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

Masliah‐Planchon, Julien; Lévy, Dominique; Héron, Delphine; Giuliano, Fabienne; Badens, Catherine; Fréneaux, Paul; Galmiche, Louise; Guinebretierre, Jean-Marc; Cellier, C.; Waterfall, Joshua J.; Aït-Raïs, Khadija; Pierron, Gaëlle; Glorion, Christophe; Desguerre, Isabelle; Soler, Christine; Deville, Anne; Delattre, Olivier; Michon, Jean; Bourdeaut, Franck

doi:10.1038/s41431-018-0147-x

Cited by 22 publications

(15 citation statements)

References 21 publications

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“…Novel variants in candidate genes, including BPTF , DNAJC21 , PLAA , BCL11A , ANK2 , FOXN1 , and RAD50 , were identified or supported using this approach, which combined with updated literature sources allowed us to resolve an additional three cases. Our diagnostic yield of 36% includes the four patients with pathogenic or likely pathogenic variants in ATRX , BPTF , BCL11A , and DNAJC21 as the phenotypes of these patients are consistent with the current literature (Dias et al 2016; Tummala et al 2016; Dhanraj et al 2017; Smolle et al 2017; Stankiewicz et al 2017; Masliah-Planchon et al 2018). In a conservative fashion, at this time we have not included the patients with variants in ANK2 , RAD50 , FOXN1 , and PLAA as the gene–disease association has not been fully established ( ANK2 , RAD50 ); the clinical phenotypes of our patient do not fit completely with what have been previously described ( PLAA ); or the observed potential inheritance pattern has not yet been proven ( FOXN1 ).…”

Section: Discussionsupporting

confidence: 86%

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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: Discussionsupporting

confidence: 86%

“…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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“…To investigate the possibility that mutant ATRX alleles were preferentially transmitted to offspring, a meta-analysis of published pedigrees with complete reporting of family structures was conducted. data on transmission of ATRX alleles for 42 mothers were extracted from papers published between 1991 and 2019 (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Probands and index cases were excluded from the calculations, as well as offspring from one mosaic mother.…”

Section: Meta-analysis Of Maternal Transmission Of Atrx Mutationsmentioning

confidence: 99%

“…The chi-square test applied to our sample was P=0.29, which does not reach statistical significance. next, the analysis was limited to a subset of families where the mutations were identified, and all members of the family were genotyped (Table II) (8)(9)(10)(11)(12)(14)(15)(16)(17). A modest sex-ratio distortion was observed in favor of the male offspring, as well as transmission-ratio distortion in favor of the ATRX mutant alleles, but these did not reach statistical significance either (Table II).…”

Section: Meta-analysis Of Maternal Transmission Of Atrx Mutationsmentioning

confidence: 99%

A novel exomal ATRX mutation with preferential transmission to offspring: A case report and review of the literature for transmission ratio distortion in ATRX families

Stabile

Colavito²,

Giudice³

et al. 2020

Mol Med Rep

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The present case report describes an italian family with three affected probands, who exhibited serious mental disability, which has not been associated with other anomalies, except with slight facial dysmorphism. Molecular multigenic analysis for intellectual disability identified a previously unreported variant, p.Ile1765Met (c.5295C>G) in the SNF domain of the ATRX protein (in exon 24). The identified mutation was found in a hemizygous state in all three affected probands and in a heterozygous state in the asymptomatic mother and the female sibling. With respect to the phenotypic similarities found in the patients with those described in previous studies, the consistency in the mode of inheritance and segregation of the mutation, the variant reported in the present case report may be considered as 'likely pathogenic'. To investigate the hypothesis that the preferential transmission of the ATRX mutation observed in this family reflected a general trend, a meta-analysis into the segregation of ATRX mutations from published pedigrees, following allelic transmission from mothers who are heterozygous carriers to their offspring, was performed. a preferential transmission of the mutant allele to male offspring (58% of males inherited the mutant allele) was found; however, the bias was not statistically significant (P=0.29; χ 2 test).

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“…It participating in a wide range of biological functions: transcriptional regulation, DNA repair and chromosome segregation ( 4 ). The latest researches show that the mutant ATRX gene is associated with an increased risk of osteosarcoma and lower-grade gliomas ( 5 , 6 ). One hundred and twenty-seven disease-causing mutations have been reported, including deletions, insertions, non-sense mutations and splicing variants ( 4 , 7 ).…”

Section: Introductionmentioning

confidence: 99%

A Novel Mutation in ATRX Causes Alpha-Thalassemia X-Linked Intellectual Disability Syndrome in a Han Chinese Family

Zheng

et al. 2022

Front. Pediatr.

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ObjectiveTo analyze genetic mutations in a Chinese pedigree affected with Alpha-thalassemia X-linked intellectual disability syndrome, providing a precise diagnosis and genetic counseling.MethodsClinical data was collected. A novel alternative splicing variant detected by whole-exome sequencing was validated by Sanger sequencing. The functional effect of the mutation was predicted with Mutation Tasting. The analysis of 5′ splice site score was estimated with MaxEntScan. Changes in amino acid sequencing were predicted with Mutalyzer. The tertiary structures of the wild type and mutation-carrying protein were predicted by I-TASSER. RNA was extracted from peripheral blood lymphocytes from the proband, his mother and a healthy control. Quantitative Real-Time PCR was used to detect mRNA expression.ResultsThe proband presented with severe intellectual disability, developmental delay, characteristic facies, seizures and cryptorchidism. A novel hemizygous duplication mutation in the ATRX gene in a splice site between exons 3 and 4, NM_000489: c.189+1dupG, was identified with WES in the proband. Sanger sequencing confirmed that the mutation was inherited from his mother, who carried a heterozygous mutation, while his father was not affected. Bioinformatics analysis indicated that the splicing region where the mutation was located is highly conserved and the variant was damaging, producing a truncated protein due to the premature translation of a stop codon. Sanger sequencing with the Quantitative Real-Time PCR product containing a G base inserted between bases 189 and 190. The level of mRNA expression showed that ATRX gene transcription decreased due to the mutation (P < 0.05).ConclusionsA novel mutation in ATRX was found in this pedigree and was confirmed to be pathogenic through functional studies. Our research expanded the spectrum of ATRX gene mutations, providing a precise diagnosis and a basis for genetic counseling.

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

Cited by 22 publications

References 21 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

A novel exomal ATRX mutation with preferential transmission to offspring: A case report and review of the literature for transmission ratio distortion in ATRX families

A Novel Mutation in ATRX Causes Alpha-Thalassemia X-Linked Intellectual Disability Syndrome in a Han Chinese Family

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