Blog
About

  • Record: found
  • Abstract: found
  • Article: found
Is Open Access

A t(5;16) translocation is the likely driver of a syndrome with ambiguous genitalia, facial dysmorphism, intellectual disability, and speech delay

Read this article at

ScienceOpenPublisherPMC
Bookmark
      There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

      Abstract

      Genetic studies grounded on monogenic paradigms have accelerated both gene discovery and molecular diagnosis. At the same time, complex genomic rearrangements are also appreciated as potent drivers of disease pathology. Here, we report two male siblings with a dysmorphic face, ambiguous genitalia, intellectual disability, and speech delay. Through quad-based whole-exome sequencing and concomitant molecular cytogenetic testing, we identified two copy-number variants (CNVs) in both affected individuals likely arising from a balanced translocation: a 13.5-Mb duplication on Chromosome 16 (16q23.1 → 16qter) and a 7.7-Mb deletion on Chromosome 5 (5p15.31 → 5pter), as well as a hemizygous missense variant in CXorf36 (also known as DIA1R). The 5p terminal deletion has been associated previously with speech delay, whereas craniofacial dysmorphia and genital/urinary anomalies have been reported in patients with a terminal duplication of 16q. However, dosage changes in either genomic region alone could not account for the overall clinical presentation in our family; functional testing of CXorf36 in zebrafish did not induce defects in neurogenesis or the craniofacial skeleton. Notably, literature and database analysis revealed a similar dosage disruption in two siblings with extensive phenotypic overlap with our patients. Taken together, our data suggest that dosage perturbation of genes within the two chromosomal regions likely drives the syndromic manifestations of our patients and highlight how multiple genetic lesions can contribute to complex clinical pathologies.

      Related collections

      Most cited references 35

      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Fast and accurate short read alignment with Burrows–Wheeler transform

      Motivation: The enormous amount of short reads generated by the new DNA sequencing technologies call for the development of fast and accurate read alignment programs. A first generation of hash table-based methods has been developed, including MAQ, which is accurate, feature rich and fast enough to align short reads from a single individual. However, MAQ does not support gapped alignment for single-end reads, which makes it unsuitable for alignment of longer reads where indels may occur frequently. The speed of MAQ is also a concern when the alignment is scaled up to the resequencing of hundreds of individuals. Results: We implemented Burrows-Wheeler Alignment tool (BWA), a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps. BWA supports both base space reads, e.g. from Illumina sequencing machines, and color space reads from AB SOLiD machines. Evaluations on both simulated and real data suggest that BWA is ∼10–20× faster than MAQ, while achieving similar accuracy. In addition, BWA outputs alignment in the new standard SAM (Sequence Alignment/Map) format. Variant calling and other downstream analyses after the alignment can be achieved with the open source SAMtools software package. Availability: http://maq.sourceforge.net Contact: rd@sanger.ac.uk
        Bookmark
        • Record: found
        • Abstract: found
        • Article: not found

        A general framework for estimating the relative pathogenicity of human genetic variants

        Our capacity to sequence human genomes has exceeded our ability to interpret genetic variation. Current genomic annotations tend to exploit a single information type (e.g. conservation) and/or are restricted in scope (e.g. to missense changes). Here, we describe Combined Annotation Dependent Depletion (CADD), a framework that objectively integrates many diverse annotations into a single, quantitative score. We implement CADD as a support vector machine trained to differentiate 14.7 million high-frequency human derived alleles from 14.7 million simulated variants. We pre-compute “C-scores” for all 8.6 billion possible human single nucleotide variants and enable scoring of short insertions/deletions. C-scores correlate with allelic diversity, annotations of functionality, pathogenicity, disease severity, experimentally measured regulatory effects, and complex trait associations, and highly rank known pathogenic variants within individual genomes. The ability of CADD to prioritize functional, deleterious, and pathogenic variants across many functional categories, effect sizes and genetic architectures is unmatched by any current annotation.
          Bookmark
          • Record: found
          • Abstract: found
          • Article: not found

          Development and applications of CRISPR-Cas9 for genome engineering.

          Recent advances in genome engineering technologies based on the CRISPR-associated RNA-guided endonuclease Cas9 are enabling the systematic interrogation of mammalian genome function. Analogous to the search function in modern word processors, Cas9 can be guided to specific locations within complex genomes by a short RNA search string. Using this system, DNA sequences within the endogenous genome and their functional outputs are now easily edited or modulated in virtually any organism of choice. Cas9-mediated genetic perturbation is simple and scalable, empowering researchers to elucidate the functional organization of the genome at the systems level and establish causal linkages between genetic variations and biological phenotypes. In this Review, we describe the development and applications of Cas9 for a variety of research or translational applications while highlighting challenges as well as future directions. Derived from a remarkable microbial defense system, Cas9 is driving innovative applications from basic biology to biotechnology and medicine. Copyright © 2014 Elsevier Inc. All rights reserved.
            Bookmark

            Author and article information

            Affiliations
            [1 ]Department of Pediatrics, Metabolism Unit, Hacettepe University, Ankara 06410, Turkey;
            [2 ]Department of Biology, Molecular Biology Section, Hacettepe University, Ankara 06800, Turkey;
            [3 ]Center for Human Disease Modeling, Duke University, Durham, North Carolina 27701, USA;
            [4 ]Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA;
            [5 ]Department of Clinical Genetics, VU University Medical Center (Amsterdam), NL-1081 HV Amsterdam, The Netherlands;
            [6 ]Department of Pediatrics, Pediatric Neurology Unit, Hacettepe University, Ankara 06410, Turkey
            Author notes
            Journal
            Cold Spring Harb Mol Case Stud
            Cold Spring Harb Mol Case Stud
            cshmcs
            cshmcs
            cshmcs
            Cold Spring Harbor Molecular Case Studies
            Cold Spring Harbor Laboratory Press
            2373-2865
            2373-2873
            March 2016
            : 2
            : 2
            27148584
            4849851
            10.1101/mcs.a000703
            OzanturkMCS000703

            This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.

            Counts
            Pages: 14
            Product
            Funding
            Funded by: Simons Foundation Autism Research Initiative
            Award ID: 239983
            Funded by: U.S. National Institutes of Health (NIH) http://dx.doi.org/10.13039/100000002
            Award ID: P50DK096415
            Award ID: U54HG003273
            Categories
            Research Report
            Keywords:

            Comments

            Comment on this article