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      Identification of a Hemizygous Novel Splicing Variant in ATRX Gene: A Case Report and Literature Review

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          Abstract

          Background

          Alpha-thalassemia/intellectual disability syndrome (ATR-X) (OMIM # 301040) was first described by Wilkie et al. ( 1). Several studies found that children who presented with significantly consistent clinical phenotypes of hemoglobin H (Hb H) disease and profound mental handicap carried ATRX chromatin remodeler ( ATRX, OMIM *300032) gene variants. With the recent development of exome sequencing (ES), ATRX gene variants of severe to profound intellectual disability without alpha-thalassemia have been implicated in intellectual disability-hypotonic facies syndrome, X-linked, 1(MRXHF1, OMIM #309580). These two diseases present similar clinical manifestations and the same pattern of inheritance.

          Case Presentation

          We reported a 3-year-old boy with intellectual disability, language impairment, hypotonia, and mild craniofacial abnormalities (flat nasal bridge, small and triangular nose, anteverted nostrils, and widely spaced incisors) and reviewed MRXHF1 cases. At an early stage, the patient developed global developmental delay (GDD). After 6 months of rehabilitation therapy, the patient's motor ability did not make big progress, as well as his speech or nonverbal communication. We performed whole-genome sequencing (WGS), Sanger sequencing, reverse transcription-polymerase chain reaction (RT-PCR), and X-inactivation studies. A novel hemizygous intronic variant in ATRX (c.5786+4A>G; NM_000489.6) was identified, which led to exon 24 skipping. The carrier mother showed extremely skewed X-chromosome inactivation (XCI). These results may contribute to the patient's phenotypes.

          Conclusions

          The novel hemizygous intronic variant in ATRX is the genetic etiology of the boy. Identification of this variant is helpful for parents to take prenatal diagnostic tests. Also, this new case expands the phenotypes of MRXHF1 and the mutational spectrum of the ATRX gene.

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          Most cited references39

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          Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

          The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants. 1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence (e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.
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            ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner.

            ATRX is an X-linked gene of the SWI/SNF family, mutations in which cause syndromal mental retardation and downregulation of α-globin expression. Here we show that ATRX binds to tandem repeat (TR) sequences in both telomeres and euchromatin. Genes associated with these TRs can be dysregulated when ATRX is mutated, and the change in expression is determined by the size of the TR, producing skewed allelic expression. This reveals the characteristics of the affected genes, explains the variable phenotypes seen with identical ATRX mutations, and illustrates a new mechanism underlying variable penetrance. Many of the TRs are G rich and predicted to form non-B DNA structures (including G-quadruplex) in vivo. We show that ATRX binds G-quadruplex structures in vitro, suggesting a mechanism by which ATRX may play a role in various nuclear processes and how this is perturbed when ATRX is mutated. Copyright © 2010 Elsevier Inc. All rights reserved.
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              Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome).

              The ATR-X syndrome is an X-linked disorder comprising severe psychomotor retardation, characteristic facial features, genital abnormalities, and alpha-thalassemia. We have shown that ATR-X results from diverse mutations of XH2, a member of a subgroup of the helicase superfamily that includes proteins involved in a wide range of cellular functions, including DNA recombination and repair (RAD16, RAD54, and ERCC6) and regulation of transcription (SW12/SNF2, MOT1, and brahma). The complex ATR-X phenotype suggests that XH2, when mutated, down-regulates expression of several genes, including the alpha-globin genes, indicating that it could be a global transcriptional regulator. In addition to its role in the ATR-X syndrome, XH2 may be a good candidate for other forms of X-linked mental retardation mapping to Xq13.
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                Author and article information

                Contributors
                Journal
                Front Pediatr
                Front Pediatr
                Front. Pediatr.
                Frontiers in Pediatrics
                Frontiers Media S.A.
                2296-2360
                04 April 2022
                2022
                : 10
                : 834087
                Affiliations
                [1] 1Rehabilitation Department, Yiwu Maternity and Child Health Care Hospital , Yiwu, China
                [2] 2Prenatal Diagnosis Center, Yiwu Maternity and Child Health Care Hospital , Yiwu, China
                [3] 3B-Ultrasound Room, Yiwu Maternity and Child Health Care Hospital , Yiwu, China
                [4] 4Radiological Department, Yiwu Maternity and Child Health Care Hospital , Yiwu, China
                Author notes

                Edited by: Corrado Romano, University of Catania, Italy

                Reviewed by: Richard Gibbons, University of Oxford, United Kingdom; Nathalie Berube, Western University, Canada

                *Correspondence: Ke Wu 754299058@ 123456qq.com

                This article was submitted to Genetics of Common and Rare Diseases, a section of the journal Frontiers in Pediatrics

                †These authors have contributed equally to this work

                Article
                10.3389/fped.2022.834087
                9015161
                35444965
                446f4d6e-bc20-4794-bb9d-e229cbf17563
                Copyright © 2022 Cong, Wu, Wang, Wu, Huang and Yang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 13 December 2021
                : 08 March 2022
                Page count
                Figures: 2, Tables: 6, Equations: 0, References: 39, Pages: 0, Words: 6019
                Categories
                Pediatrics
                Case Report

                splicing abnormalities,atrx gene,x-chromosome inactivation,genetic counseling,intellectual disability-hypotonic facies syndrome

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