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      Genomic and phenotypic delineation of congenital microcephaly

      research-article
      , PhD 1 , , PhD 1 , , BSc 1 , , MD 1 , , MD 2 , , MD, PhD 2 , , MD 3 , , MD 4 , 23 , , MD 5 , , MD 6 , , PhD 1 , , MD 1 , , PhD 1 , , BSc 1 , , MSc 1 , , BSc 1 , , MSc 1 , , BSc 1 , , BSc 1 , , MD 7 , , MD, FBPN 4 , , MD 8 , , MD 9 , , MD 7 , , MD 7 , , MD 10 , , MD, PhD 11 , , B.A 11 , , MD 12 , , MD 4 , , MD 13 , , MD 13 , , MD, PhD 2 , , MD, PhD 2 , , MD, PhD 2 , , MBBS, MD 14 , , MD 15 , , MD 16 , , MD 7 , , PhD 1 , 17 , , MSc 18 , , MSc, CCGC 19 , 20 , , MS, CGC 20 , , PhD 18 , , MD 21 , , MD, PhD 20 , 22 , , MD, ABMG 1 , 17 , 23
      Genetics in medicine : official journal of the American College of Medical Genetics
      autozygome, primary microcephaly, dwarfism, CNTRL

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          Abstract

          Purpose:

          Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM.

          Methods:

          Clinical phenotyping, targeted or exome sequencing, and autozygome analysis.

          Results:

          We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly —as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference—is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2, YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1.

          Conclusion:

          Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect.

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          Most cited references6

          • Record: found
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          Is Open Access

          Comprehensive gene panels provide advantages over clinical exome sequencing for Mendelian diseases

          (2015)
          Background To understand the contribution of Mendelian mutations to the burden of undiagnosed diseases that are suspected to be genetic in origin, we developed a next-generation sequencing-based multiplexing assay that encompasses the ~3000 known Mendelian genes. This assay, which we term the Mendeliome, comprises 13 gene panels based on clinical themes, covering the spectrum of pediatric and adult clinical genetic medicine. We explore how these panels compare with clinical whole exome sequencing (WES). Results We tested 2357 patients referred with suspected genetic diagnoses from virtually every medical specialty. A likely causal mutation was identified in 1018 patients, with an overall clinical sensitivity of 43 %, comparing favorably with WES. Furthermore, the cost of clinical-grade WES is high (typically more than 4500 US dollars), whereas the cost of running a sample on one of our panels is around 75–150 US dollars, depending on the panel. Of the “negative” cases, 11 % were subsequently found by WES to harbor a likely causal mutation in a known disease gene (largely in genes identified after the design of our assay), as inferred from a representative sample of 178. Although our study population is enriched for consanguinity, 245 (24 %) of solved cases were autosomal dominant and 35 (4 %) were X-linked, suggesting that our assay is also applicable to outbred populations. Conclusions Despite missing a significant number of cases, the current version of the Mendeliome assay can account for a large proportion of suspected genetic disorders, and provides significant practical advantages over clinical WES. Electronic supplementary material The online version of this article (doi:10.1186/s13059-015-0693-2) contains supplementary material, which is available to authorized users.
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            Drosophila Liprin-α and the Receptor Phosphatase Dlar Control Synapse Morphogenesis

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              Molecular analysis of 23 Pakistani families with autosomal recessive primary microcephaly using targeted next-generation sequencing

              Primary microcephaly is genetically heterogeneous, with most cases showing autosomal recessive inheritance. We designed a panel containing 46 primary microcephaly-causing genes and performed mutation screening in 23 Pakistani families with autosomal recessive primary microcephaly. We found mutations that were pathogenic or likely to be pathogenic in 22 families, including 18 families with known mutations in ASPM, three with novel mutations in WDR62 and one with a novel in-frame deletion mutation in CASC5. Affected individuals harbored the c.3978G>A (p.W1326*) ASPM mutation in 15 families (nine consanguineous and six non-consanguineous), suggesting a high carrier rate of the nonsense mutation in Pakistani individuals. We identified three novel homozygous WDR62 mutations, including an intragenic deletion of 10 299 bp, a splicing mutation and a nonsense mutation. Our results confirm that mutations in ASPM or WDR62 are the major cause of autosomal recessive primary microcephaly in the Pakistani population.
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                Author and article information

                Journal
                9815831
                22061
                Genet Med
                Genet. Med.
                Genetics in medicine : official journal of the American College of Medical Genetics
                1098-3600
                1530-0366
                27 November 2019
                14 September 2018
                March 2019
                28 January 2020
                : 21
                : 3
                : 545-552
                Affiliations
                [1 ]Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
                [2 ]Clinical Genetics Department, Human Genetics and Genome Research Division, Centre of Excellence of Human Genetics, National Research Centre, Cairo, Egypt.
                [3 ]Department of Pediatrics, Genetic Unit, Armed Forces Hospital Southern Region, Khamis Mushayt, Saudi Arabia.
                [4 ]Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
                [5 ]King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia.
                [6 ]Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
                [7 ]Division of Pediatric Neurology, College of Medicine and King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.
                [8 ]Pediatric Neurology Department, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia.
                [9 ]Pediatrics Department, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
                [10 ]Faculty of Medicine, Physiology Department, Bursa Uludag University, Bursa, Turkey.
                [11 ]Department of Neurology, University of California, San Francisco, California, USA.
                [12 ]Department of Medical Genetics, King Fahad General Hospital, Jeddah, Saudi Arabia.
                [13 ]Maternity and Children Hospital, Dammam, Saudi Arabia.
                [14 ]Department of Medical Genetics Kasturba Medical College, Manipal University (currently Manipal Academy of Higher Education), Manipal, India.
                [15 ]Department of obstetrics and gynecology king Faisal specialist hospital and research center, Riyadh, Saudi Arabia.
                [16 ]Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia.
                [17 ]Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
                [18 ]Computational Bioscience Research Center (CBRC), Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
                [19 ]Department of Paediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
                [20 ]Division of Genetics and Genomics, Department of Medicine, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, Massachusetts, USA.
                [21 ]Department of Pediatric Subspecialties, Children’s Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
                [22 ]Harvard Medical School, Boston, Massachusetts, USA.
                [23 ]Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
                Author notes
                Correspondence: Fowzan S. Alkuraya ( falkuraya@ 123456kfshrc.edu.sa )
                Article
                NIHMS1061370
                10.1038/s41436-018-0140-3
                6986385
                30214071
                3c889dcd-4727-4dd2-99f0-25297e25fead

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                History
                Categories
                Article

                Genetics
                autozygome,primary microcephaly,dwarfism,cntrl
                Genetics
                autozygome, primary microcephaly, dwarfism, cntrl

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