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Making Chromosome Abnormalities Treatable Conditions American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 169C:209–215 (2015) INTRODUCTION Making Chromosome Abnormalities Treatable Conditions JANNINE DEMARS CODY* AND DANIEL ESTEN HALE Individuals affected by the classic chromosome deletion syndromes which were first identified at the beginning of the genetic age, are now positioned to benefit from genomic advances. This issue highlights five of these conditions (4p-, 5p-, 11q-, 18p-, and 18q-). It focuses on the increased in understanding of the molecular underpinnings and envisions how these can be transformed into effective treatments. While it is scientifically exciting to see the phenotypic manifestations of hemizygosity being increasingly understood at the molecular and cellular level, it is even more amazing to consider that we are now on the road to making chromosome abnormalities treatable conditions. © 2015 Wiley Periodicals, Inc. KEY WORDS: chromosome abnormalities; gene dosage; haploinsufficiency; hemizygosity How to cite this article: Cody JD,Hale DE. 2015. Making chromosome abnormalities treatable conditions. Am J Med Genet Part C Semin Med Genet 169C:209–215. WHAT IS THE GOAL OF empiric, for example, hearing aids for changes in many other medical disci- THIS ISSUE? those that are hearing impaired, rather plines. The problematic and pervasive than scientific, for example, therapeutic attitude, recently voiced in the Septem- Emerging science on chromosomal gene up-regulation. This journal issue ber 2014 issue of Discover Magazine,inan abnormalities suggests that we now will provide the most contemporary article about a child with 22q11.2 have the opportunity not only to expand information on genotype/phenotype deletion is, “But there is no treatment our understanding of these multigene correlation, thus setting the stage for for contiguous gene syndromes like disorders, but also, for the first time, to new and more integrative approaches 22q11.2 deletion; too many genes and develop specific targeted interventions. for both chromosome abnormality complex biological systems are af- The goal of this series of articles on five research and treatment. fected.” The authors in this Seminars in of the earliest described chromosome Medical Genetics issue obviously disagree deletions (4p-, 5p-, 11q-, 18p-, and with the widely-held sentiment and will WHAT IS THE MAJOR 18q-) is to fundamentally shift the suggest possible pathways to effective CHALLENGE? medical discussions and research direc- treatments. tions about chromosomal abnormalities One of the major challenges confronting We also wished to address the away from phenotypic description and the study of chromosome abnormalities perception problem in a more literal toward genetically informed treatment. is that they suffer from a perception sense. The images shown in this issue are Although these conditions have been problem. This perception, set when of people with the classic chromosome well described for almost 50 years, they were first described decades ago, abnormalities who were all photo- current treatment remains largely has not evolved, despite startling graphed by Rick Guidotti of Positive Jannine DeMars Cody, PhD is a Professor in the Department of Pediatrics and Director of the Chromosome 18 Clinical Research Center. Additionally, she is the Founder and President of the Chromosome 18 Registry and Research Society, a lay advocacy group for the families and friends of people with chromosome 18 conditions. She earned her PhD from the UT Health Science Center and has focused her career on making the chromosome 18 conditions treatable. Daniel E. Hale, MD earned his medical degree from the University of Texas at Houston and is a Professor and Chief of the Division of Endocrinology and Diabetes in the Department of Pediatrics at the UT Health Science Center. He is the Medical Director of the Chromosome 18 Clinical Research Center and the Chromosome 18 Registry & Research Society. He has been a part of the Chromosome 18 team for 21 years specializing in the endocrine and growth issues of children with chromosome 18 abnormalities. Drs. Cody and Hale have authored over 50 publications on the chromosome 18 conditions. In an effort to create a scientific community and ignite research interest on all chromosome abnormalities, they along with Dr. John Carey, hosted the World Congress on Chromosome Abnormalities in 2004 with over 500 families and scientists in attendance. *Correspondence to: Jannine D. Cody, Ph.D., Department of Pediatrics, UT Health Science Center, 7703 Floyd Curl Drive, San Antonio 78229, TX. E-mail: [email protected] DOI 10.1002/ajmg.c.31447 Article first published online 3 August 2015 in Wiley Online Library (wileyonlinelibrary.com). ß 2015 Wiley Periodicals, Inc. 210 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) INTRODUCTION Exposure. This program is dedicated to the discovery that principle contributors be upregulated is only a small percentage portraying the beauty of individuals to normal genetic variation (i.e., with- of the total. regardless of their differences. And we, out overt adverse phenotypic effect) are in like fashion, dedicate this issue to gene copy number variants (CNVs). HAPLOINSUFFICIENCY these individuals, many of whom we These CNVs, identified in large control know as truly remarkable people from populations, show that 91.24% of the Three basic mechanisms have been amazing families, who embrace their genes in the OMIM Morbid Map and suggested for haploinsufficiency; sub- challenges with a smile and welcome us 91.18% of transcripts are overlapped by unit imbalance, metabolic rate limiting into their lives with open arms and CNVs [MacDonald et al., 2013]. If 91% steps, and developmental regulation hearts. of genes and transcripts are found in [Wilkie, 1994; Veitia and Birchler, The critical breakthrough to trans- CNVs in an apparently normal popula- 2010]. As we learn more about the form simple phenotypic description tion, then these data imply that, at a molecular mechanism of specific exam- into effective interventions was the minimum, 91% of gene products are not ples these mechanisms are likely to be mapping of the human genome. Hence, sufficiently sensitive to hemizygosity to both expanded and refined. we now know exactly which genes are be haplosufficient and produce an One example of haploinsufficiency present in an abnormal number of copies abnormal phenotype. resulting from subunit imbalance is in an individual. The next step is to Second, the 1000 Genomes project illustrated by protein components of determine the consequences, or lack of demonstrates that each individual has cell adhesion complexes such as consequences, when a particular gene is roughly 80 heterozygous and 20 homo- d-catenin (cadherin-associated protein), present in an abnormal copy number, zygous loss of function mutations delta 2 (CTNND2) on 5p15.2 at 11 Mb. thus defining the dosage sensitive genes. [MacArthur et al., 2012]. A heterozygous d-catenin is involved in neural cell This is our current challenge. Once loss-of-function mutation would be adhesion and dendritic spine formation those critical genes are identified, the functionally equivalent to hemizygosity. through its role with cadherin to create a potential pathways to treatment will Additionally, 26% of genes were deter- cell adhesion complex [Yuan et al., become clear. mined to have heterozygous loss-of- 2013]. Reduced levels of d-catenin function mutations in an Icelandic could disrupt the integrity of the population [Sulem et al., 2015]. Together adhesion complex resulting in failed HOW DO CHROMOSOME these suggest that many cellular processes cell adhesion and signal transduction. ABNORMALITIES CAUSE are unaffected when there is a single Hemizygosity of this gene (in 5p-) leads DISEASE? functional copy of a gene. to intellectual disability and impaired The molecular mechanisms leading to Third, the converse of the dosage angiogenesis [DeBusk et al., 2010; adverse outcomes in hemizygosity (i.e., insensitive hypotheses is data on the Turner et al., 2015]. haploinsufficiency) are fundamentally percent of genes that are dosage sensi- Haploinsufficiency caused by a different from those of most single tive. These data show that 5% of all metabolic rate limiting step is illustrated gene diseases. In recessive conditions, genes have very low heterozygosity by CYB5A on 18q22.3 at 70 Mb. there are no functional copies of a gene [Samocha et al., 2014]. This means CYB5A enhances the activity of Cyto- and in most dominant conditions, that these genes are evolutionarily con- chrome P450 17A1 (CYP17,20 lyase) mutations confer an adverse gain of strained with little functional coding which is in the biosynthetic pathway to function. In contrast, in hemizygous variation demonstrating the evolution- dihydrotestosterone. Males who are conditions, there is almost always one ary pressure for their being present in hemizygous for this enzyme are at risk perfectly normal gene. This raises the two functional copies. for cryptorchidism, hypospadias, and/or question; “How hard can it be to Given these estimates, Table I micropenis [Cody et al., 2014]. upregulate a gene?” shows the number of hemizygous genes An example of developmental reg- The major challenge is the sheer for each of the conditions described in ulation haploinsufficiency can be found number of genes involved in the this issue and the estimated number of in individuals with hemizygosity for the relatively large chromosome abnormal- dosage sensitive genes
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