A novel mutation in <i>ATRX</i> associated with intellectual disability, syndromic features, and osteosarcoma

Smolle, Maria Anna; Heitzer, Ellen; Geigl, Jochen B.; Kaissi, Ali Al; Liegl‐Atzwanger, Bernadette; Seidel, Markus G.; Holzer, Lukas A.; Leithner, Andreas

doi:10.1002/pbc.26522

Cited by 18 publications

(15 citation statements)

References 15 publications

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“…Notably, we were the first to report ATRX as a potential cancer predisposition gene for osteosarcoma using our WES platform (Patient 72) (Ji et al 2017). The association between a germline pathogenic ATRX variant and osteosarcoma was subsequently reported (Smolle et al 2017; Masliah-Planchon et al 2018).…”

Section: Resultsmentioning

confidence: 99%

A semiautomated whole-exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants

Shen

Bootwalla

et al. 2019

Cold Spring Harb Mol Case Stud

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Advancing the clinical utility of whole-exome sequencing (WES) for patients with suspected genetic disorders is largely driven by bioinformatics approaches that streamline data processing and analysis. Herein, we describe our experience with implementing a semiautomated and phenotype-driven WES diagnostic workflow, incorporating both the DRAGEN pipeline and the Exomiser variant prioritization tool, at an academic children's hospital with an ethnically diverse pediatric patient population. We achieved a 41% molecular diagnostic rate for 66 duo-, quad-, or trio-WES cases, and 28% for 40 singleton-WES cases. Preliminary results were returned to ordering physicians within 1 wk for 12 of 38 (32%) probands with positive findings, which were instrumental in guiding the appropriate clinical management for a variety of patients, especially in critical care settings. The semiautomated and streamlined WES workflow also enabled us to identify novel variants in candidate disease genes in patients with developmental delay and autism and immune disorders and cancer, including ANK2 , BPTF , BCL11A , FOXN1 , PLAA, ATRX, DNAJC21 , and RAD50 . Together, we demonstrated the implementation of a streamlined WES workflow that was successfully applied for both clinical and research purposes.

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Section: Resultsmentioning

confidence: 99%

A semiautomated whole-exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants

Shen

Bootwalla

et al. 2019

Cold Spring Harb Mol Case Stud

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“…Altogether those two cases emphasize the possibility that those germline variants had promoted the formation of osteosarcomas in our patients. Furthermore, recent reports from two different teams also described three additional cases of patients with ATR-X syndrome who developed osteosarcomas [6,7]. The rarity of ATRX germline variants with only a limited number of cases described so far could explain why this association has not been described sooner.…”

Section: Discussionmentioning

confidence: 99%

“…Until the recent report of three patients with ATRX germline variant who all developed osteosarcomas [6,7], ATR-X syndrome was not known to be associated with an increased risk of cancer. Here we present the case of two additional children with ATRX germline variants and clinical ATR-X syndrome who developed osteosarcomas.…”

Section: Introductionmentioning

confidence: 99%

Does ATRX germline variation predispose to osteosarcoma? Three additional cases of osteosarcoma in two ATR-X syndrome patients

et al. 2018

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Osteosarcoma is the most common malignant bone tumor in adolescents and young adults. Most osteosarcomas are sporadic but the risk of osteosarcoma is also increased by germline variants in TP53, RB1 and RECQL4 genes. ATRX germline variations are responsible for the rare genetic disorder X-linked alpha-thalassemia mental retardation (ATR-X) syndrome characterized by severe developmental delay and alpha-thalassemia but no obvious increased risk of cancer. Here we report two children with ATR-X syndrome who developed osteosarcoma. Notably, one of the children developed two osteosarcomas separated by 10 years. Those two cases raise the possibility that ATRX germline variant could be associated with an increased risk of osteosarcoma.

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“…The first report of diagnosed osteosarcoma in two brothers with ATRX syndrome suggested a potential increased risk of cancer in patients with this disorder (28). A 22-year-old Caucasian man was reported in 2017 to exhibit a previously unidentified mutation in ATRX associated with osteosarcoma (29). All these data suggested that patients with ATRX syndrome may be at a potential increased risk of developing osteosarcoma, although the molecular mechanism of ATRX loss-of-function mutations in osteosarcoma remains unclear at present (30,31).…”

Section: Loss Of Atrx In Sarcomasmentioning

confidence: 99%

Alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas (Review)

Ren

Tang

et al. 2018

Oncol Lett

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Abstract. Sarcoma is a rare and heterogeneous type of cancer with an early mean onset age and a poor prognosis. However, its genetic basis remains unclear. A series of recent genomic studies in sarcomas have identified the occurrence of mutations in the α-thalassemia/mental retardation syndrome X-linked (ATRX) gene. The ATRX protein belongs to the SWI/SNF family of chromatin remodeling proteins, which are frequently associated with α-thalassemia syndrome. Cancer cells depend on telomerase or the alternative lengthening of telomeres (ALT) pathway to overcome replicative programmed mortality. Loss of ATRX is associated with ALT in sarcoma. In the present review, recent whole genome and/or whole exome genomic studies are summarized. In addition ATRX immunohistochemistry and ALT fluorescence in situ hybridization in sarcomas of various subtypes and at diverse sites, including osteosarcoma, leiomyosarcoma, liposarcoma, angiosarcoma and chondrosarcoma are evaluated. The present review involves certain studies associated with the molecular mechanisms underlying the loss of ATRX controlling the activation of ALT in sarcomas. Identification of the loss of ATRX and ALT in sarcomas may provide novel methods for the treatment of aggressive sarcomas.

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A novel mutation in ATRX associated with intellectual disability, syndromic features, and osteosarcoma

Cited by 18 publications

References 15 publications

A semiautomated whole-exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants

A semiautomated whole-exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants

Does ATRX germline variation predispose to osteosarcoma? Three additional cases of osteosarcoma in two ATR-X syndrome patients

Alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas (Review)

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