Publications by authors named "Lina Basel-Salmon"

35 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

Re-evaluating the pathogenicity of the c.783+2T>C BAP1 germline variant.

Hum Mutat 2021 Feb 18. Epub 2021 Feb 18.

Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Tel-Hashomer, Israel.

BAP1 germline pathogenic sequence variants (PSVs) underlie a unique tumor predisposition syndrome (BAP1 - TPDS) associated with increased lifetime risk for developing primarily pleural and peritoneal mesothelioma and uveal and cutaneous melanoma. Overwhelmingly, BAP1 PSVs are unique, family specific inactivating variants. We identified seven families, 6 of Jewish Iraqi origin, harboring an identical BAP1 splice variant (c.783+2T>C), currently assigned a "likely pathogenic" status. Given a non-classical BAP1-TPDS tumor type clustering, and low penetrance in these families, the pathogenicity of this variant was re-evaluated by a combined approach including literature analysis, revised bioinformatics analysis, allelic loss, effect on transcript, and tumor protein expression patterns. None of three available tumors showed allelic loss, there was no discernable effect on alternative splicing based on reverse transcription PCR, and there was no decrease or loss of somatic protein expression in 2/3 analyzed tumors. This led to assigning a Benign Strong (BS) criteria, BS4, supporting BS3 criteria, and to weakening the Pathogenic Supporting (PP) criteria PP5. Combined, these data suggest that this sequence variant should be re-classified as a variant of unknown significance by ACMG criteria. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/humu.24189DOI Listing
February 2021

A recurrent, homozygous EMC10 frameshift variant is associated with a syndrome of developmental delay with variable seizures and dysmorphic features.

Genet Med 2021 Feb 2. Epub 2021 Feb 2.

Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.

Purpose: The endoplasmic reticulum membrane complex (EMC) is a highly conserved, multifunctional 10-protein complex related to membrane protein biology. In seven families, we identified 13 individuals with highly overlapping phenotypes who harbor a single identical homozygous frameshift variant in EMC10.

Methods: Using exome, genome, and Sanger sequencing, a recurrent frameshift EMC10 variant was identified in affected individuals in an international cohort of consanguineous families. Multiple families were independently identified and connected via Matchmaker Exchange and internal databases. We assessed the effect of the frameshift variant on EMC10 RNA and protein expression and evaluated EMC10 expression in normal human brain tissue using immunohistochemistry.

Results: A homozygous variant EMC10 c.287delG (Refseq NM_206538.3, p.Gly96Alafs*9) segregated with affected individuals in each family, who exhibited a phenotypic spectrum of intellectual disability (ID) and global developmental delay (GDD), variable seizures and variable dysmorphic features (elongated face, curly hair, cubitus valgus, and arachnodactyly). The variant arose on two founder haplotypes and results in significantly reduced EMC10 RNA expression and an unstable truncated EMC10 protein.

Conclusion: We propose that a homozygous loss-of-function variant in EMC10 causes a novel syndromic neurodevelopmental phenotype. Remarkably, the recurrent variant is likely the result of a hypermutable site and arose on distinct founder haplotypes.
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http://dx.doi.org/10.1038/s41436-021-01097-xDOI Listing
February 2021

Two intronic cis-acting variants in both alleles of the POLR3A gene cause progressive spastic ataxia with hypodontia.

Clin Genet 2021 Jan 24. Epub 2021 Jan 24.

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

POLR3A encodes the largest subunit of the DNA-dependent RNA polymerase III. Pathogenic variants in this gene are associated with dysregulation of tRNA production and other non-coding RNAs. POLR3A-related disorders include variable phenotypes. The genotype-phenotype correlation is still unclear. Phenotypic analysis and exome sequencing were performed in four affected siblings diagnosed clinically with hereditary spastic ataxia, two healthy siblings and their unaffected mother. All four affected siblings (ages 46-55) had similar clinical features of early childhood-onset hypodontia and adolescent-onset progressive spastic ataxia. None had progeria, gonadal dysfunction or dysmorphism. All affected individuals had biallelic POLR3A pathogenic variants composed by two cis-acting intronic splicing-altering variants, c.1909 + 22G > A and c.3337-11 T > C. The two healthy siblings had wild-type alleles. The mother and another unaffected sibling were heterozygous for the allele containing both variants. This is the first report addressing the clinical consequence associated with homozygosity for a unique pathogenic intronic allele in the POLR3A gene. This allele was previously reported in compound heterozygous combinations in patients with Wiedemann-Rautenstrauch syndrome, a severe progeroid POLR3A-associated phenotype. We show that homozygosity for this allele is associated with spastic ataxia with hypodontia, and not with progeroid features. These findings contribute to the characterization of genotype-phenotype correlation in POLR3A-related disorders.
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http://dx.doi.org/10.1111/cge.13929DOI Listing
January 2021

The role of phenotype-based search approaches using public online databases in diagnostics of Mendelian disorders.

Genet Med 2021 Jan 20. Epub 2021 Jan 20.

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

Purpose: To investigate the effectiveness of phenotype-based search approaches using publicly available online databases.

Methods: We included consecutively solved cases from our exome database. For each case, the combination of Human Phenotype Ontology terms reported by the referring clinician was used to perform a search in three commonly used databases: OMIM (first 300 results), Phenolyzer (first 300 results), and Mendelian (all 100 results).

Results: One hundred cases were included (43 females; mean age: 10 years). The actual molecular diagnosis identified through exome sequencing was not included in the search results of any of the queried databases in 33% of cases. In 85% of cases it was not found within the top five search results. When included, its median rank was 61 (range: 1-295), 21 (1-270), and 29 (1-92) in OMIM, Phenolyzer and Mendelian, respectively.

Conclusion: This study demonstrates that, in most cases, phenotype-based search approaches using public online databases is ineffective in providing a probable diagnosis for Mendelian conditions. Genotype-first approach through molecular-guided diagnostics with backward phenotyping may be a more appropriate approach for these disorders, unless a specific diagnosis is considered a priori based on highly unique phenotypic features or a specific facial gestalt.
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http://dx.doi.org/10.1038/s41436-020-01085-7DOI Listing
January 2021

Epilepsy and electroencephalogram evolution in YWHAG gene mutation: A new phenotype and review of the literature.

Am J Med Genet A 2021 03 4;185(3):901-908. Epub 2021 Jan 4.

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

A male patient with a de novo mutation in the YWHAG gene and mild phenotype is presented. He had normal delivery and normal development, with normal speech and social milestones. At the age of 9 months, myoclonic seizures started, with generalized epileptiform discharges. The child responded well to levetiracetam monotherapy with complete seizure resolution. Levetiracetam was stopped and he remained seizure-free for 10 months. His development was appropriate for age according to psychological evaluation and he attended a regular kindergarten. At the age of approximately 4 years, the seizures reappeared with different semiology of staring with eye blinking. Electroencephalogram (EEG) showed multifocal spikes. Brain magnetic resonance imaging did not reveal any structural abnormality. Genetic analysis revealed a de novo likely pathogenic missense variant in the YWHAG gene (c.619G>A p.Glu207Lys). We compared our case to the other cases published in the literature. Our case is unique in its seizure semiology and evolution of EEG. Moreover, in contrast to our case, the majority of cases described in the literature have dysmorphism and intellectual disability or autistic spectrum disorder. This report emphasizes the phenotypic heterogeneity of YWHAG mutation as is the case in other developmental encephalopathies.
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http://dx.doi.org/10.1002/ajmg.a.62026DOI Listing
March 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

Impact of a national population-based carrier-screening program on spinal muscular atrophy births.

Neuromuscul Disord 2020 12 20;30(12):970-974. Epub 2020 Oct 20.

Community Genetics, Public Health Services, Ministry of Health, Jerusalem 9101002, Israel.

Spinal muscular atrophy (SMA) is a genetic neurodegenerative disease. Population carrier screening for SMA was introduced in Israel in 2008 through health-care services' insurance plans and expanded to the entire Israeli population in 2013 by a national health program. The aim of the study was to evaluate the impact of carrier screening on reducing the rate of birth of infants with SMA. All cases of prenatal and postnatal diagnosis of SMA in 2008-2017 were identified from databases of relevant government organizations, genetic laboratories in medical centers, and health care systems in Israel. Since 2013, screening was performed in 309,352 individuals, of whom 5741 were found to be carriers (carrier rate 1:54). Given an average of 180,000 live births annually, the predicted rate of SMA diagnosis was 15 cases per year. Prior to 2013, the average rate of prenatally diagnosed SMA was 4.66 cases per year, compared with 7.75 cases per year following population-wide provision of screening. The annual rate of postnatally diagnosed cases remained steady since 2008, with an average of 7- 7.25 cases per year. Screening has been effective in increasing prenatal detection of SMA but has had no effect on the rate of confirmed postnatal diagnoses. We speculate that screening rates may be affected by social, cultural, and religious factors.
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http://dx.doi.org/10.1016/j.nmd.2020.10.005DOI Listing
December 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

Ten points to consider when providing genetic counseling for variants of incomplete penetrance and variable expressivity detected in a prenatal setting.

Acta Obstet Gynecol Scand 2020 11;99(11):1427-1429

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

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http://dx.doi.org/10.1111/aogs.13963DOI Listing
November 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

When phenotype does not match genotype: importance of "real-time" refining of phenotypic information for exome data interpretation.

Genet Med 2021 Jan 17;23(1):215-221. Epub 2020 Aug 17.

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

Purpose: Clinical data provided to genetic testing laboratories are frequently scarce. Our purpose was to evaluate clinical scenarios where phenotypic refinement in proband's family members might impact exome data interpretation.

Methods: Of 614 exomes, 209 were diagnostic and included in this study. Phenotypic information was gathered by the variant interpretation team from genetic counseling letters and images. If a discrepancy between reported clinical findings and presumably disease-causing variant segregation was observed, referring clinicians were contacted for phenotypic clarification.

Results: In 16/209 (7.7%) cases, phenotypic refinement was important due to (1) lack of cosegregation of disease-causing variant with the reported phenotype; (2) identification of different disorders with overlapping symptoms in the same family; (3) similar features in proband and family members, but molecular cause identified in proband only; and (4) previously unrecognized maternal condition causative of child's phenotype. As a result of phenotypic clarification, in 12/16 (75%) cases definition of affected versus unaffected status in one of the family members has changed, and in one case variant classification has changed.

Conclusion: Detailed description of phenotypes in family members including differences in clinical presentations, even if subtle, are important in exome interpretation and should be communicated to the variant interpretation team.
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http://dx.doi.org/10.1038/s41436-020-00938-5DOI Listing
January 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

High-frequency low-penetrance copy-number variant classification: should we revise the existing guidelines?

Genet Med 2020 Jul 28;22(7):1276-1277. Epub 2020 Apr 28.

Genetics Institute, Carmel Medical Center, Haifa, Israel.

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http://dx.doi.org/10.1038/s41436-020-0795-4DOI Listing
July 2020

Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures.

Am J Hum Genet 2020 04 26;106(4):467-483. Epub 2020 Mar 26.

Central European Institute of Technology, Masaryk University, Kamenice 735/5, A35, Brno 62500, Czech Republic. Electronic address:

The RNA editing enzyme ADAR2 is essential for the recoding of brain transcripts. Impaired ADAR2 editing leads to early-onset epilepsy and premature death in a mouse model. Here, we report bi-allelic variants in ADARB1, the gene encoding ADAR2, in four unrelated individuals with microcephaly, intellectual disability, and epilepsy. In one individual, a homozygous variant in one of the double-stranded RNA-binding domains (dsRBDs) was identified. In the others, variants were situated in or around the deaminase domain. To evaluate the effects of these variants on ADAR2 enzymatic activity, we performed in vitro assays with recombinant proteins in HEK293T cells and ex vivo assays with fibroblasts derived from one of the individuals. We demonstrate that these ADAR2 variants lead to reduced editing activity on a known ADAR2 substrate. We also demonstrate that one variant leads to changes in splicing of ADARB1 transcript isoforms. These findings reinforce the importance of RNA editing in brain development and introduce ADARB1 as a genetic etiology in individuals with intellectual disability, microcephaly, and epilepsy.
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http://dx.doi.org/10.1016/j.ajhg.2020.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118584PMC
April 2020

MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis.

Brain 2020 01;143(1):55-68

Laboratory of Embryology and Genetics of Human Malformation, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France.

MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.
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http://dx.doi.org/10.1093/brain/awz379DOI Listing
January 2020

Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability.

J Clin Invest 2020 03;130(3):1431-1445

Rosalind and Morris Goodman Cancer Research Centre and Department of Medicine, McGill University, Montreal, Quebec, Canada.

Epigenetic integrity is critical for many eukaryotic cellular processes. An important question is how different epigenetic regulators control development and influence disease. Lysine acetyltransferase 8 (KAT8) is critical for acetylation of histone H4 at lysine 16 (H4K16), an evolutionarily conserved epigenetic mark. It is unclear what roles KAT8 plays in cerebral development and human disease. Here, we report that cerebrum-specific knockout mice displayed cerebral hypoplasia in the neocortex and hippocampus, along with improper neural stem and progenitor cell (NSPC) development. Mutant cerebrocortical neuroepithelia exhibited faulty proliferation, aberrant neurogenesis, massive apoptosis, and scant H4K16 propionylation. Mutant NSPCs formed poor neurospheres, and pharmacological KAT8 inhibition abolished neurosphere formation. Moreover, we describe KAT8 variants in 9 patients with intellectual disability, seizures, autism, dysmorphisms, and other anomalies. The variants altered chromobarrel and catalytic domains of KAT8, thereby impairing nucleosomal H4K16 acetylation. Valproate was effective for treating epilepsy in at least 2 of the individuals. This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies 9 individuals with KAT8 variants, and links deficient H4K16 acylation directly to intellectual disability, epilepsy, and other developmental anomalies.
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http://dx.doi.org/10.1172/JCI131145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269600PMC
March 2020

De novo variants in PAK1 lead to intellectual disability with macrocephaly and seizures.

Brain 2019 11;142(11):3351-3359

Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany.

Using trio exome sequencing, we identified de novo heterozygous missense variants in PAK1 in four unrelated individuals with intellectual disability, macrocephaly and seizures. PAK1 encodes the p21-activated kinase, a major driver of neuronal development in humans and other organisms. In normal neurons, PAK1 dimers reside in a trans-inhibited conformation, where each autoinhibitory domain covers the kinase domain of the other monomer. Upon GTPase binding via CDC42 or RAC1, the PAK1 dimers dissociate and become activated. All identified variants are located within or close to the autoinhibitory switch domain that is necessary for trans-inhibition of resting PAK1 dimers. Protein modelling supports a model of reduced ability of regular autoinhibition, suggesting a gain of function mechanism for the identified missense variants. Alleviated dissociation into monomers, autophosphorylation and activation of PAK1 influences the actin dynamics of neurite outgrowth. Based on our clinical and genetic data, as well as the role of PAK1 in brain development, we suggest that gain of function pathogenic de novo missense variants in PAK1 lead to moderate-to-severe intellectual disability, macrocephaly caused by the presence of megalencephaly and ventriculomegaly, (febrile) seizures and autism-like behaviour.
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http://dx.doi.org/10.1093/brain/awz264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821231PMC
November 2019

Paediatric systemic lupus erythematosus as a manifestation of constitutional mismatch repair deficiency.

J Med Genet 2020 07 9;57(7):505-508. Epub 2019 Sep 9.

Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, Israel

Biallelic mutations in any of the four mismatch repair genes , , and result in one of the most aggressive childhood cancer predisposition syndromes, termed constitutional mismatch repair deficiency (CMMRD) syndrome. In addition to a very high tumour risk, the CMMRD phenotype is often characterised by the presence of signs reminiscent of neurofibromatosis type 1. Although paediatric systemic lupus erythematosus (pSLE) has been reported so far in three patients with CMMRD, it has not been considered a diagnostic feature of the syndrome. We report here two additional female patients with pSLE and CMMRD due to biallelic pathogenic variants in Hence, there are a total of five out of approximately 200 (2.5%) currently reported patients with CMMRD that also have pSLE, suggesting pSLE should raise the suspicion of a diagnosis of CMMRD, especially if supported by additional indicative features.
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http://dx.doi.org/10.1136/jmedgenet-2019-106303DOI Listing
July 2020

Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.

Am J Hum Genet 2019 10 5;105(4):689-705. Epub 2019 Sep 5.

Department of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands. Electronic address:

Sphingomyelinases generate ceramide from sphingomyelin as a second messenger in intracellular signaling pathways involved in cell proliferation, differentiation, or apoptosis. Children from 12 unrelated families presented with microcephaly, simplified gyral pattern of the cortex, hypomyelination, cerebellar hypoplasia, congenital arthrogryposis, and early fetal/postnatal demise. Genomic analysis revealed bi-allelic loss-of-function variants in SMPD4, coding for the neutral sphingomyelinase-3 (nSMase-3/SMPD4). Overexpression of human Myc-tagged SMPD4 showed localization both to the outer nuclear envelope and the ER and additionally revealed interactions with several nuclear pore complex proteins by proteomics analysis. Fibroblasts from affected individuals showed ER cisternae abnormalities, suspected for increased autophagy, and were more susceptible to apoptosis under stress conditions, while treatment with siSMPD4 caused delayed cell cycle progression. Our data show that SMPD4 links homeostasis of membrane sphingolipids to cell fate by regulating the cross-talk between the ER and the outer nuclear envelope, while its loss reveals a pathogenic mechanism in microcephaly.
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http://dx.doi.org/10.1016/j.ajhg.2019.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817560PMC
October 2019

Phenotype and mutation expansion of the PTPN23 associated disorder characterized by neurodevelopmental delay and structural brain abnormalities.

Eur J Hum Genet 2020 01 8;28(1):76-87. Epub 2019 Aug 8.

Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10599, USA.

PTPN23 is a His-domain protein-tyrosine phosphatase implicated in ciliogenesis, the endosomal sorting complex required for transport (ESCRT) pathway, and RNA splicing. Until recently, no defined human phenotype had been associated with alterations in this gene. We identified and report a cohort of seven patients with either homozygous or compound heterozygous rare deleterious variants in PTPN23. Combined with four patients previously reported, a total of 11 patients with this disorder have now been identified. We expand the phenotypic and variation spectrum associated with defects in this gene. Patients have strong phenotypic overlap, suggesting a defined autosomal recessive syndrome caused by reduced function of PTPN23. Shared characteristics of affected individuals include developmental delay, brain abnormalities (mainly ventriculomegaly and/or brain atrophy), intellectual disability, spasticity, language disorder, microcephaly, optic atrophy, and seizures. We observe a broad range of variants across patients that are likely strongly reducing the expression or disrupting the function of the protein. However, we do not observe any patients with an allele combination predicted to result in complete loss of function of PTPN23, as this is likely incompatible with life, consistent with reported embryonic lethality in the mouse. None of the observed or reported variants are recurrent, although some have been identified in homozygosis in patients from consanguineous populations. This study expands the phenotypic and molecular spectrum of PTPN23 associated disease and identifies major shared features among patients affected with this disorder, while providing additional support to the important role of PTPN23 in human nervous and visual system development and function.
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http://dx.doi.org/10.1038/s41431-019-0487-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906308PMC
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

The rare 13q33-q34 microdeletions: eight new patients and review of the literature.

Hum Genet 2019 Oct 18;138(10):1145-1153. Epub 2019 Jul 18.

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

The objective of this study is to shed light on the phenotype and inheritance pattern of rare 13q33-q34 microdeletions. Appropriate cases were retrieved using local databases of two largest Israeli centers performing CMA analysis. In addition, literature search in PubMed, DECIPHER and ClinVar databases was performed. Local database search yielded eight new patients with 13q33.1-q34 microdeletions (three of which had additional copy number variants). Combined with 15 cases detected by literature search, an additional 23 cases were reported in DECIPHER database, and 17 cases from ClinVar, so overall 60 patients with isolated 13q33.1-q34 microdeletions were described. Developmental delay and/or intellectual disability were noted in the vast majority of affected individuals (81.7% = 49/60). Of the 23 deletions involving the 13q34 cytoband only, in 3 cases, developmental delay and/or intellectual disability was not reported. Interestingly, in two of these cases (66.7%), the deletions did not involve the terminal CHAMP1 gene, as opposed to 3/20 (15%) of patients with 13q34 deletions and neurocognitive disability. Facial dysmorphism and microcephaly were reported in about half of the overall cases, convulsions were noted in one-fifth of the patients, while heart anomalies, short stature and hypotonia each involved about 10-30% of the cases. None of the 13q33-q34 deletions were inherited from a reported healthy parent. 13q33-q34 microdeletions are rare chromosomal aberrations, associated with high risk for neurodevelopmental disability. The rarity of this chromosomal aberration necessitates continuous reporting and collection of available evidence, to improve the ability to provide accurate genetic counseling, especially in the context of prenatal setting.
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http://dx.doi.org/10.1007/s00439-019-02048-yDOI Listing
October 2019

Variable Features of Juvenile Polyposis Syndrome With Gastric Involvement Among Patients With a Large Genomic Deletion of BMPR1A.

Clin Transl Gastroenterol 2019 07;10(7):e00054

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

Objectives: Loss-of-function mutations of BMPR1A cause juvenile polyposis syndrome (JPS), but large genomic deletions in BMPR1A are rare, reported in few families only, and data regarding the associated phenotype are limited.

Methods: We investigated clinical features and genomic data of 7 extended seemingly unrelated families with a genomic deletion of the entire coding region of BMPR1A. We defined mutation size, mutation prevalence, and tumor pathogenesis using whole-genome sequencing, targeted genotyping, and haplotype analysis.

Results: Patients with JPS from 7 families of Bukharin Jewish ancestry carried a deletion of 429 kb, encompassing the BMPR1A coding sequence and 8 downstream genes. Haplotype analysis and testing controls identified this as a common founder mutation occurring in 1/124 individuals of Bukharin origin. Tumor testing did not demonstrate loss of heterozygosity. Among carriers, JPS was almost fully penetrant, but clinical features varied widely, ranging from mild to very severe, including pan-enteric polyps, gastritis, and colorectal, esophageal, and testicular cancer, and carriers with phenotypes, which would not have raised suspicion of JPS.

Discussion: The phenotype in this large cohort was extremely variable, although all carriers shared the same variant and the same genetic background. New observations include a preponderance of adenomatous rather than juvenile polyps, possible association with testicular cancer, and unexpected upper gastrointestinal involvement.
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http://dx.doi.org/10.14309/ctg.0000000000000054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708668PMC
July 2019

Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel.

Genet Med 2019 11 4;21(11):2442-2452. Epub 2019 Jun 4.

Al Jalila Children's Specialty Hospital, Dubai, UAE.

Purpose: Pathogenic variants in GJB2 are the most common cause of autosomal recessive sensorineural hearing loss. The classification of c.101T>C/p.Met34Thr and c.109G>A/p.Val37Ile in GJB2 are controversial. Therefore, an expert consensus is required for the interpretation of these two variants.

Methods: The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants. Functional, computational, allelic, and segregation data were also obtained. Case-control statistical analyses were performed.

Results: The panel reviewed the synthesized information, and classified the p.Met34Thr and p.Val37Ile variants utilizing professional variant interpretation guidelines and professional judgment. We found that p.Met34Thr and p.Val37Ile are significantly overrepresented in hearing loss patients, compared with population controls. Individuals homozygous or compound heterozygous for p.Met34Thr or p.Val37Ile typically manifest mild to moderate hearing loss. Several other types of evidence also support pathogenic roles for these two variants.

Conclusion: Resolving controversies in variant classification requires coordinated effort among a panel of international multi-institutional experts to share data, standardize classification guidelines, review evidence, and reach a consensus. We concluded that p.Met34Thr and p.Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and incomplete penetrance.
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http://dx.doi.org/10.1038/s41436-019-0535-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235630PMC
November 2019

Chromosomal microarray vs. NIPS: analysis of 5541 low-risk pregnancies.

Genet Med 2019 11 24;21(11):2462-2467. Epub 2019 May 24.

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

Purpose: To evaluate the diagnostic yield of chromosomal microarray (CMA) in pregnancies with normal ultrasound.

Methods: This retrospective cohort analysis included all pregnancies with normal ultrasound undergoing CMA testing between the years 2010 and 2016. We calculated the rate of detection of clinically significant CMA findings in the whole cohort and according to various indications.

Results: Of 5541 CMA analyses, clinically significant findings were yielded in 78 cases (1.4%). Of these, 31 (39.7%) variants could have theoretically been detected by karyotyping (e.g., sized above 10 Mb), and 28 (35.9%) by noninvasive prenatal screening aimed at five common aneuploidies. Of the 47 submicroscopic findings detectable by CMA only, the majority (37 cases, 78.7%) represented known recurrent syndromes. Detection of clinically significant CMA findings in women with no indication for invasive testing was 0.76% (21/2752), which was significantly lower compared with 1.8% in advanced maternal age group (41/2336), 2.8% in abnormal biochemical serum screening (6/211), and 4.1% (10/242) in fetuses with sonographic soft markers.

Conclusion: Clinically significant CMA aberrations are detected in 1 of 71 pregnancies with normal ultrasound, and in 1 of 131 women with no indication for invasive testing. Thus, CMA might be recommended a first-tier test in pregnancies with normal ultrasound.
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http://dx.doi.org/10.1038/s41436-019-0550-xDOI Listing
November 2019

Homozygosity for CHEK2 p.Gly167Arg leads to a unique cancer syndrome with multiple complex chromosomal translocations in peripheral blood karyotype.

J Med Genet 2020 07 11;57(7):500-504. Epub 2019 Mar 11.

The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.

Background: Chromosomal instability, as reflected by structural or copy-number changes, is a known cancer characteristic but are rarely observed in healthy tissue. Mutations in DNA repair genes disrupt the maintenance of DNA integrity and predispose to hereditary cancer syndromes.

Objective: To clinically characterise and genetically diagnose two reportedly unrelated patients with unique cancer syndromes, including multiorgan tumourogenesis (patient 1) and early-onset acute myeloid leukaemia (patient 2), both displaying unique peripheral blood karyotypes.

Methods: Genetic analysis in patient 1 included TruSight One panel and whole-exome sequencing, while patient 2 was diagnosed by FoundationOne Heme genomic analysis; Sanger sequencing was used for mutation confirmation in both patients. Karyotype analysis was performed on peripheral blood, bone marrow and other available tissues.

Results: Both patients were found homozygous for c.499G>A; p.Gly167Arg and exhibited multiple different chromosomal translocations in 30%-60% peripheral blood lymphocytes. This karyotype phenotype was not observed in other tested tissues or in an ovarian cancer patient with a different homozygous missense mutation in (c.1283C>T; p.Ser428Phe).

Conclusions: The multiple chromosomal translocations in patient lymphocytes highlight the role of CHK2 in DNA repair. We suggest that homozygosity for p.Gly167Arg increases patients' susceptibility to non-accurate correction of DNA breaks and possibly explains their increased susceptibility to either multiple primary tumours during their lifetime or early-onset tumourigenesis.
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http://dx.doi.org/10.1136/jmedgenet-2018-105824DOI Listing
July 2020

Bayesian-based noninvasive prenatal diagnosis of single-gene disorders.

Genome Res 2019 03 20;29(3):428-438. Epub 2019 Feb 20.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 6997801, Israel.

In the last decade, noninvasive prenatal diagnosis (NIPD) has emerged as an effective procedure for early detection of inherited diseases during pregnancy. This technique is based on using cell-free DNA (cfDNA) and fetal cfDNA (cffDNA) in maternal blood, and hence, has minimal risk for the mother and fetus compared with invasive techniques. NIPD is currently used for identifying chromosomal abnormalities (in some instances) and for single-gene disorders (SGDs) of paternal origin. However, for SGDs of maternal origin, sensitivity poses a challenge that limits the testing to one genetic disorder at a time. Here, we present a Bayesian method for the NIPD of monogenic diseases that is independent of the mode of inheritance and parental origin. Furthermore, we show that accounting for differences in the length distribution of fetal- and maternal-derived cfDNA fragments results in increased accuracy. Our model is the first to predict inherited insertions-deletions (indels). The method described can serve as a general framework for the NIPD of SGDs; this will facilitate easy integration of further improvements. One such improvement that is presented in the current study is a machine learning model that corrects errors based on patterns found in previously processed data. Overall, we show that next-generation sequencing (NGS) can be used for the NIPD of a wide range of monogenic diseases, simultaneously. We believe that our study will lead to the achievement of a comprehensive NIPD for monogenic diseases.
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http://dx.doi.org/10.1101/gr.235796.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396420PMC
March 2019