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      New Genotypes and Phenotypes in Patients with 3 Subtypes of Waardenburg Syndrome Identified by Diagnostic Next-Generation Sequencing

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          Abstract

          Background

          Waardenburg syndrome (WS) is one of the most common forms of syndromic deafness with heterogeneity of loci and alleles and variable expressivity of clinical features.

          Methods

          The technology of single-nucleotide variants (SNV) and copy number variation (CNV) detection was developed to investigate the genotype spectrum of WS in a Chinese population.

          Results

          Ninety WS patients and 24 additional family members were recruited for the study. Fourteen mutations had not been previously reported, including c.808C>G, c.117C>A, c.152T>G, c.803G>T, c.793-3T >G, and c.801delT on PAX3; c.642_650delAAG on MITF; c.122G>T and c.127C>T on SOX10; c.230C>G and c.365C>T on SNAI2; and c.481A>G, c.1018C>G, and c.1015C>T on EDNRB. Three CNVs were de novo and first reported in our study. Five EDNRB variants were associated with WS type 1 in the heterozygous state for the first time, with a detection rate of 22.2%. Freckles occur only in WS type 2. Yellow hair, amblyopia, congenital ptosis, narrow palpebral fissures, and pigmentation spots are rare and unique symptoms in WS patients from China.

          Conclusions

          EDNRB should be considered as another prevalent pathogenic gene in WS type 1. Our study expanded the genotype and phenotype spectrum of WS, and diagnostic next-generation sequencing is promising for WS.

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          Most cited references29

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          Deletions at the SOX10 gene locus cause Waardenburg syndrome types 2 and 4.

          Waardenburg syndrome (WS) is an auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair and skin. Depending on additional symptoms, WS is classified into four subtypes, WS1-WS4. Absence of additional features characterizes WS2. The association of facial dysmorphic features defines WS1 and WS3, whereas the association with Hirschsprung disease (aganglionic megacolon) characterizes WS4, also called "Waardenburg-Hirschsprung disease." Mutations within the genes MITF and SNAI2 have been identified in WS2, whereas mutations of EDN3, EDNRB, and SOX10 have been observed in patients with WS4. However, not all cases are explained at the molecular level, which raises the possibility that other genes are involved or that some mutations within the known genes are not detected by commonly used genotyping methods. We used a combination of semiquantitative fluorescent multiplex polymerase chain reaction and fluorescent in situ hybridization to search for SOX10 heterozygous deletions. We describe the first characterization of SOX10 deletions in patients presenting with WS4. We also found SOX10 deletions in WS2 cases, making SOX10 a new gene of WS2. Interestingly, neurological phenotypes reminiscent of that observed in WS4 (PCWH syndrome [peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS, and Hirschsprung disease]) were observed in some WS2-affected patients with SOX10 deletions. This study further characterizes the molecular complexity and the close relationship that links the different subtypes of WS.
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            Function of the zinc-finger transcription factor SNAI2 in cancer and development.

            Elucidation of the molecular mechanisms that underlie disease development is still a tremendous challenge for basic science, and a prerequisite to the development of new and disease-specific targeted therapies. This review focuses on the function of SNAI2, a member of the Snail family of zinc-finger transcription factors, and discusses its possible role in disease development. SNAI2 has been implicated in diseases of melanocyte development and cancer in humans. Many malignancies arise from a rare population of cells that alone have the ability to self-renew and sustain the tumor (i.e., cancer stem cells). SNAI2 controls key aspects of stem cell function in mouse and human, suggesting that similar mechanisms control normal development and cancer stem cell properties. These insights are expected to contribute significantly to the genetics of cancer and to the development of both cancer therapy and new methods for assessing treatment efficacy.
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              SLUG (SNAI2) deletions in patients with Waardenburg disease.

              Waardenburg syndrome (WS; deafness with pigmentary abnormalities) is a congenital disorder caused by defective function of the embryonic neural crest. Depending on additional symptoms, WS is classified into four types: WS1, WS2, WS3 and WS4. WS1 and WS3 are caused by mutations in PAX3, whereas WS2 is heterogenous, being caused by mutations in the microphthalmia (MITF) gene in some but not all affected families. The identification of Slugh, a zinc-finger transcription factor expressed in migratory neural crest cells, as the gene responsible for pigmentary disturbances in mice prompted us to analyse the role of its human homologue SLUG in neural crest defects. Here we show that two unrelated patients with WS2 have homozygous deletions in SLUG which result in absence of the SLUG product. We further show that Mitf is present in Slug-deficient cells and transactivates the SLUG promoter, and that Slugh and Kit genetically interact in vivo. Our findings further define the locus heterogeneity of WS2 and point to an essential role of SLUG in the development of neural crest-derived human cell lineages: its absence causes the auditory-pigmentary symptoms in at least some individuals with WS2.
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                Author and article information

                Contributors
                Journal
                Neural Plast
                Neural Plast
                NP
                Neural Plasticity
                Hindawi
                2090-5904
                1687-5443
                2019
                27 February 2019
                : 2019
                : 7143458
                Affiliations
                1Department of Otolaryngology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, China
                2Province Key Laboratory of Otolaryngology Critical Diseases, Changsha, Hunan, China
                3Health Management Center, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, China
                4Department of Otolaryngology, University of Miami, Miller School of Medicine, Miami, USA
                5Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA
                6Institute of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
                Author notes

                Guest Editor: Jolanta Dorszewska

                Author information
                http://orcid.org/0000-0003-2558-739X
                http://orcid.org/0000-0003-1779-8218
                http://orcid.org/0000-0001-7054-5119
                http://orcid.org/0000-0003-3824-3780
                Article
                10.1155/2019/7143458
                6415303
                1227570c-6e7d-4d65-96f3-da8f86002c38
                Copyright © 2019 Wu Li et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 26 September 2018
                : 22 November 2018
                Funding
                Funded by: China Postdoctoral Science Foundation
                Award ID: 2018M632999
                Award ID: 2017M620359
                Funded by: Major State Basic Research Development Program of China
                Award ID: 2014CB541702
                Funded by: National Natural Science Foundation of China
                Award ID: 81500803
                Award ID: 81771023
                Award ID: 81470705
                Award ID: 81873705
                Funded by: National Institutes of Health
                Award ID: R01 DC005575
                Award ID: R01 DC012115
                Funded by: National Institute on Deafness and Other Communication Disorders
                Categories
                Research Article

                Neurosciences
                Neurosciences

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