Publications by authors named "Mordechai Shohat"

98 Publications

The phenotype of 15 cases with rare 8q24.13-q24.3 deletions-A new syndrome or still an enigma?

Am J Med Genet A 2021 Feb 22. Epub 2021 Feb 22.

Genetics Institute, Carmel Medical Center, affiliated to the Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.

Diagnosis of rare copy number variants (CNVs) with scarce literature evidence poses a major challenge for interpretation of the clinical significance of chromosomal microarray analysis (CMA) results, especially in the prenatal setting. Bioinformatic tools can be used to assist in this issue; however, this prediction can be imprecise. Our objective was to describe the phenotype of the rare copy number losses encompassing the 8q24.13-q24.3 locus, and to find common features in terms of genomic coordinates, gene content, and clinical phenotypic characteristics. Appropriate cases were retrieved using local databases of two largest Israeli centers performing CMA analysis. In addition, literature and public databases search was performed. Local database search yielded seven new patients with del (8)(q24.13q24.3) (one of these with an additional copy number variant). Literature and public databases search yielded eight additional patients. The cases showed high phenotypic variability, ranging from asymptomatic adults and fetuses with normal ultrasound to patients with autism/developmental delay (6/11 postnatal cases, 54.5%). No clear association was noted between the specific disease-causing/high-pLI gene content of the described del (8)(q24.13q24.3) to neurodevelopmental disorders, except for a possibly relevant locus encompassing the KCNQ3 gene. We present the challenges in classification of rare variants with limited clinical information. In such cases, genotype-phenotype correlation must be assessed with extra-caution and possibly using additional methods to assist the classification, especially in the prenatal setting.
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http://dx.doi.org/10.1002/ajmg.a.62131DOI Listing
February 2021

Biallelic variants in ETV2 in a family with congenital heart defects, vertebral abnormalities and preaxial polydactyly.

Eur J Med Genet 2021 Feb 8;64(2):104124. Epub 2021 Jan 8.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Genomic Center, Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel; Maccabi Health Maintenance Organization, Rehovot, Israel.

The combination of congenital heart defects and vertebral anomalies with or without additional abnormalities has been reported in many genetic disorders. We describe a family in which four consecutive pregnancies were characterized by the combination of fetal congenital heart malformations and vertebral anomalies. In addition, preaxial polydactyly was detected in one of the fetuses. Reanalysis of the non-diagnostic clinical exome data revealed compound heterozygous variants c.350del, p.(Gly117AlafsTer90) and c.757G > T, p.(Asp253Tyr) in ETV2 which have previously not been known to be associated with a phenotype in humans. In mice, Etv2 encodes an obligatory transcription factor involved in the generation of hematopoietic and endothelial cells. Its homozygous disruption results in embryonic lethality due to severe blood and vessel defects. The Etv2 promoter may be bound by Nkx2-5, a key transcription factor in heart development. Pathogenic variants in the NKx2-5 homolog in humans (NKX2-5) are related to congenital heart defects. The identification of additional fetuses or live-born individuals with biallelic pathogenic variants in ETV2 will shed further light on this presumably novel gene-phenotype association and on the full phenotypic spectrum.
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http://dx.doi.org/10.1016/j.ejmg.2020.104124DOI Listing
February 2021

Eculizumab-Responsive Adult Onset Protein Losing Enteropathy, Caused by Germline CD55-Deficiency and Complicated by Aggressive Angiosarcoma.

J Clin Immunol 2021 Feb 19;41(2):477-481. Epub 2020 Nov 19.

Institute of Thrombosis and Hemostasis, Sheba Medical Center, and Sackler Faculty of Medicine, University of Tel Aviv, Tel Aviv, Israel.

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http://dx.doi.org/10.1007/s10875-020-00910-7DOI Listing
February 2021

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

A study of normal copy number variations in Israeli population.

Hum Genet 2021 Mar 27;140(3):553-563. Epub 2020 Sep 27.

Genomic Bioinformatics Laboratory, Department of Molecular Biology, Ariel University, Ariel, Israel.

The population of Israel is ethnically diverse, and individuals from different ethnic groups share specific genetic variations. These variations, which have been passed on from common ancestors, are usually reported in public databases as rare variants. Here, we aimed to identify ethnicity-based benign copy number variants (CNVs) and generate the first Israeli CNV database. We applied a data-mining approach to the results of 10,193 chromosomal microarray tests, of which 2150 tests were from individuals of 13 common ethnic backgrounds (n ≥ 10). We found 165 CNV regions (> 50 kbp) that are unique to specific ethnic groups (uCNVRs). The frequency of more than 19% of these uCNVRs is between 1 and 20% of the common ethnic origin, while their frequency in the overall cohort is between 0.5 and 1.6%. Of these 165 uCNVRs, 98 are reported as variants of unknown significance or as not available in dbVar; we postulate that these uCNVRs should be annotated as either "likely benign" or "benign". The ethnic-specific CNVs extracted in this study will allow geneticists to distinguish between relevant pathogenic genomic aberrations and benign ethnicity-related variations, thus preventing variant misinterpretation that may lead to unnecessary pregnancy terminations.
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http://dx.doi.org/10.1007/s00439-020-02225-4DOI Listing
March 2021

Should We Report 15q11.2 BP1-BP2 Deletions and Duplications in the Prenatal Setting?

J Clin Med 2020 Aug 11;9(8). Epub 2020 Aug 11.

Recanati Genetic Institute, Rabin Medical Center, Petah Tikva 49100, Israel.

Copy number variations of the 15q11.2 region at breakpoints 1-2 (BP1-BP2) have been associated with variable phenotypes and low penetrance. Detection of such variations in the prenatal setting can result in significant parental anxiety. The clinical significance of pre- and postnatally detected 15q11.2 BP1-BP2 deletions and duplications was assessed. Of 11,004 chromosomal microarray tests performed in a single referral lab (7596 prenatal, 3408 postnatal), deletions were detected in 66 cases: 39 in prenatal tests (0.51%) and 27 in postnatal tests (0.79%). Duplications were detected in 94 cases: 62 prenatal tests (0.82%) and 32 postnatal tests (0.94%). The prevalence of deletions and duplications among clinically indicated prenatal tests (0.57% and 0.9%, respectively) did not differ significantly in comparison to unindicated tests (0.49% and 0.78%, respectively). The prevalence of deletions and duplications among postnatal tests performed for clinical indications was similar to the prevalence in healthy individuals (0.73% and 1% vs. 0.98% and 0.74%, respectively). The calculated penetrance of deletions and duplications over the background risk was 2.18% and 1.16%, respectively. We conclude that the pathogenicity of 15q11.2 BP1-BP2 deletions and duplications is low. Opting out the report of these copy number variations to both clinicians and couples should be considered.
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http://dx.doi.org/10.3390/jcm9082602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463673PMC
August 2020

Based on a cohort of 52,879 microarrays, recurrent intragenic FBN2 deletion encompassing exons 1-8 does not cause Beals syndrome.

Eur J Med Genet 2020 Oct 21;63(10):104008. Epub 2020 Jul 21.

Genetics Institute, Carmel Medical Center, Affiliated to the Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel. Electronic address:

Introduction: Congenital contractural arachnodactyly (CCA) is a rare connective tissue disorder, associated with heterozygous mutations in the FBN2 gene. The objective of this study was to evaluate the prevalence of an intragenic deletion encompassing exons 1-8 of FBN2 gene in Israeli population.

Materials And Methods: A search for intragenic FBN2 microdeletions was performed in two databases of chromosomal microarray analysis (CMA) - genetic laboratory of a tertiary medical center (the primary cohort) and one of the largest Israeli health maintenance organizations (replication cohort).

Results: Overall, 52,879 microarray tests were searched for FBN2 microdeletions. The primary cohort constituted of 18,301 CMA tests, among which 33 intragenic FBN2 microdeletions in unrelated individuals were found (0.18%). Prenatal prevalence of this variant was 0.23% (28/12,604), and specifically in low risk pregnancies - 0.29% (22/7464). Of the 28 cases with known parental origin, 27 (96.4%) were of full or partial Ashkenazi Jewish ethnic background. The approximate allele incidence in the Ashkenazi Jewish origin was 0.4% (18/4961). Combined with the 34,578 CMA tests in the replication cohort, the overall frequency of FBN2 microdeletions was 0.24% (125/52,879). None of the pre- or postnatal cases had any clinical manifestations of CCA.

Discussion: Intragenic FBN2 microdeletions are found in one of every 420 CMA analyses in Israeli population, and in particular one of every 340 low-risk pregnancies. Due to high allele incidence in Ashkenazi Jewish population (1:275), we suggest that FBN2 gene deletion detected by CMA among Ashkenazi Jews should be interpreted as benign copy number variant.
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http://dx.doi.org/10.1016/j.ejmg.2020.104008DOI Listing
October 2020

Teaching clinicians practical genomic medicine: 7 years' experience in a tertiary care center.

Genet Med 2020 Oct 3;22(10):1703-1709. Epub 2020 Jul 3.

Recanati Genetic Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel.

Purpose: Increased implementation of complex genetic technologies in clinical practice emphasizes the urgency of genomic literacy and proficiency for medical professionals. We evaluated our genomic education model.

Methods: We assessed the 5-day, extended format program, encompassing lectures, videos, interactive tests, practice cases, and clinical exercises. Pre- and post questionnaires assessed knowledge change, using t-tests to compare groups. Satisfaction on program completion and after 3 years were evaluated. Implementation in other centers determined acceptability.

Results: During 2012-2018, 774 clinicians from multiple disciplines and career stages attended 35 programs; 334 (43%) attended the 5-day extended format. Evaluations showed significant improvement of genomic literacy (mean 15.05/100 points, p < 0.001). Residents initially had higher scores than specialists (pre: 66.3 ± 17.3 vs. 58.7 ± 16.6, respectively, p = 0.002); both significantly improved, with specialists "catching up" (post: 79.1 ± 17.2 vs. 75.7 ± 15.9, nonsignificant (NS)); there was a similar trend between fellows and subspecialists (pre: 70 ± 18 vs. 59.4 ± 16.4, respectively, p = 0.007; post: 78.6 ± 16.4 vs. 73.2 ± 17.7, respectively, NS). Younger specialists (≤10 years residency) had significantly higher pre- and post scores. Absolute improvement in scores did not depend on medical specialties.

Conclusion: Our program is effective in improving genomics literacy for clinicians, irrespective of career length or expertise, and could be a model for improving skills in practical genomics for all medical professionals.
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http://dx.doi.org/10.1038/s41436-020-0868-4DOI Listing
October 2020

Smith-Lemli-Opitz syndrome: what is the actual risk for couples carriers of the DHCR7:c.964-1G>C variant?

Eur J Hum Genet 2020 07 13;28(7):938-942. Epub 2020 Feb 13.

Hadassah-Hebrew University Medical School, Jerusalem, Israel.

The founder variant DHCR7:c.964-1G>C causing autosomal recessive Smith-Lemli-Opitz (SLOS) was introduced into the Israeli preconception carrier program for Ashkenazi Jews in 2017 because of the high carrier frequency in this population (2.3%). Other disease-causing variants in DHCR7 are relatively rare in Israeli population. Discrepancy between the carrier frequency and disease prevalence raises the question of the actual risks for affected offspring for couples detected by the screening program. We performed a literature review of all relevant publications regarding homozygous DHCR7:c.964-1G>C fetuses/patients. We also collected clinical data about couples identified in the national screening program, including reproductive history. Out of 32 homozygous fetuses, six died in utero, 11 pregnancies were terminated during second trimester, and 15 children were born. All died between first days of life till 3 months of age. Reproductive history of SLOS-at-risk couples showed that after correction for ascertainment bias, out of 61 pregnancies, there was an absence of affected fetuses/children and an excess of miscarriages even if assumed that all the homozygous fetuses were miscarried. Out of these, eight families were Israelis, they had a total of one sick child, 21 healthy children, and 21 miscarriages. Our observations support the previous knowledge that homozygosity for c.964-1G>C in DHCR7 leads to a severe phenotype or early miscarriage. An unexpected observation was the excess of early miscarriages. This phenomenon is unclear and awaits further studies.
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http://dx.doi.org/10.1038/s41431-020-0577-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316738PMC
July 2020

Grandparental genotyping enhances exome variant interpretation.

Am J Med Genet A 2020 04 6;182(4):689-696. Epub 2020 Feb 6.

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

Trio exome sequencing is a powerful tool in the molecular investigation of monogenic disorders and provides an incremental diagnostic yield over proband-only sequencing, mainly due to the rapid identification of de novo disease-causing variants. However, heterozygous variants inherited from unaffected parents may be inadvertently dismissed, although multiple explanations are available for such scenarios including mosaicism in the parent, incomplete penetrance, imprinting, or skewed X-inactivation. We report three probands, in which a pathogenic or likely pathogenic variant was identified upon exome sequencing, yet was inherited from an unaffected parent. Segregation of the variants (in NOTCH1, PHF6, and SOX10) in the grandparent generation revealed that the variant was de novo in each case. Additionally, one proband had skewed X-inactivation. We discuss the possible genetic mechanism in each case, and urge caution in data interpretation of exome sequencing data. We illustrate the utility of expanding segregation studies to the grandparent generation and demonstrate the impact on exome interpretation strategies, by showing that objective genotype data can overcome subjective parental report of lack of symptoms.
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http://dx.doi.org/10.1002/ajmg.a.61511DOI Listing
April 2020

Isolated ventricular septal defects demonstrated by fetal echocardiography: prenatal course and postnatal outcome.

J Matern Fetal Neonatal Med 2020 Jan 12:1-5. Epub 2020 Jan 12.

Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

We assessed the natural history of the different types of isolated ventricular septal defects (VSDs) diagnosed by fetal echocardiography and analyzed their postnatal outcomes. This is a retrospective cohort study of 86 fetuses with isolated VSDs, detected in 7466 sequential echocardiographic examinations. The subtype and size of the VSDs were assessed during fetal life and the following birth. Data on the spontaneous closure of the VSD, need for intervention, additional abnormalities and chromosomal aberrations was analyzed. From the original cohort 75 cases of isolated VSDs with complete data on outcome were further analyzed. Muscular and perimembranous VSDs were found in 85.3 and 14.7%, respectively. Spontaneous closure of the VSDs occurred prenatally in 31/64 and 3/11 of fetuses with muscular VSD and perimembranous VSD, respectively. Spontaneous closure of the VSD by the age of 2 years occurred in 92.2 and 45.5% of cases with muscular and perimembranous VSDs respectively ( = 0.001). Isolated muscular VSDs usually close spontaneously during pregnancy or in the first 2 years of life and probably do not increase the risk for chromosomal aberrations. On the other hand, isolated perimembranous VSDs may need intervention following birth and may be associated with a chromosomal anomaly.
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http://dx.doi.org/10.1080/14767058.2020.1712710DOI Listing
January 2020

The yield of full BRCA1/2 genotyping in Israeli Arab high-risk breast/ovarian cancer patients.

Breast Cancer Res Treat 2019 Nov 31;178(1):231-237. Epub 2019 Jul 31.

Recanati Genetics Institute, Beilinson Hospital, Rabin Medical Center, Petach Tikva, Israel.

Purpose: While the spectrum of germline mutations in BRCA1/2 genes in the Israeli Jewish population has been extensively studied, there is a paucity of data pertaining to Israeli Arab high-risk cases.

Methods: Consecutive Israeli Arab breast and/or ovarian cancer patients were recruited using an ethically approved protocol from January 2012 to February 2019. All ovarian cancer cases were referred for BRCA genotyping. Breast cancer patients were offered BRCA sequencing and deletion/duplication analysis after genetic counseling, if the calculated risk for carrying a BRCA mutation by risk prediction algorithms was ≥10%.

Results: Overall, 188 patients participated; 150 breast cancer cases (median age at diagnosis: 40 years, range 22-67) and 38 had ovarian cancer (median age at diagnosis: 52.5 years, range 26-79). Of genotyped cases, 18 (10%) carried one of 12 pathogenic or likely-pathogenic variants, 12 in BRCA1, 6 in BRCA2. Only one was a rearrangement. Three variants recurred in more than one case; one was detected in five seemingly unrelated families. The detection rate for all breast cancer cases was 4%, 5% in bilateral breast cancer cases and 3% if breast cancer was diagnosed < 40 years. Of patients with ovarian cancer, 12/38 (32%) were carriers; the detection rate reached 75% (3/4) among patients diagnosed with both breast and ovarian cancer.

Conclusions: The overall yield of comprehensive BRCA1/2 testing in high-risk Israeli Arab individuals is low in breast cancer patients, and much higher in ovarian cancer patients. These results may guide optimal cancer susceptibility testing strategy in the Arab-Israeli population.
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http://dx.doi.org/10.1007/s10549-019-05379-6DOI Listing
November 2019

BRPF1-associated intellectual disability, ptosis, and facial dysmorphism in a multiplex family.

Mol Genet Genomic Med 2019 06 24;7(6):e665. Epub 2019 Apr 24.

Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Background: Over 500 epigenetic regulators have been identified throughout the human genome. Of these, approximately 30 chromatin modifiers have been implicated thus far in human disease. Recently, variants in BRPF1, encoding a chromatin reader, have been associated with a previously unrecognized autosomal dominant syndrome manifesting with intellectual disability (ID), hypotonia, dysmorphic facial features, ptosis, and/or blepharophimosis in 22 individuals.

Patients And Methods: We report a multiply affected nonconsanguineous family of mixed Jewish descent who presented due to ID in three male siblings. Molecular analysis of the family was pursued using whole exome sequencing (WES) and subsequent Sanger sequencing.

Results: Whole exome sequencing analysis brought to the identification of a novel heterozygous truncating mutation (c.556C>T, p.Q186*) in the BRPF1 gene in the affected siblings and their mother. The four affected individuals showed varying degrees of intellectual disability, distinct facial features including downslanted palpebral fissures, ptosis, and/or blepharophimosis. Their clinical characteristics are discussed in the context of previously reported patients with the BRPF1-related phenotype.

Conclusion: The reported family contributes to the current knowledge regarding this unique and newly recognized genetic disorder, and further implicates the role of BRPF1 in human brain development.
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http://dx.doi.org/10.1002/mgg3.665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565580PMC
June 2019

Progressive Pseudorheumatoid Dysplasia resolved by whole exome sequencing: a novel mutation in WISP3 and review of the literature.

BMC Med Genet 2019 03 29;20(1):53. Epub 2019 Mar 29.

Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52621, Tel-Hashomer, Israel.

Background: Progressive pseudorheumatoid dysplasia (PPRD) is a rare autosomal-recessive, non-inflammatory arthropathy, shown to be caused by mutations in the WNT1-inducible signaling pathway protein 3 (WISP3) gene. Although several hundred cases were reported worldwide, the diagnosis remains challenging. Subsequently, the syndrome is often unrecognized and misdiagnosed (for instance, as Juvenile Idiopathic Arthritis), leading to unnecessary procedures and treatments. The objective of the current study was to identify the molecular basis in a family with PPRD and describe their phenotype and course of illness.

Patients And Methods: We present here a multiply affected consanguineous family of Iraqi-Jewish descent with PPRD. The proband, a 6.5 years old girl, presented with bilateral symmetric bony enlargements of the 1st interphalangeal joints of the hands, without signs of synovitis. Molecular analysis of the family was pursued using Whole Exome Sequencing (WES) and homozygosity mapping.

Results: WES analysis brought to the identification of a novel homozygous missense mutation (c.257G > T, p.C86F) in the WISP3 gene. Following this diagnosis, an additional 53 years old affected family member was found to harbor the mutation. Two other individuals in the family were reported to have had similar involvement however both had died of unrelated causes.

Conclusion: The reported family underscores the importance of recognition of this unique skeletal dysplasia by clinicians, and especially by pediatric rheumatologists and orthopedic surgeons.
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http://dx.doi.org/10.1186/s12881-019-0787-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439983PMC
March 2019

c.259A>C in the fibrinogen gene of alpha chain () is a fibrinogen with thrombotic phenotype.

Appl Clin Genet 2019 28;12:27-33. Epub 2019 Feb 28.

Cancer Research Center, Wohl Institute of Translational Medicine, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Introduction: Dysfibrinogenemia is a rare inherited disease that results from mutation in one of the three fibrinogen genes. Diagnosis can be misleading since it may present as a bleeding tendency or thrombosis and a specific coagulation test for diagnosis is not routinely available.

Aim: To search for a new candidate gene of thrombophilia in a family with three generations of arterial and venous thrombosis.

Methods: Whole exome sequencing followed by Sanger validation and segregation analysis was carried out. In addition, structural modeling was performed. Screening for thrombophilia along with blood counts, prothrombin time, activated partial thromboplastin, thrombin, reptilase time, and fibrinogen was done in each patient.

Results And Discussion: A missense c.259A>C, p.K87Q (g.chr4: 155510050A-C) (rs764281241) in gene was found in all three siblings without any other known thrombophilia marker to explain thrombosis in all three siblings. It is expected to be damaging by six out of seven prediction programs and is very rare in the entire population with Exac=0.000008.

Conclusion: The occurrence of the c.259A>C mutation in may well explain the thrombosis phenotype of the affected family and is suggested as a new marker for thrombophilia phenotype.
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http://dx.doi.org/10.2147/TACG.S190599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400116PMC
February 2019

Biallelic mutations in EXOC3L2 cause a novel syndrome that affects the brain, kidney and blood.

J Med Genet 2019 05 16;56(5):340-346. Epub 2018 Oct 16.

Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.

Background: Dandy-Walker malformation features agenesis/hypoplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle and enlargement of posterior fossa. Although Dandy-Walker malformation is relatively common and several genes were linked to the syndrome, the genetic cause in the majority of cases is unknown.

Objective: To identify the mutated gene responsible for Dandy-Walker malformation, kidney disease and bone marrow failure in four patients from two unrelated families.

Methods: Medical assessment, sonographic, MRI and pathological studies were used to define phenotype. Chromosomal microarray analysis and whole-exome sequence were performed to unravel the genotype.

Results: We report four subjects from two unrelated families with homozygous mutations in the Exocyst Complex Component 3-Like-2 gene (). functions in trafficking of post-Golgi vesicles to the plasma membrane. In the first family a missense mutation in a highly conserved amino acid, p.Leu41Gln, was found in three fetuses; all had severe forms of Dandy-Walker malformation that was detectable by prenatal ultrasonography and confirmed by autopsy. In the second family, the affected child carried a nonsense mutation, p.Arg72*, and no detected protein. He had peritrigonal and cerebellar white matter abnormalities with enlargement of the ventricular trigones, developmental delay, pituitary hypoplasia, severe renal dysplasia and bone marrow failure.

Conclusion: We propose that biallelic mutations lead to a novel syndrome that affects hindbrain development, kidney and possibly the bone marrow.
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http://dx.doi.org/10.1136/jmedgenet-2018-105421DOI Listing
May 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

The yield of full BRCA1/2 genotyping in Israeli high-risk breast/ovarian cancer patients who do not carry the predominant mutations.

Breast Cancer Res Treat 2018 Nov 16;172(1):151-157. Epub 2018 Jul 16.

Recanati Genetics Institute, Beilinson Hospital, Rabin Medical Center, Petach Tikva, Israel.

Purpose: BRCA1 and BRCA2 genotyping results have clinical implications for cancer risk assessment and targeted therapy. Current practice in Israel is to genotype for the predominant BRCA1/2 mutations first, followed by full gene analysis in eligible mutation-negative individuals. This work assessed the rate of non-predominant mutations in BRCA1/2 in ethnically diverse high-risk cases.

Methods: Breast and/or ovarian cancer patients who tested negative for the predominant BRCA1/2 mutations were referred for comprehensive BRCA1/2 genotyping if calculated risk for carrying a BRCA mutation was ≥ 10%.

Results: Of 1258 eligible patients, 41 (3.3%) carried one of 38 mutations: 3% of Ashkenazi Jews and 3.4% of mixed ethnicities. Detection rate was < 5% among patients diagnosed with cancer younger than 40 or with bilateral breast cancer, and was 5.5% of ovarian cancer patients. Three of the carriers (7.3%) carried gene rearrangements. Three mutations were reported in more than one case.

Conclusions: The overall yield of comprehensive BRCA1/2 testing in ethnically diverse high-risk Israeli individuals is 3.3%. This is lower than expected by probability models. A slightly higher rate of BRCA1/2 carriers was seen among ovarian cancer cases. These data should guide BRCA1/2 optimal testing strategy in Israel.
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http://dx.doi.org/10.1007/s10549-018-4887-7DOI Listing
November 2018

When genotype is not predictive of phenotype: implications for genetic counseling based on 21,594 chromosomal microarray analysis examinations.

Genet Med 2018 01 20;20(1):128-131. Epub 2017 Jul 20.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

PurposeTo compare the frequency of copy-number variants (CNVs) of variable penetrance in low-risk and high-risk prenatal samples and postnatal samples.MethodsTwo cohorts were categorized according to chromosomal microarray analysis (CMA) indication: group I, low-risk prenatal-women with uneventful pregnancy (control group); group II, high-risk prenatal-women whose fetuses had congenital malformations; and group III, postnatal-individuals with unexplained developmental delay/intellectual disability, autism spectrum disorders, or multiple congenital anomalies. CNVs were categorized based on clinical penetrance: (i) high (>40%), (ii) moderate (10-40%), and (iii) low (<10%).ResultsFrom 2013 to 2016, 21,594 CMAs were performed. The frequency of high-penetrance CNVs was 0.1% (21/15,215) in group I, 0.9% (26/2,791) in group II, and 2.6% (92/3,588) in group III. Moderate-penetrance CNV frequency was 0.3% (47/15,215), 0.6% (19/2,791), and 1.2% (46/3,588), respectively. These differences were statistically significant. The frequency of low-penetrance CNVs was not significantly different among groups: 0.6% (85/15,215), 0.9% (25/2,791), and 1.0% (35/3,588), respectively.ConclusionHigh-penetrance CNVs might be a major factor in the overall heritability of developmental, intellectual, and structural anomalies. Low-penetrance CNV alone does not seem to contribute to these anomalies. These data may assist pre- and posttest CMA counseling.
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http://dx.doi.org/10.1038/gim.2017.89DOI Listing
January 2018

[UTILIZATION OF WHOLE EXOME SEQUENCING IN DIAGNOSTICS OF GENETIC DISEASE: RABIN MEDICAL CENTER'S EXPERIENCE].

Harefuah 2017 Apr;156(4):212-216

Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel.

Introduction: Whole exome sequencing is a diagnostic approach for the identification of molecular etiology in patients with suspected monogenic diseases. In this article we report on our experience with whole-exome sequencing (WES) of DNA samples taken from patients referred for genetic evaluation due to suspected undiagnosed genetic conditions.

Methods: Exome enrichment was achieved by Nextera Rapid Capture Expanded Exome Kit. Whole-exome sequencing was performed on Illumina HiSeq 2500. Potentially damaging rare variants were selected for familial cosegregation analysis.

Results: A total of 39 patients presenting a wide range of phenotypes suspected to have a genetic cause were sent to WES. Approximately 80% were children with neurological phenotypes. Variations having a high probability of being causative were identified in 20 families, achieving a 51.3% molecular diagnostic rate. Among these, 7 exhibited autosomal dominant disease, 12 autosomal recessive diseases and one X-linked disease; 28% of the patients (11/39) were found to carry a novel mutation located in previously reported genes. Novel mutations located in genes not known to be associated with genetic disease were identified in 23% of the patients (9/39).

Conclusions: Whole exome sequencing identified the underlying genetic cause in more than half of the patients referred for evaluation in the genetics clinic at the tertiary hospital. These data demonstrate the utility of WES as a powerful tool for effective diagnostics of monogenic genetic diseases.
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April 2017

Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepimetaphyseal dysplasia.

J Clin Invest 2017 Apr 6;127(4):1475-1484. Epub 2017 Mar 6.

Shohat-type spondyloepimetaphyseal dysplasia (SEMD) is a skeletal dysplasia that affects cartilage development. Similar skeletal disorders, such as spondyloepiphyseal dysplasias, are linked to mutations in type II collagen (COL2A1), but the causative gene in SEMD is not known. Here, we have performed whole-exome sequencing to identify a recurrent homozygous c.408+1G>A donor splice site loss-of-function mutation in DDRGK domain containing 1 (DDRGK1) in 4 families affected by SEMD. In zebrafish, ddrgk1 deficiency disrupted craniofacial cartilage development and led to decreased levels of the chondrogenic master transcription factor sox9 and its downstream target, col2a1. Overexpression of sox9 rescued the zebrafish chondrogenic and craniofacial phenotype generated by ddrgk1 knockdown, thus identifying DDRGK1 as a regulator of SOX9. Consistent with these results, Ddrgk1-/- mice displayed delayed limb bud chondrogenic condensation, decreased SOX9 protein expression and Col2a1 transcript levels, and increased apoptosis. Furthermore, we determined that DDRGK1 can directly bind to SOX9 to inhibit its ubiquitination and proteasomal degradation. Taken together, these data indicate that loss of DDRGK1 decreases SOX9 expression and causes a human skeletal dysplasia, identifying a mechanism that regulates chondrogenesis via modulation of SOX9 ubiquitination.
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http://dx.doi.org/10.1172/JCI90193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373861PMC
April 2017

Congenital dilated cardiomyopathy caused by biallelic mutations in Filamin C.

Eur J Hum Genet 2016 12 7;24(12):1792-1796. Epub 2016 Sep 7.

Departamento de Bioquımicay Biologıa Molecular, Facultad de Medicina, Instituto Universitario de Oncologıa-IUOPA, Universidad de Oviedo, Oviedo, Spain.

In the vast majority of pediatric patients with dilated cardiomyopathy, the specific etiology is unknown. Studies on families with dilated cardiomyopathy have exemplified the role of genetic factors in cardiomyopathy etiology. In this study, we applied whole-exome sequencing to members of a non-consanguineous family affected by a previously unreported congenital dilated cardiomyopathy syndrome necessitating early-onset heart transplant. Exome analysis identified compound heterozygous variants in the FLNC gene. Histological analysis of the cardiac muscle demonstrated marked sarcomeric and myofibrillar abnormalities, and immunohistochemical staining demonstrated the presence of Filamin C aggregates in cardiac myocytes. We conclude that biallelic variants in FLNC can cause congenital dilated cardiomyopathy. As the associated clinical features of affected patients are mild, and can be easily overlooked, testing for FLNC should be considered in children presenting with dilated cardiomyopathy.
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http://dx.doi.org/10.1038/ejhg.2016.110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5117915PMC
December 2016

Chromosomal Microarray Analysis (CMA) a Clinical Diagnostic Tool in the Prenatal and Postnatal Settings.

Pediatr Endocrinol Rev 2015 Sep;13(1):448-54

Chromosomal microarray analysis (CMA) is a technology used for the detection of clinically-significant microdeietions or duplications, with a high sensitivity for submicroscopic aberrations. It is able to detect changes as small as 5-10Kb in size - a resolution up to 1000 times higher than that of conventional karyotyping. CMA is used for uncovering copy number variants (CNVs) thought to play an important role in the pathogenesis of a variety of disorders, primarily neurodevelopmental disorders and congenital anomalies. CMA may be applied in the prenatal or postnatal setting, with unique benefits and limitations in each setting. The growing use of CMA makes it essential for practicing physicians to understand the principles of this technology and be aware of its powers and limitations.
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September 2015

Nonvisualization of the Fetal Gallbladder: Can Levels of Gamma-Glutamyl Transpeptidase in Amniotic Fluid Predict Fetal Prognosis?

Fetal Diagn Ther 2016 3;39(1):50-5. Epub 2015 Jun 3.

Helen Schneider Hospital for Women, Rabin Medical Center, Petah Tiqwa, Israel.

Objective: In cases of nonvisualization of the fetal gallbladder (NVFGB), we investigated whether amniotic fluid levels of gamma-Glutamyl transpeptidase (GGTP) can distinguish normal development or benign gallbladder agenesis from severe anomaly such as biliary atresia.

Methods: This is a retrospective cohort study of pregnancies in which the gallbladder was not visualized in the second-trimester fetal anatomy scan. Levels of GGTP in amniotic fluid were analyzed prior to 22 weeks of gestation by amniocentesis. Data were collected regarding other fetal malformations, fetal karyotype, and screening results for cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations.

Results: Of 32 cases of NVFGB, 27 (84%) had normal GGTP levels and a normal CFTR gene screening, and 1 of them had an abnormal karyotype. Three of the 5 cases with low GGTP were diagnosed with extrahepatic biliary atresia, proven by histopathological examination following termination of pregnancy. The fourth case had hepatic vasculature abnormality and the fifth isolated gallbladder agenesis. In 22 of 32 cases (68.7%), the gallbladder was detected either later in pregnancy or after delivery.

Conclusion: The findings support low levels of GGTP in amniotic fluid, combined with NVFGB, as a sign of severe disease, mainly biliary atresia. Normal GGTP levels, concomitant with isolated NVFGB, carry a good prognosis.
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http://dx.doi.org/10.1159/000430440DOI Listing
November 2016

Homozygous MED25 mutation implicated in eye-intellectual disability syndrome.

Hum Genet 2015 Jun 20;134(6):577-87. Epub 2015 Mar 20.

Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel,

Genetic syndromes involving both brain and eye abnormalities are numerous and include syndromes such as Warburg micro syndrome, Kaufman oculocerebrofacial syndrome, Cerebro-oculo-facio-skeletal syndrome, Kahrizi syndrome and others. Using exome sequencing, we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four unrelated families, all originating from the same village. The protein encoded by MED25 belongs to Mediator complex or MED complex, which is an evolutionary conserved multi-subunit RNA polymerase II transcriptional regulator complex. The MED25 point mutation is located in the von Willebrand factor type A (MED25 VWA) domain which is responsible for MED25 recruitment into the Mediator complex; co-immunoprecipitation experiment demonstrated that this mutation dramatically impairs MED25 interaction with the Mediator complex in mammalian cells.
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http://dx.doi.org/10.1007/s00439-015-1541-xDOI Listing
June 2015

Mutations in TAX1BP3 cause dilated cardiomyopathy with septo-optic dysplasia.

Hum Mutat 2015 Apr 16;36(4):439-42. Epub 2015 Mar 16.

The Raphael Recanati Genetic Institute, Rabin Medical Center, Israel; Sackler School of Medicine, Tel Aviv University, Israel.

We describe a Bedouin family with a novel autosomal recessive syndrome characterized by dilated cardiomyopathy and septo-optic dysplasia. Genetic analysis revealed a homozygous missense mutation in TAX1BP3, which encodes a small PDZ domain containing protein implicated in regulation of the Wnt/β-catenin signaling pathway, as the causative mutation. The mutation affects a conserved residue located at the core of TAX1BP3 binding pocket and is predicted to impair the nature of a crucial hydrophobic patch, thereby interrupting the structure and stability of the protein, and its ability to interact with other proteins. TAX1BP3 is highly expressed in heart and brain and consistent with the clinical findings observed in our patients; a knockdown of TAX1BP3 causes elongation defects, enlarged pericard, and enlarged head structures in zebrafish embryos. Thus, we describe a new genetic disorder that expands the monogenic cardiomyopathy disease spectrum and suggests that TAX1BP3 is essential for heart and brain development.
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http://dx.doi.org/10.1002/humu.22759DOI Listing
April 2015

Personalized prostate cancer screening among men with high risk genetic predisposition- study protocol for a prospective cohort study.

BMC Cancer 2014 Jul 21;14:528. Epub 2014 Jul 21.

Division of Urology, Rabin Medical Center, Beilinson Campus, Petah-Tikva, Israel.

Background: Prostate cancer screening among the general population is highly debatable. Nevertheless, screening among high-risk groups is appealing. Prior data suggests that men carrying mutations in the BRCA1& 2 genes may be at increased risk of developing prostate cancer. Additionally, they appear to develop prostate cancer at a younger age and with a more aggressive course. However, prior studies did not systematically perform prostate biopsies and thus cannot determine the true prevalence of prostate cancer in this population.

Methods: This will be a prospective diagnostic trial of screening for prostate cancer among men with genetic predisposition. The target population is males (40-70 year old) carrying a BRCA1 and/or BRCA2 germ line mutation. They will be identified via our Genetic counseling unit. All men after signing an informed consent will undergo the following tests: PSA, free to total PSA, MRI of prostate and prostate biopsy. The primary endpoint will be to estimate the prevalence, stage and grade of prostate cancer in this population. Additionally, the study aims to estimate the impact of these germ line mutations on benign prostatic hyperplasia. Furthermore, this study aims to create a bio-bank of tissue, urine and serum of this unique cohort for future investigations. Finally, this study will identify an inception cohort for future interventional studies of primary and secondary prevention.

Discussion: The proposed research is highly translational and focuses not only on the clinical results, but on the future specimens that will be used to advance our understanding of prostate cancer patho-physiology. Most importantly, these high-risk germ-line mutation carriers are ideal candidates for primary and secondary prevention initiatives.

Trial Registration: ClinicalTrials.gov: NCT02053805.
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http://dx.doi.org/10.1186/1471-2407-14-528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223504PMC
July 2014

Abnormal brain magnetic resonance imaging in two patients with Smith-Magenis syndrome.

Am J Med Genet A 2014 Aug 30;164A(8):1940-6. Epub 2014 Apr 30.

The Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.

Smith-Magenis syndrome (SMS) is a clinically recognizable contiguous gene syndrome ascribed to an interstitial deletion in chromosome 17p11.2. Seventy percent of SMS patients have a common deletion interval spanning 3.5 megabases (Mb). Clinical features of SMS include characteristic mild dysmorphic features, ocular anomalies, short stature, brachydactyly, and hypotonia. SMS patients have a unique neurobehavioral phenotype that includes intellectual disability, self-injurious behavior and severe sleep disturbance. Little has been reported in the medical literature about anatomical brain anomalies in patients with SMS. Here we describe two patients with SMS caused by the common deletion in 17p11.2 diagnosed using chromosomal microarray (CMA). Both patients had a typical clinical presentation and abnormal brain magnetic resonance imaging (MRI) findings. One patient had subependymal periventricular gray matter heterotopia, and the second had a thin corpus callosum, a thin brain stem and hypoplasia of the cerebellar vermis. This report discusses the possible abnormal MRI images in SMS and reviews the literature on brain malformations in SMS. Finally, although structural brain malformations in SMS patients are not a common feature, we suggest baseline routine brain imaging in patients with SMS in particular, and in patients with chromosomal microdeletion/microduplication syndromes in general. Structural brain malformations in these patients may affect the decision-making process regarding their management.
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http://dx.doi.org/10.1002/ajmg.a.36583DOI Listing
August 2014