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      The advances of genetics research on Hirschsprung's disease

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          Abstract

          Hirschsprung's disease ( HSCR) is a rare and complex congenital disorder characterized by the absence of the enteric neurons in lower digestive tract with an incidence of 1/5 000. Affected infant usually suffer from severe constipation with megacolon and distended abdomen, and face long‐term complications even after surgery. In the last 2 decades, great efforts and progresses have been made in understanding the genetics and molecular biological mechanisms that underlie HSCR. However, only a small fraction of the genetic risk can be explained by the identified mutations in the previously established genes. To search novel genetic alterations, new study designs with advanced technologies such as genome/exome‐wide association studies ( GWASs/ EWASs) and next generation sequencing ( NGS) on target genes or whole genome/exome, were applied to HSCR. In this review, we summaries the current development of the genetics researches on HSCR based on GWASs/ EWASs and NGS, focusing on the newly discovered variants and genes, and their potential roles in HSCR pathogenesis.

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          Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.

          Jeanne Amiel, Béatrice Laudier, Tania Attie-Bitach … (2003)
          Congenital central hypoventilation syndrome (CCHS or Ondine's curse; OMIM 209880) is a life-threatening disorder involving an impaired ventilatory response to hypercarbia and hypoxemia. This core phenotype is associated with lower-penetrance anomalies of the autonomic nervous system (ANS) including Hirschsprung disease and tumors of neural-crest derivatives such as ganglioneuromas and neuroblastomas. In mice, the development of ANS reflex circuits is dependent on the paired-like homeobox gene Phox2b. Thus, we regarded its human ortholog, PHOX2B, as a candidate gene in CCHS. We found heterozygous de novo mutations in PHOX2B in 18 of 29 individuals with CCHS. Most mutations consisted of 5-9 alanine expansions within a 20-residue polyalanine tract probably resulting from non-homologous recombination. We show that PHOX2B is expressed in both the central and the peripheral ANS during human embryonic development. Our data support an essential role of PHOX2B in the normal patterning of the autonomous ventilation system and, more generally, of the ANS in humans.
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            What can exome sequencing do for you?

            Jacek Majewski, Jeremy Schwartzentruber, Emilie Lalonde … (2011)
            Recent advances in next-generation sequencing technologies have brought a paradigm shift in how medical researchers investigate both rare and common human disorders. The ability cost-effectively to generate genome-wide sequencing data with deep coverage in a short time frame is replacing approaches that focus on specific regions for gene discovery and clinical testing. While whole genome sequencing remains prohibitively expensive for most applications, exome sequencing--a technique which focuses on only the protein-coding portion of the genome--places many advantages of the emerging technologies into researchers' hands. Recent successes using this technology have uncovered genetic defects with a limited number of probands regardless of shared genetic heritage, and are changing our approach to Mendelian disorders where soon all causative variants, genes and their relation to phenotype will be uncovered. The expectation is that, in the very near future, this technology will enable us to identify all the variants in an individual's personal genome and, in particular, clinically relevant alleles. Beyond this, whole genome sequencing is also expected to bring a major shift in clinical practice in terms of diagnosis and understanding of diseases, ultimately enabling personalised medicine based on one's genome. This paper provides an overview of the current and future use of next generation sequencing as it relates to whole exome sequencing in human disease by focusing on the technical capabilities, limitations and ethical issues associated with this technology in the field of genetics and human disease.
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              Differential contributions of rare and common, coding and noncoding Ret mutations to multifactorial Hirschsprung disease liability.

              Eileen Sproat Emison, Merce Garcia-Barcelo, Elizabeth Grice … (2010)
              The major gene for Hirschsprung disease (HSCR) encodes the receptor tyrosine kinase RET. In a study of 690 European- and 192 Chinese-descent probands and their parents or controls, we demonstrate the ubiquity of a >4-fold susceptibility from a C-->T allele (rs2435357: p = 3.9 x 10(-43) in European ancestry; p = 1.1 x 10(-21) in Chinese samples) that probably arose once within the intronic RET enhancer MCS+9.7. With in vitro assays, we now show that the T variant disrupts a SOX10 binding site within MCS+9.7 that compromises RET transactivation. The T allele, with a control frequency of 20%-30%/47% and case frequency of 54%-62%/88% in European/Chinese-ancestry individuals, is involved in all forms of HSCR. It is marginally associated with proband gender (p = 0.13) and significantly so with length of aganglionosis (p = 7.6 x 10(-5)) and familiality (p = 6.2 x 10(-4)). The enhancer variant is more frequent in the common forms of male, short-segment, and simplex families whereas multiple, rare, coding mutations are the norm in the less common and more severe forms of female, long-segment, and multiplex families. The T variant also increases penetrance in patients with rare RET coding mutations. Thus, both rare and common mutations, individually and together, make contributions to the risk of HSCR. The distribution of RET variants in diverse HSCR patients suggests a "cellular-recessive" genetic model where both RET alleles' function is compromised. The RET allelic series, and its genotype-phenotype correlations, shows that success in variant identification in complex disorders may strongly depend on which patients are studied. Copyright 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Xiaoping Miao: miaoxp@hust.edu.cn
                Journal
                Journal ID (nlm-ta): Pediatr Investig
                Journal ID (iso-abbrev): Pediatr Investig
                Journal ID (doi): 10.1002/(ISSN)2574-2272
                Journal ID (publisher-id): PED4
                Title: Pediatric Investigation
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 2096-3726
                ISSN (Electronic): 2574-2272
                Publication date (Electronic): 17 October 2018
                Publication date Collection: September 2018
                Volume: 2
                Issue: 3 ( doiID: 10.1002/ped4.2018.2.issue-3 )
                Pages: 189-195
                Affiliations
                [ 1 ] State Key Laboratory of Environment Health (Incubation) Key Laboratory of Environment & Health (Ministry of Education), Ministry of Environmental Protection Key Laboratory of Environment and Health (Wuhan) Wuhan China
                [ 2 ] Department of Epidemiology and Biostatistics School of Public Health Tongji Medical College Huazhong University of Science and Technology Wuhan China
                Author notes
                [*] [* ] Correspondence

                Xiaoping Miao, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Email: miaoxp@ 123456hust.edu.cn

                Article
                Publisher ID: PED412062
                DOI: 10.1002/ped4.12062
                PMC ID: 7391411
                PubMed ID: 32851260
                SO-VID: bf0be1f2-8edf-4126-bfcc-cf2aeef5d217
                Copyright © © 2018 Chinese Medical Association. Pediatric Investigation published by John Wiley & Sons Australia, Ltd on behalf of Futang Research Center of Pediatric Development.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                Date received : 03 August 2018
                Date accepted : 05 September 2018
                Page count
                Figures: 0, Tables: 2, Pages: 7, Words: 4740
                Categories
                Subject: Review
                Subject: Review
                Custom metadata
                source-schema-version-number 2.0
                cover-date September 2018
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.5 mode:remove_FC converted:01.07.2020

                Keywords: genetics,genome/exome‐wide association study,hirschsprung's disease,next generation sequencing
                Data availability:
                Keywords: genetics, genome/exome‐wide association study, hirschsprung's disease, next generation sequencing

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