named "Michal Macarov"

14 Publications

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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 synonymous variant in MYO15A enriched in the Ashkenazi Jewish population causes autosomal recessive hearing loss due to abnormal splicing.

Eur J Hum Genet 2021 Jan 4. Epub 2021 Jan 4.

Harvard Medical School Center for Hereditary Deafness, Boston, MA, 02115, USA.

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.
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http://dx.doi.org/10.1038/s41431-020-00790-wDOI Listing
January 2021

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

Spectrum of genes for inherited hearing loss in the Israeli Jewish population, including the novel human deafness gene ATOH1.

Clin Genet 2020 10 24;98(4):353-364. Epub 2020 Aug 24.

Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.

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.
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http://dx.doi.org/10.1111/cge.13817DOI Listing
October 2020

Universal chromosomal microarray analysis reveals high proportion of copy number variants in low risk pregnancies.

Ultrasound Obstet Gynecol 2020 Mar 23. Epub 2020 Mar 23.

Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Objectives: This study's purpose was to evaluate the yield and utility of routine use of Chromosomal Microarray Analysis (CMA) for prenatal genetic diagnosis in a large cohort of pregnancies with normal Ultrasound (US), termed low risk pregnancies, compared to pregnancies with abnormal US findings, termed high risk pregnancies.

Methods: We reviewed all prenatal CMA results in our center between November 2013 and December 2018. The prevalence of the different CMA results in the Low Risk Pregnancies was compared with CMA results in the high risk pregnancies. Prevalence of the different CMA results in the groups were stratified according to specific indications for testing. We also searched medical records in order to evaluate subsequent US follow-up and the outcome of pregnancies in the low risk pregnancies with clinically significant abnormal CMA results.

Results: In a cohort of 6431 CMAs performed in low risk pregnancies the prevalence of clinically significant early onset abnormal CMA results was 1.12% (72/6431), significantly lower than the prevalence in high risk pregnancies (4.98%, 66/1326). Some 0.42% (27/6431) of the low risk pregnancies had pathogenic or likely pathogenic Copy Number Variation (CNV) and another 0.7% (45/6431) had a susceptibility locus with more than 10% penetrance. Follow-up of the pregnancies revealed that 32% (23/72) of pregnancies were terminated when there was a clinically significant early onset CNV. In 17% (12/72) of these pregnancies US abnormalities were discovered later on, after genetic testing was performed.

Conclusion: Albeit lower than observed in high risk pregnancies, the background risk of identifying an abnormal clinically significant CMA result in pregnancies at a low a priori risk for these findings is substantial, and should be conveyed to all pregnant women. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/uog.22026DOI Listing
March 2020

Information Women Choose to Receive About Prenatal Chromosomal Microarray Analysis.

Obstet Gynecol 2020 01;135(1):149-157

Braun School of Public Health, the Hebrew University of Jerusalem; and the Department of Genetics and Metabolic Diseases, Hebrew University Hadassah Medical Center, Jerusalem, Israel.

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.
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http://dx.doi.org/10.1097/AOG.0000000000003610DOI Listing
January 2020

Non-confined long-standing blood chimerism in a spontaneous monochorionic dizygotic twin pregnancy.

Int J Gynaecol Obstet 2020 03 26;148(3):399-400. Epub 2019 Nov 26.

Department of Obstetrics & Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

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http://dx.doi.org/10.1002/ijgo.13022DOI Listing
March 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

Mild aniridia phenotype: an under-recognized diagnosis of a severe inherited ocular disease.

Graefes Arch Clin Exp Ophthalmol 2018 Nov 30;256(11):2157-2164. Epub 2018 Aug 30.

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

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.
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http://dx.doi.org/10.1007/s00417-018-4119-1DOI Listing
November 2018

Preimplantation genetic diagnosis as a strategy to prevent having a child born with an heritable eye disease.

Ophthalmic Genet 2018 08 21;39(4):450-456. Epub 2018 May 21.

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

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.
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http://dx.doi.org/10.1080/13816810.2018.1474368DOI Listing
August 2018

An Ashkenazi founder mutation in the PKHD1 gene.

Eur J Med Genet 2016 Feb 23;59(2):86-90. Epub 2015 Dec 23.

Department of Human Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Electronic address:

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_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_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.
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http://dx.doi.org/10.1016/j.ejmg.2015.12.013DOI Listing
February 2016

MDC1 is ubiquitylated on its tandem BRCT domain and directly binds RAP80 in a UBC13-dependent manner.

DNA Repair (Amst) 2011 Aug 31;10(8):806-14. Epub 2011 May 31.

Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Givat Ram, Jerusalem, 91904, Israel.

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.
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http://dx.doi.org/10.1016/j.dnarep.2011.04.016DOI Listing
August 2011

Genetic screening for Krabbe disease: learning from the past and looking to the future.

Am J Med Genet A 2011 Mar 22;155A(3):574-6. Epub 2011 Feb 22.

Department of Human Genetics and Metabolic Diseases, Hadassah, Hebrew University Hospital, Jerusalem, Israel.

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.
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http://dx.doi.org/10.1002/ajmg.a.33815DOI Listing
March 2011

Novel and recurrent FERMT1 gene mutations in Kindler syndrome.

Acta Derm Venereol 2011 May;91(3):267-70

St John’s Institute of Dermatology, King’s College London, UK.

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.
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http://dx.doi.org/10.2340/00015555-1063DOI Listing
May 2011