Molecular diagnosis of thrombocytopenia‐absent radius syndrome using next‐generation sequencing

Nicchia, Elena; Giordano, Paola; Greco, Chiara; Rocco, Daniela De; Savoia, Anna

doi:10.1111/ijlh.12516

Cited by 10 publications

(15 citation statements)

References 25 publications

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“…Genomic DNA extracted from peripheral blood was used to screen for the ACTN1 gene. Mutational analysis was performed by whole exome sequencing (WES) or by target next generation sequencing (NGS) of 22 IT genes as previously reported (Marconi et al , ; Nicchia et al , ). Variants were confirmed by Sanger sequencing.…”

Section: Methodsmentioning

confidence: 99%

ACTN1 mutations lead to a benign form of platelet macrocytosis not always associated with thrombocytopenia

et al. 2018

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M.F. and F.M. contributed equally to this study. SummaryThe inherited thrombocytopenias (IT) are a heterogeneous group of diseases resulting from mutations in more than 30 different genes. Among them, ACTN1-related thrombocytopenia (ACTN1-RT; Online Mendelian Inheritance in Man: 615193) is one of the most recently identified forms. It has been described as a mild autosomal dominant macrothrombocytopenia caused by mutations in ACTN1, a gene encoding for one of the two nonmuscle isoforms of a-actinin. We recently identified seven new unrelated families with ACTN1-RT caused by different mutations. Two of them are novel missense variants (p.Trp128Cys and p.Pro233Leu), whose pathogenic role has been confirmed by in vitro studies. Together with the 10 families we have previously described, our cohort of ACTN1-RT now consists of 49 individuals carrying ACTN1 mutations. This is the largest case series ever collected and enabled a critical evaluation of the clinical aspects of the disease. We concluded that ACTN1-RT is the fourth most frequent form of IT worldwide and it is characterized by platelet macrocytosis in all affected subjects and mild thrombocytopenia in less than 80% of cases. The risk of bleeding, either spontaneous or upon haemostatic challenge, is negligible and there are no other associated defects, either congenital or acquired. Therefore, ACTN1-RT is a benign form of IT, whose diagnosis provides affected individuals and their families with a good prognosis.

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Section: Methodsmentioning

confidence: 99%

ACTN1 mutations lead to a benign form of platelet macrocytosis not always associated with thrombocytopenia

et al. 2018

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“…RBM8A encodes the Y14 protein, a ribonucleoprotein with an RNA binding motif that preferably binds to mRNAs during splicing. This protein is involved in basic cellular functions, such as nuclear export and subcellular localization of specific transcripts, translational enhancement and nonsense‐mediated RNA decay (Nicchia et al , ).…”

Section: Disorders Of Platelet Productionmentioning

confidence: 99%

The genomics of inherited bone marrow failure: from mechanism to the clinic

Wegman-Ostrosky

Savage

2017

Br J Haematol

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The inherited bone marrow failure syndromes (IBMFS) typically present with significant cytopenias in at least one haematopoietic cell lineage that may progress to pancytopenia, and are associated with increased risk of cancer. Although the clinical features of the IBMFS are often diagnostic, variable disease penetrance and expressivity may result in diagnostic dilemmas. The discovery of the genetic aetiology of the IBMFS has been greatly facilitated by next-generation sequencing methods. This has advanced understanding of the underlying biology of the IBMFS and been essential in improving clinical management and genetic counselling for affected patients. Herein we review the clinical features, underlying biology, and new genomic discoveries in the IBMFS, including Fanconi anaemia, dyskeratosis congenita, Diamond Blackfan anaemia, Shwachman Diamond syndrome and some disorders of the myeloid and megakaryocytic lineages.

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“…The SNPs are typically identified by Sanger sequencing. Alternatively, next generation sequencing approaches are sensitive enough to detect both the SNP and the microdeletion by a reduced number of reads, when the relevant probes have been carefully selected to cover the non‐coding 5′UTR and intronic SNPs (Nicchia et al , ; Andres et al , ). The clinical features are overall specific and rather distinct, but a small series of differential diagnoses and additional non‐haematological features might mask the diagnosis.…”

Section: Discussionmentioning

confidence: 99%

“…Following the identification of the two SNPs, at least 22 new TAR cases have been reported (Omran et al , ; Bottillo et al , ; Baken et al , ; Idahosa et al , ; Papoulidis et al , ; Reid et al , ; Yassaee et al , ; Al Kaissi et al , ; Kumar et al , ,b; Pereira et al , ; Tassano et al , ; Nicchia et al , ; Jameson‐Lee et al , ). However, the presence of the microdeletion on chromosome 1q21.1 or of the hemizygous SNPs has not been reported in more than half of the described patients (Omran et al , ; Baken et al , ; Idahosa et al , ; Reid et al , ; Al Kaissi et al , ; Kumar et al , ; Pereira et al , ).…”

Section: Diagnosis/differential Diagnosesmentioning

confidence: 99%

“…It is worth considering whether this should still be referred to as TAR syndrome. The trait remains complex, digenetic and should not be designated autosomal-recessive, as found in some recent review articles (e.g., Idahosa et al, 2014;Al-Qattan, 2016;Nicchia et al, 2016). Knowledge of the underlying genetics in addition to parental segregation will allow to further substantiate the diagnosis and to discuss options for the risk of having a second child with TAR syndrome, which depends on whether the microdeletion is inherited or occurred de novo.…”

Section: Diagnosticsmentioning

confidence: 99%

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Impact of genetic variants on haematopoiesis in patients with thrombocytopenia absent radii (TAR) syndrome

et al. 2017

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Thrombocytopenia absent radii (TAR) syndrome is clearly defined by the combination of radial aplasia and reduced platelet counts. The genetics of TAR syndrome has recently been resolved and comprises a microdeletion on Chromosome 1 including the RBM8A gene and a single nucleotide polymorphism (SNP) either at the 5' untranslated region (5'UTR) or within the first intron of RBM8A. Although phenotypically readily diagnosed after birth, the genetic determination of particular SNPs in TAR syndrome harbours valuable information to evaluate disease severity and treatment decisions. Here, we present clinical data in a cohort of 38 patients and observed that platelet counts in individuals with 5'UTR SNP are significantly lower compared to patients bearing the SNP in intron 1. Moreover, elevated haemoglobin values could only be assessed in patients with 5'UTR SNP whereas white blood cell count is unaffected, indicating that frequently observed anaemia in TAR patients could also be SNP-dependent whereas leucocytosis does not correlate with genetic background. However, this report on a large cohort provides an overview of important haematological characteristics in TAR patients, facilitating evaluation of the various traits in this disease and indicating the importance of genetic validation for TAR syndrome.

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Molecular diagnosis of thrombocytopenia‐absent radius syndrome using next‐generation sequencing

Abstract: We concluded that NGS approaches could be used as a cost-effective method for molecular investigation of TAR as they could simultaneously detect CNV and point mutations.

Cited by 10 publications

References 25 publications

ACTN1 mutations lead to a benign form of platelet macrocytosis not always associated with thrombocytopenia

ACTN1 mutations lead to a benign form of platelet macrocytosis not always associated with thrombocytopenia

The genomics of inherited bone marrow failure: from mechanism to the clinic

Impact of genetic variants on haematopoiesis in patients with thrombocytopenia absent radii (TAR) syndrome

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